Accord Healthcare Limited & Ors v The Regents of The University of California & Anor

The Poster is headed “Development of Androgen Receptor Inhibitors for Hormone-Refractory Prostate Cancer”. It describes what it calls a “rational design” of “non-steroidal compounds as potent antagonists for both HS and HR prostate cancer”. It is well designed and conveys a large amount of useful information to the Skilled Team. By way of overview, the Poster looks like this:

Professor Ward said that the Skilled Medicinal Chemist would understand that “rational design” involves making a series of structural changes to a compound and studying the resulting changes to its properties to try to develop an understanding of the SAR.

The Poster depicts the step-wise process of development undertaken by the inventors, starting with RD2 at the top and flowing clockwise around the SAR studies undertaken to the most potent compound following the SAR (RD37) through the PK optimisation to arrive at RD162. A skilled chemist can see from the numbers used for the compounds that not all are depicted and would understand that many more are likely to have been made and tested.

Under the heading is a yellow box with a two-line summary explaining that AR upregulation is responsible for the progression of hormone-sensitive to hormone-refractory prostate cancer. This was one of the known explanations for why this progression occurred (see [78.iv)] above. In footnote 1 there is a cross reference to a prior paper by the Sawyers group published in Nature Medicine 2004 (this paper is attributed “Sawyers” as last-named author, but in the Slides and elsewhere to “Chen” as first-named author, but it is the same paper).

In the central blue box, it is explained that “Exploiting the existing knowledge such as crystal structure,² binding affinity³ and homology modeling ⁴ led to a rational design of non-steroidal compounds as potent antagonists for both HS and HR prostate cancer”.

“HR” prostate cancer would be understood to be shorthand for hormone-refractory prostate cancer and “HS” prostate cancer to be referring to hormone-sensitive prostate cancer.

The structures of nilutamide (a well-known antiandrogen used at the Application Date in the treatment of prostate cancer) and a compound called RU59063 are shown in the white central box.

Footnote 2 is the Sack paper, footnote 3 is the Teutsch paper, and footnote 4 is the Marhefka paper. It is common ground that the skilled reader would have regard to the cross-referenced papers. On doing so, they would see that:

It is common ground that the skilled reader would understand that the best way to read the Poster is to start in the middle as the document shows a progression in the design of small molecule (non-steroidal) inhibitors according to the direction of the arrows around the page. SAR studies are shown on the right, followed by PK-DM optimisation on the left.

Following the upward arrow in the centre of the page shows that the authors had progressed from the starting compounds (nilutamide and RU59063) to RD2 and then through various further “RD” compounds in a clockwise direction.

The Skilled Medicinal Chemist would understand that in these studies the authors were seeking to optimise the structure by making rational modifications in a step wise fashion to investigate the impact on activity in the relevant prostate cancer models.

The first compound is RD2, which the skilled medicinal chemist would note had structural similarities to nilutamide and in particular to RU59063 (the only difference being the change from a hydroxy group (OH) to an azide group (N₃) on the right-hand side of the molecule.

The authors then move to RD6 where they have introduced a phenyl group on the nitrogen. RD6 still contains the azide group but it now sits on the phenyl ring, rather than the alkyl chain in RD2.

The next molecule is RD7 where the azide group has been replaced with a methyl group (of similar size to an azide but less reactive and which is also lipophilic).

The difference between RD7 and RD37 is at the position X, with a dimethyl replaced with a cyclobutyl group. This can be characterised as a small chemical change with the introduction of an additional CH₂ group.

The final compound in this section is RD54 which has two differences over RD37:

The other half of the page (on the left-hand side) is labelled PK-DM Optimisation and features three RD compounds, RD131, RD161 and RD162.

In RD131, the left-hand side and centre are the same as in RD37 (including the cyclobutyl group at position X). The authors have started to modify the right-hand ring and have introduced new substituents at the 4-position, specifically an N-methylbutyramide group (i.e. a methyl amide linked to the phenyl group via a propyl chain).

In RD161, the methylamide group is directly attached to the phenyl ring, and the Skilled Medicinal Chemist would note this would make the compound more rigid.

In RD162 (shown in a different colour to the other compounds) the authors have added a fluorine on the phenyl ring. The Skilled Medicinal Chemist would consider this had likely been done to improve metabolic stability compared to RD161 (although the PK data for RD161 is not shown), since s/he would know that the phenyl ring might be susceptible to oxidation, a precursor to elimination of the drug metabolite and a measure of instability, and adding a fluorine was a common approach to preventing metabolic oxidation.

From those changes, the Claimants drew attention to the following particular points:

The chart at the top right shows data from an antagonist assay on hormone sensitive (HS) prostate cancer (“HSPC”), and the chart at the bottom shows data from an antagonist assay on hormone refractory (HR) prostate cancer. These would both be understood to be cell-based assays, which are measuring relative PSA (prostate-specific antigen) levels and assessing the dose response of each of the compounds. PSA expression is being used as a surrogate for cell growth. A lower value for the relative PSA level indicates higher antagonist activity.

The HS assay data (reproduced above) shows bicalutamide (‘Bic’) reducing relative PSA level in a dose-dependent manner i.e. it is behaving as an antagonist as expected in HSPC. It also shows a dose response for both RD2 and RD6, with at least RD6 performing better than bicalutamide.

The HR assay data (reproduced above) shows that bicalutamide (‘Bic’) is not reducing PSA levels, indicating that it is not behaving as an antagonist in HRPC. However, all the RD compounds show much improved antagonist profiles and more significant reduction of PSA levels (particularly from RD6 onwards).

In the centre on the right of the Poster is data from an in vivo assay which measures change in tumour volume over time following administration of bicalutamide, RD7 and RD37 over a number of days. A smaller increase in tumour size over the same period would be understood to show higher activity of a compound. The reference to “LNCaP/HR” would be understood to be a reference to the cell line that was used, with “HR” standing for hormone refractory. It would be understood that the experiment likely involved implantation of cells from this human cell line into an animal (immunocompromised mouse) model in order to measure tumour growth in vivo.

The data show that bicalutamide does not have an effect on HR tumour growth compared to the vehicle. In contrast, RD7 and RD37 have a discernible impact, both slowing tumour growth at a similar rate. The extent to which any meaningful distinction can be drawn between the performance of RD7 vs RD37 (i.e. the blue vs yellow lines) was a point in dispute which I address later.

The left-hand side of the Poster relates to ‘PK-DM optimisation’. ‘PK-DM’ means “pharmacokinetics drug metabolism” which broadly relates to how a compound behaves in the body. Three RD compounds are shown on this side: RD131, RD161 and RD162.

The chart on the middle of the left-hand side (reproduced above) shows that the serum concentration of RD37 and RD131 drops off very quickly after administration whereas RD162 takes longer to clear and has a profile closer to that of bicalutamide. It is common ground that the PK profiles for RD131 and RD37 would be off-putting for once daily oral dosing, whereas that of RD162 is significantly better.

The table at the top of the left-hand side of the Poster (above) compares the IC₅₀, LogP and steady-state concentration of RD37, RD131 and RD162. The following was common ground:

Prof Westwell was of the view that, having reviewed the data presented, the Skilled Medicinal Chemist would understand the following from the Poster:

Furthermore, although there is no data for RD162 in the HS model, the Skilled Medicinal Chemist would assume that RD162 had potential for therapeutic activity in HSPC. RD2 and RD6 were shown to be active in the HS assay and the HR assay. Given that all the RD compounds were suggested to be AR antagonists, the Skilled Medicinal Chemist would expect the RD compounds that follow those also to show activity in the HS assay. Therefore, the Skilled Medicinal Chemist would assume that RD162 would be active in both assays.

In the parties’ opening skeleton arguments, my attention was drawn to familiar authority. However, in view of the critical importance of obviousness in this case, I will set out the parties’ contentions to ensure I have them well in mind.

Naturally both sides referred me to the principles regarding classical obviousness as reviewed by the Supreme Court in Actavis v ICOS [2019] UKSC 15.

At [57] Lord Hodge explained that the general principle of ensuring that the extent of monopoly corresponds to the technical contribution of the patent permeates all aspects of validity:

57.

The general principle that the extent of the patent monopoly should correspond to and be justified by the actual technical contribution to the art is thus part of the jurisprudence of both the EPO and the UK courts and, as Lord Sumption observed in Generics v Warner-Lambert (above), para 17, "the principal conditions of validity, novelty, inventive step, industrial application and sufficiency are all, in one way or another, directed to satisfying the principle thus expressed". 

It was also reiterated that the statutory question is whether the invention is obvious, having regard to the state of the art at the priority date. In some cases, it is helpful to answer this question by adopting the structured approach set out in Pozzoli. In other cases, it is helpful to adopt the problem/solution approach (PSA) favoured by the EPO. But neither approach can replace the statutory question itself. It must be assessed by reference to the facts and circumstances of the case. See [58]-[62].

At [63] Lord Hodge cited Kitchin J (as he then was) in Generics (UK) Ltd v H Lundbeck [2007] EWHC 1040 (Pat), [2007] RPC 32 emphasising the importance of the facts and presenting a list of illustrative, but not exhaustive, factors to take into account (emphasis added):

63.

In Conor Medsystems Inc v Angiotech Pharmaceuticals Inc [2008] UKHL 49; [2008] RPC 28; [2008] 4 All ER 621, at para 42 Lord Hoffmann endorsed the fact-specific approach which Kitchin J set out in Generics (UK) Ltd v H Lundbeck [2007] RPC 32, para 72 where he stated: 

"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."

Kitchin J's list of factors is illustrative and not exhaustive. Another factor which needs to be considered in the present case is the routineness of the research. Much of the interest and controversy which the Court of Appeal's judgment has generated relates to how people have understood or misunderstood the significance which that court has attached to the routine nature of the pre-clinical and clinical research which I have described. 

Whether the inventive step would have been “obvious to try” is a question that has been considered in many cases. In Actavis v ICOS at [65] Lord Hodge stated:

65.

First, it is relevant to consider whether at the priority date something was “obvious to try”, in other words whether it was obvious to undertake a specific piece of research which had a reasonable or fair prospect of success: Conor v Angiotech (above) para 42 per Lord Hoffmann; MedImmune Ltd v Novartis Pharmaceuticals UK Ltd [2012] EWCA Civ 1234; [2013] RPC 27, paras 90 and 91 per Kitchin LJ. In many cases the consideration that there is a likelihood of success which is sufficient to warrant an actual trial is an important pointer to obviousness. But as Kitchin LJ said in Novartis AG v Generics (UK) Ltd [2012] EWCA Civ 1623, para 55, there is no requirement that it is manifest that a test ought to work; that would impose a straightjacket which would preclude a finding of obviousness in a case where the results of an entirely routine test are unpredictable. As Birss J observed in this case (para 276), some experiments which are undertaken without any particular expectation as to result are obvious. The relevance of the “obvious to try” consideration and its weight when balanced against other relevant considerations depend on the particular facts of the case.

There can be multiple obvious avenues or routes and an obvious route is not rendered less obvious for this reason. At [69] in Actavis v ICOS the Supreme Court approved the well-known passage from Brugger v Medic-Aid at 661:

“[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.”

Lord Hodge noted his agreement and added that “[a]s a result, the need to make value judgments on how to proceed in the course of a research programme is not necessarily a pointer against obviousness.”

Further, the Supreme Court in Actavis v ICOS was clear that if a Skilled Team engages in familiar and routine testing and it is obvious to undertake that testing as part of routine development, that is sufficient for obviousness. The end result of those routine tests does not need to be known or to be anticipated or expected. It is obtained by the application of routine work (see for instance [85] and [88]).

The Claimants submitted that three particular issues that arise in this case concern Astellas’ arguments that (1) there was no motivation to make any change to the prior art, (2) there was a perceived prejudice against taking a particular step (namely, of including a geminal dimethyl group) and (3) the irrelevance of ‘a golden bonus’. I address these points in turn.

Motivation was a key issue identified by both sides. For their part, the Claimants submitted that the following points of principle need to be kept in mind, and in this section, all the emphasis in the cited passages is that of the Claimants.

First, the correct way to frame any question about motivation is in terms of whether the skilled person “would have a motive to find a solution to the problem the patent addresses”. See Lord Hodge in Actavis v ICOS at [63], which is cited above. It is wrong to jump straight to the question of whether “the skilled person would have a motivation to change the prior art” until one has decided what the problem is that the patent is addressing. That is important in this case because, the Claimants submit, the Patent is not addressing the problem of making a better compound than RD162, merely an alternative.

Second, the reason it is often wrong to pose any question about motivation in terms of whether there is a motivation to change the prior art is because doing so risks putting the notional skilled person into the shoes of the author of the prior art and thereby confounding the question of obviousness with irrelevant considerations. See Laddie J in Brugger v Medic-Aid Ltd [1996] R.P.C. 635 at 655:

The plaintiffs' case was that there had been no sea-change between 1966 and 1984 in what nebulizer manufacturers were trying to achieve by way of performance characteristics of their products and that the existing nebulizers made in accordance with '355 were highly regarded. In particular they said:

"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."

On the basis of this they say there is no reason why it should have been obvious to modify the prior art in any particular direction. That, it appears to me, is a non sequitur. The fact, if it be one, that existing commercial products are highly successful and satisfactory does not indicate that there are no obvious modifications to make to them. It merely demonstrates that there may be little incentive to those already making those products to change the design - a quite different matter.

On this point, the Claimants also referred to this passage from the judgment of Mr Daniel Alexander QC in Meter-Tech Llc & Anor v British Gas Trading Ltd (Rev 1) [2016] EWHC 2278 (Pat) at [325]:

325.

The issue of mindset, in so far as it enters the picture, is one aspect of an overall evaluation of whether there was or was not a motivation or reason for the skilled person to take a given step. Motivation can of course be important in evaluations of obviousness (see for example Hoechst Celanese v. BP Chemicals [1997] FSR 547 – "necessary to demonstrate that there is some reason for taking [the step from the prior art]" and Lundbeck above). However, again here, it is dangerous to make too much of it as an isolated factor, because a product can be obvious even if there was no reason actually to make it at the priority date and a skilled person would believe it to be unusable (a 100cm dinner plate, to adapt a familiar example). It is also important to bear in mind that motivation can lie in the wish to make a different product which operates in a similar way, not necessarily a better one.

Third, that is not to say that commercial considerations that the Skilled Team may have are completely irrelevant. As Lewison J observed in Ivax v Akzo Nobel BV (No.2) [2007] RPC 3 at [47]:

Commercial reasons may, in my judgment, be sufficient reason to take a skilled person down a particular path. I see no reason why those commercial reasons should exclude the desire to emulate a successful product, without infringing a patent, if the means of doing so are technically obvious.

The Claimants also submitted that it has also been observed that an important influence that encourages the making of analogues of prior art compounds is “a desire to obtain a novel, as well as effective, compound” and that “the requirement of novelty for the grant of a patent provides a powerful driving force to investigations of this kind”. See Pumfrey J in Monsanto v Merck [2000] RPC 709 at [169]. The Claimants made this point in view of some evidence they adduced under their CEA notice as to what motivated the inventors to go beyond what was disclosed in the prior art.

Fourth, motivation to take a particular step is, in any event, not a necessary condition to a finding of obviousness. See Floyd J. in Research In Motion UK Ltd v Visto Corp [2008] EWHC 335 (Pat):

“73.

A question which often arises, and arises here, is whether the absence of a particular motive to take a particular step between the prior art and the invention is fatal to an obviousness attack. It must now be regarded as settled law that it is not. In Pharmacia v Merck [2001] EWCA Civ 1610; [2002] R.P.C. 41 , Aldous L.J. cited with approval a passage in Laddie J.'s judgment in Hoechst Celanese v BP Chemicals [1997] F.S.R. 547 at 573. The court will readily assume that technicians and businessmen will wish to make trivial changes to what is known in order to produce essentially the same result. That is not to say motive is irrelevant: it is one of the many factors that has to be balanced in answering the statutory question. It is easier to show a step is obvious if there is a strong motivation to take it. If the advance is not as trivial as the Pharmacia and  Hoechst cases require, the absence of motivation is a factor of which account must be taken in the balancing exercise.” 

…

112.

RIM accepts that there was no motive, in this scenario, to make the change. But it submits that that does not matter for Pharmacia / Hoechst reasons. The modified system is nevertheless obvious technically: it does essentially the same thing in a different way. The technique of passing data through a firewall using HTTP was a well known tool. Why should anyone not be free to use it if the need ever arose? 

113.

Visto's rejoinder is this: it is not correct that HTTP tunnelling does the same thing. The use of HTTP tunnelling solves a technical problem: how one gets through the firewall without having to reconfigure it. So the Pharmacia / Hoechst reasoning does not apply.

114.

I think these difficulties are created by fixing on a starting point where it has already been decided how the e-mail is to be transported through the firewall. If one has already decided to do something in a particular way, it will be seldom to be a logical step to retrace one's steps and do it in another way, particularly if that alternative way provides no advantage, as it would not in the case of a licensed Lotus Notes user. To say to a Lotus Notes user who has already configured his firewall that a different port is available would not solve any technical problem with which he is faced or provide him with any technical benefit. To use the familiar example: if a piece of wood is satisfactorily screwed to another, there is no reason to take it apart and glue it instead; but it is certainly not inventive to do so. And it does not make it inventive if you say that doing so avoids the technical problem of how to fix together two pieces of wood without using screws.

In terms of the applicable principles, I accept the Claimants’ submission that a patentee cannot rely upon a perceived problem in taking a particular course of action in support of inventive step, unless the patent itself overcomes that problem, based on Philips v Asustek [2019] EWCA Civ 2230 at [73], and Jacob LJ in Pozzoli v BDMO [2007] EWCA Civ 588 at [28]. The Claimants’ submission was that, in this case, if there was any perceived problem associated with geminal dimethyl groups, that problem would be just as apparent having read the Patent as having read the prior art.

The applicable principle is best explained in the context where it is said to arise. The Claimants make this point in response to any suggestion from Astellas that the skilled person would not expect RD162’ to be a ‘superior’ compound to RD162, and they say this does not assist the Defendants. The Claimants’ position is that it would have been obvious to the Skilled Team that replacing the cyclobutyl group at position X of RD162 with a gem-dimethyl moiety would likely give rise to an active compound of similar potential to RD162. Even if (which is not accepted) RD162’ turned out to be a ‘superior’ compound that does not help if it was obvious to make it anyway. See e.g. Lord Hodge in Actavis v ICOS at [73] (a “golden bonus” does not found a valid patent if the claimed invention was obvious for another purpose), and Napp v ratiopharm [2009] EWCA Civ 252 at [115].

For their part, Astellas particularly stressed the well-known passage from Kitchin J in Generics v Lundbeck (quoted in [‎181] above). Astellas also emphasised that motivation (a) almost always plays a part in the overall assessment of obviousness and (b) is an important tool to avoid a hindsight approach. Furthermore, as they submitted, it is settled law that the Skilled Team does not undertake technical tasks for the sake of doing so or out of idle curiosity (citing Lord Hodge in ICOS and the TBA in AgrEvo, as quoted by Lord Hodge at [70]).

In both their opening and closing submissions, Astellas addressed a number of submissions directed to their perception that the Claimants’ case was that the change from RD162 to RD162’ was trivial and obviously so. These comprised a series of reminders from the relevant case law which I summarise as follows.

First, I agree that there can be real danger in saying that just because a modification is “small” or “conservative” in structural terms, that it is obviously “trivial” and will obviously have no material effect. Chemical structures are very different from plate diameters.

Second, a case run on “obvious immateriality” does not absolve the Claimants from having to consider the actual teaching of the prior art or allow them to generalise it into oblivion. It is also important not to work backwards from the solution as disclosed in the Patent. The test remains whether the Patent is obvious over the cited prior art teaching. Floyd LJ stated in Philips v Asustek [2019] EWCA Civ 2230; [2020] RPC 1 at [61] that the Court does not approach obviousness by taking the prior art and “stripping out from it detail which the skilled person would otherwise have taken into account, or ignoring paths down which the skilled person would probably be led”.

Although there is no attack based on CGK in this case, it is nonetheless relevant that the “generalised to oblivion” approach is why an approach based on the CGK alone can be so unfair on patentees. As Floyd J (as he then was) explained in ratiopharm v Napp [2008] EWHC 3070 (Pat); [2009] RPC 11 at [158], the danger is that the starting point is not “obviously encumbered with inconvenient details of the kind found in documentary disclosures”.

Third, such an approach cannot be used to try to conceal or dodge a lack of any motive to take a step or that the prior art might teach away from it. Motive almost always has a role to play in any obviousness analysis. In Napp v ratiopharm [2009] EWCA Civ 252; [2009] RPC 18, the difference between the claimed invention and the prior art was a slower release formulation. The obviousness case was rejected by the Court, with Jacob LJ explaining at [111] that “Unless there was a point in pressing on, why should the skilled person embark on what would be a somewhat troublesome, even if uninventive development programme? The answer is the same as for the case on common general knowledge – there was no point”. The Judge explained at [113]: “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.”

This is mirrored by the Supreme Court in Actavis v ICOS where it was explained (at [70]) that “the motive of the skilled person is a relevant consideration. The notional skilled person is not assumed to undertake technical trials for the sake of doing so but rather because he or she has some end in mind”.

As Kitchin J (as he then was) explained in the passage from Generics v Lundbeck quoted above, motivation is usually important. There are some cases where motivation may play a lesser role or is not determinative, for instance where the change from the prior art is arbitrary or entirely trivial (and where the prior art does not teach away or is neutral), meaning that the need for motivation to take a particular step might not play a part in the analysis. Jacob LJ used the example of changing the diameter of a plate by ¼ inch, but such cases are rare, and Astellas submitted, particularly so in a chemical or pharmaceutical context.

Finally, I was reminded (again) that care must be taken in approaching the Pozzoli questions to avoid hindsight. The statutory question is always whether the claimed invention is obvious without knowledge of the Patent or the claimed invention.

In their closing, Astellas responded to the case law cited by the Claimants in their Opening on this topic, as follows.

Once again, Astellas warned that great care must be taken in seeking to apply case law on obviously trivial changes to a pharmaceutical context. In Hoechst Celanese v BP Chemicals [1997] FSR 547 at [573], Laddie J had used the phrase “workshop modification” and suggested that almost no motivation is needed to make such a change. The Court of Appeal in Pharmacia v Merck did not agree that it was appropriate to refer to “workshop modifications” as this was introducing a test not in the statute: the statutory test is obviousness (at [124]).

The Claimants in the present case rely on RIM v Visto. The invention in RIM v Visto concerned how to send and synchronise emails from outside and inside a firewall. In that case, the invention used an HTTP communication, and the prior art Lotus Notes application used RPC (through a different port) rather than HTTP (see Judgment at [65] and [106]).

The argument was that there was no reason to change Lotus Notes as it worked perfectly well crossing the firewall using RPC through port 1352, there was no reason to use HTTP through port 80. It was in that context that the Judge considered the case law on modifications which do essentially the same thing in a different way and therefore need little or no motivation to do (see at [111]-[121]).

In RIM v Visto, it was CGK that HTTP could be used to transfer data (and that it used port 80) and that it was a “generic request/response protocol that can be used for a variety of tasks” (at [14]). The distinction was to change one CGK protocol to transfer emails with another CGK protocol for doing the same thing. That took no invention and required no motivation to do: it could just be done without any concern and without any uncertainty as to the outcome.

The problems in applying such an approach to a case of chemical substitution on medicinal compounds are plain. If such an approach is to be applied, it truly must be obvious that the change will make no material difference (i.e. it is obvious that the components at issue can be swapped without concern or impact). That was the case in RIM v Visto and is the case when considering diameters of plates or different fixing means. Astellas submitted that this point simply does not apply in the present case.

Astellas submitted that the fallacy in the present case lies in the proposition that a seemingly small structural change is tantamount to an obviously immaterial one. The one does not follow from the other in medicinal chemistry.

These points were aimed by Astellas at the ‘obvious to do SAR’ case.

In ICOS the issue arose over obviousness of routine tests. Lord Hodge made the following observations which are important to keep in mind:

In ICOS, the claim was to a maximum of 5mg tadalafil per day. The Judge had found that the Skilled Team would investigate the lowest dosage possible under a routine dosage study but would not have known the 5mg in advance. In the Court of Appeal and Supreme Court it was held that this did not matter: the dosage would be found in any event by entirely routine testing which was obvious (indeed necessary) to undertake.

The ICOS judgment cannot be used to advance the proposition that just because embarking on testing is routinely done or even “bread and butter” in nature, the results are thereby obvious. That would be contrary to the important public policy of supporting pharmaceutical research.

The point about the dose ranging studies in ICOS is that they were always done to seek to obtain the lowest dose possible consistent with effectiveness, whatever that dose might be. Lord Hodge explained at [77] that “The target of the skilled person’s research is in large measure pre-determined” (emphasis added). This is because, for any drug, the lowest effective dose will exist and it is simply a pre-determined matter of lowering the dose successively to identify it.

The key to the finding in ICOS was that the routine testing was obvious to do and the end result was in large part pre-determined (all that was left was to put a number on the minimum effective dose). As Lord Hodge said at [88]:

“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.” (emphasis added).

In opening, the Claimants placed considerable emphasis on the judgment of Pumfrey J (as he then was) in Monsanto v Merck [JA/2] concerning COX II inhibitors (see their opening skeleton at §106 and T1/29₂₀-32₂₃). No wider propositions of law are relied upon that are said to arise from this case. Astellas suggest that the Claimants rely on it because it is a case where it was held there was motivation to do a SAR and that the patent was obvious as a result. Astellas also submitted that the dangers of seeking to draw wider propositions from something so factual are plain. Indeed, what was not pointed out in opening was how different the facts of Monsanto were to the present case.

In Monsanto, the prior art “Gans” was a paper that disclosed the anti-inflammatory activity of the compound DuP 697 in rats and stated it did not produce intestinal or gastric ulcers (the problem with non-steroidal anti-inflammatory drugs). DuP 697 was the 2,3 isomer of the claimed compound (the 3,4 isomer).

The Judge accepted that it would be obvious to undertake a routine SAR and find the 3,4 isomer of the claim. But the evidence was telling. Not only was DuP 697 the focus of Gans (and so the starting point was not in doubt) but both the Claimant and the Defendant in that case had independently seen DuP 697 and both had quickly synthesised the 3,4 isomer. It is perhaps not surprising that the Judge held that the 3,4-diaryl substitution would be “one of the first things which would occur to the medicinal chemist” (see at [159] and [164]-[172]).

This was not a case where just “doing a SAR” of some unknown scope and aim was held to be obvious. It was a case where the starting compound was not in doubt and where both parties had actually themselves started from it and both got to the same place quickly and which on the evidence the Judge held would be one of the first things that would be done to the disclosed compound.

Astellas contended the present case is very different indeed.

Finally, Astellas emphasised that it is impermissible to seek to mix up what is said to be the technical contribution over a piece of prior art and the question of obviousness.

In Conor v Angiotech, it was argued that obviousness should be assessed based on a watered-down version of the alleged invention (said to be based on what was the actual contribution of the patent over the cited prior art), rather than by the claimed invention. This was rejected. Lord Hoffmann explained (at [15]-[17]) that this type of argument is an “illegitimate amalgam of the requirements of inventiveness (Art. 56 of the EPC) and either sufficiency (Art. 83) or support (Art. 84) or both”. Lord Hoffmann explained that it is the claimed invention which has to involve an inventive step. The invention means prima facie that specified in the claim: see s.125(1) of the 1977 Act.

Finally, under this heading, Astellas made the well-known point that the actual teaching of the prior art (as a whole) also cannot be ignored, relying on the dictum of Floyd LJ in Asustek which I set out at [199] above.

I have endeavoured to keep all these principles in mind.

Although it is trite that the Poster and the Slides must be considered separately (since, as I understand matters, the Claimants abandoned in advance of trial their case that the Poster and the Slides would be read together by the Skilled Team), much of the reasoning and the attacks related to both. Nonetheless the disclosures are not the same and it is important not to elide the two, so I consider the case over the Poster first.

The Claimants submitted in opening that their case on obviousness can be stated very simply as follows.

At the relevant date there was a motivation to find treatments for HRPC. Applying Pozzoli:

The Claimants’ closing was slightly more nuanced – indeed Astellas say the case was different. So far as the Poster was concerned, the Claimants emphasised the following ‘key teachings’:

On that basis, the Claimants submitted that it was (i) obvious that replacing the cyclobutyl in RD162 with gem-dimethyl would make a compound which is likely to have therapeutic potential as measured by an in vitro assay and/or (ii) it was obvious to test such a compound in an in vitro assay for that purpose, in which case it would be shown that it would have therapeutic potential.

I will start by addressing the Claimants’ primary evidence on obviousness over the Poster, together with the attacks on that evidence, before considering Astellas’ positive case of inventiveness.

Prof Westwell’s key reasoning regarding the Poster was set out in his first report as follows:

‘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 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.

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].

Having identified that the Teutsch paper (referenced in the Poster) gave a general synthetic route to the core arylhydantoin structure of the RD series, Prof Westwell said in [9.52] that through appropriate choice of commercially available starting materials, that method could be extended to provide the RD series structures.

Prof Westwell then went on to consider changes to the other parts of RD162. In [9.53] he said this (with my emphasis 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.’

The possible changes which Prof Westwell considered were:

Before I return to consider the attacks on the Claimants’ evidence, it is convenient first to consider the three reasons which Astellas put forward as to why they said RD162’ was inventive. Each was based on evidence given by Prof Ward. In summary these were:

The Claimants were dismissive of each of these three reasons, characterising each as, respectively, misguided, misleading and abandoned. These reasons were also the focus of the Claimants’ criticisms of Prof Ward. Accordingly, it is necessary to analyse the evidence and the arguments. I will first consider the criticisms of Prof Ward which were not directly related to the three reasons.

An overarching point made by the Claimants was that Prof Ward had experience giving expert evidence in patent cases, but that cannot, of itself, be a criticism.

I shall deal with the Claimants’ specific points relatively succinctly. The first point was that Prof Ward had failed to equip himself with the relevant CGK of the Skilled Medicinal Chemist working on HRPC. However, as he stated in his first report, he had read the technical primer and the draft CGK section in Prof Clarke’s report, indeed the whole of his draft. He read the Chen, Marhefka, Sack and Teutsch papers and made various comments on the relevant content. The only part of his evidence where this criticism might have mattered was the suggestion that he did not have the experience to interpret biological assay data. He accepted he did not do the assays himself, but: ‘my job is interpreting assay data with the help of the biologist’. I reject this point.

The second point was an accusation that he failed to answer questions put to him on three particular issues:

The third allegation was that Prof Ward refused to accept propositions he had advanced himself. Again, three examples were relied upon:

The fourth allegation was that Prof Ward refused to answer questions on the issue of inventive step. The first point under this head concerned the assumption(s) which Prof Ward was asked to make about the results of the in vitro testing shown in the Poster. I address this topic at [309]-[318] below - see [315] in particular. I agree that the assumption(s) were unrealistic.

The second point under this head concerned questions arising from [72] in his first report. The Claimants cited this passage:

“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 cross-examiner was attempting to obtain a concession that methyl/fluorine groups could be appended on the right-hand side of RD7 or RD54. However, Prof Ward pointed out that his observation was made in relation to a comparison between RD37, RD131 and RD162. Underpinning his answers was the notion that the Skilled Team would not go back to RD7 or RD54 from RD162. I did not see anything in this criticism.

The further (and more substantial) criticisms made in the Claimants’ Annex B are dealt with in the context of Astellas’ three reasons for inventiveness, to which I can now turn.

Prof Ward’s opinion that there was no motivation to carry forward the disclosure of the Poster was a consequence of his assumption that the Poster represented a completed drug discovery and development project “marking the end of the journey” in which the authors have “reached their goal of developing an AR inhibitor for prostate cancer”, namely RD162, as he made clear in his first report.

As the Claimants submitted, the basis for this opinion was unclear and in cross-examination Prof Ward accepted there was no statement in the Poster to that effect. Indeed, Prof Ward volunteered that it “may be an ongoing project or it may be a complete project” and “I accept that there are two scenarios which could be either that the team is carrying on work and is doing further analogues, or that that is the endpoint and they are taking that compound forwards. I think both of those could be possible” (XX Ward T4/387₁₁-388₁₃).

In their opening, Astellas sought to make the same point, based on the arrows:

‘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.’

This submission was undermined by both medicinal chemistry experts who were clear that no scientific conclusions could be drawn from the arrows.

Prof Clarke did not consider that RD162 was the ‘endpoint’ of the development of the RD series of compounds based on the disclosure of the Poster and he said there is no reason to believe that a decision has been taken to take RD162 forward into clinical trials, not least because it had not been tested for activity in vivo (XX Clarke T3/258₁₄-259₉). Ultimately Prof Ward accepted that the Skilled Team would not know that it was the end of the journey for the authors, not least because they have not tested RD162 in an in vivo efficacy model or using luciferase (XX Ward T4/476₁₀-479₂₀).

In the course of his cross-examination, it emerged that a further aspect of Prof Ward’s reasoning was that the Skilled Medicinal Chemist would understand from the Poster that the cyclobutyl had been ‘actively’ selected and was therefore the preferred group at position X. On that basis, modifying RD162 to introduce a dimethyl substituent would represent a ‘backward’ step.

The Claimants submitted this was a bizarre position for Prof Ward to adopt given that he did not know why it was the preferred group. Given the paucity of data presented he eventually accepted it was difficult to draw any conclusions as to the rationale behind the compound selected:

‘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 T4/386_10-12.’

Furthermore, Prof Ward’s view that the Skilled Medicinal Chemist would not be motivated to take the disclosure of the Poster forward was inconsistent with his description of drug discovery and development as set out in his own publications. His review entitled “Hit-to-Lead Medicinal Chemistry” (co-authored with Paul Beswick), identified (at section 2.1) several sources of ‘hit’ compounds including “molecules already known to bind to the target, for example, from competitor patent”. So, as he had to accept, the Skilled Team could use another team’s ‘lead’ compound as a ‘hit’ compound on which to build their own drug development programme (XX Ward T3/359₁₇-360₁₈). He was unable to explain why he had not considered this CGK approach to identifying lead compounds in his analysis on inventive step (XX Ward T4/457₁₄-458₁₁).

The Claimants characterised this as an important omission, bearing in mind that Prof Ward also accepted that if the Skilled Team had identified RD162 as a starting point, they would want to make analogues of RD162 and compare the data from pairwise analogues in the manner described in the book chapter he co-authored with Stephen Connolly (XX Ward T4/458₁₂-463₂₃).

The Claimants’ final point under this heading was that Prof Ward’s analysis on inventive step failed to take any account of the fact that the Skilled Team would be motivated to develop a novel compound (XX Ward T4/437₂₄-440₁₃). In Prof Ward’s review, the need to identify a novel candidate compound was described in Table 1 in his review as ‘essential’.

The key issue however concerns what degree of novelty the Skilled Team would aim for. The point which was put (repeatedly) to Prof Ward was the Skilled Team would want to take forward a novel compound. It is true, as the Claimants’ submitted, that Prof Ward sought to avoid accepting this proposition when applied in the context of the Poster and RD162 and this was one of the Claimants’ major criticisms of Prof Ward, since the cross examination continued for some time (XX Ward T4/433₁₃ onwards).

Eventually, Prof Ward did accept that proposition (see T4/438₂₄), but it was clear that he had not considered this in his reports. His evidence down to T4/455₂₂ was very grudging in nature. For example:

In this whole passage of cross-examination, Prof Ward seemed to me to be bending over backwards to avoid accepting (either at all or without qualification) some fairly straightforward propositions, including some which he had previously written about in textbooks. He was also bending over backwards to avoid considering any changes at position X.

On the basis of this passage of cross-examination, the Claimants submitted ‘Plainly, the desire for a novel candidate compound would itself be motivation for creating close analogues of the promising candidate disclosed in the Poster, namely RD162. This straight-forward proposition was put to Prof Ward who simply refused to engage, apparently unable (or unwilling) to understand the question being put to him.’

Overall, in my view, there is no support for the ‘no motivation’ contention and I do not consider that Prof Ward’s point represented the position or views of the Skilled Team. Furthermore, there was a degree of exaggeration in Prof Ward’s suggestion that there had been an active selection of the cyclobutyl at position X. It is clear that the authors of the Poster had made the change from dimethyl to cyclobutyl and retained cyclobutyl. It would be fair to conclude there does appear to have been a preference for cyclobutyl, but there was no pairwise comparison nor any other data directed to this. On this point, Prof Ward was reading too much into the Poster, in my judgment.

In his first report, Prof Ward said (at [139]) that “The Skilled Chemist would know that there are known metabolic liabilities associated with terminal methyl groups where oxidative metabolism can typically occur, and as such a terminal dimethyl substitution would typically be viewed as less metabolically stable than its cyclobutyl analogue” (emphasis added). In his second report he repeated this contention under his section on Inventive Step.

I agree that it was clear that Prof Ward was putting this forward as a reason why the Skilled Team would not seek to make and test an alternative compound with the gem-dimethyl substitution. It was advanced as part of Prof Ward’s positive evidence in support of non-obviousness.

In his oral evidence Prof Ward, faced with numerous contrary statements, including examples of dimethyl groups featuring in a number of commercial products, he sought to recast this evidence. He first said that he was not saying this was a reason not to go forward with the dimethyl just that if you see metabolism at this group cyclisation might be a solution.

‘Q. You see that. Did you consider it appropriate to draw to the court’s attention that a number of commercial products have gem-dimethyl groups when giving evidence that you give in paragraph 139; do you not feel that would be a more balanced picture?

A. I think we covered this ground yesterday as well. So what I am not saying is you should not incorporate a gem-dimethyl group. I am not saying that the gem-dimethyl group is one of those serious structural alerts that chemists are averse to, or actively avoid. What I am saying is if you have metabolism, if you see metabolism at the methyl of the gem-dimethyl group, then cyclisation would be an effective strategy to overcome that metabolism, if that is happening. What I was doing was trying to use my judgment of saying well why did I think there had been an active selection of the cyclobutyl. So I am not trying to advocate that the gem-dimethyl is not a group you can see in drugs or you can have. What I was trying to do was think "Well, why might it have been preferred?"’ – XX Ward T4/420₁₃-421₇ (my emphasis)

As the Claimants submitted, Prof Ward then speculated that a possible explanation for why they went with the cyclobutyl is that they encountered stability problems with the gem-dimethyl. However, I agree that there was simply nothing in the PKDM data presented to support this. It was speculation. Moreover, it was not what he had written in his expert report (XX Ward T4/425₂₃-432₁₉). However, the Claimants submitted that Prof Ward had abandoned the metabolism of methyl substitutions as a factor in support of inventive step (XX Ward T4/430_4-15), in the light of his answers under cross-examination.

The Claimants made a number of submissions on this issue:

In my view, Prof Ward’s point had little or no substance. Furthermore, he raised it in a misleading way.

The further point made in Prof Ward’s first report was that he said the Skilled Medicinal Chemist would consider that the “bulkier cyclobutyl substituent potentially filling better in such a pocket (at least relative to a gem-dimethyl substituent)” (Ward 1, para 138).

Prof Ward alluded to this point again in the passage of cross-examination I mentioned above. At T4/453, Prof Ward said that when he saw RD162’ he was surprised that they had gone ‘backwards on the cyclobutyl to the gem-dimethyl’. He said: ‘There is an active selection of the cyclobutyl; that seems to me very clear’. Later he justified that in this way [T4/456]:

At [153] above, I set out a summary of what the Skilled Team would derive from the papers referenced in the Poster, which was based on material set out by Prof Ward in his first report.

It is clear, however, that the Poster makes no reference to a hydrophobic pocket of particular size, shape or dimensions. The Marhefka paper is referenced in a footnote. On p7, Marhefka reports that “One of the methyl groups on the hydantoin ring binds in the hydrophobic pocket below the 17 carbon of TES, and the other occupies the space of the 16 carbon of TES.” On the basis of this, Prof Westwell’s view was that the fact that only one of the methyl groups of nilutamide binds in the hydrophobic pocket would suggest it is something of a simplification to associate the bulk of the substituent with a ‘better’ fit into that pocket (Westwell 2, para 2.13). Prof Ward was unable to identify what (if any) aspects of Prof Westwell’s evidence on this point he actually disagreed with (XX Ward T4/469₆-474₁₈).

Ultimately, Prof Ward conceded that this was no more than his suggestion as to why the cyclobutyl might have been chosen by the authors (XX Ward T4/481_5-15). In other words, this was just a hypothesis. Ultimately it was clear that if the Skilled Medicinal Chemist identified this hypothesis, s/he would test at least the dimethyl variant against the cyclobutyl variant to see if this hypothesis was correct.

On a side issue, I should briefly mention some diagrams which were put to Prof Westwell in cross-examination which purported to illustrate the size of the hydrophobic pocket. However, Prof Westwell was dismissive of these ‘cartoons’ and said they were a crude, two-dimensional schematic (XX Westwell T2/132_2-10). Furthermore, there was no evidence that these diagrams bore any likeness to the actual shape of the hydrophobic pocket (XX Westwell T2/130₂₀-132₁₀).

Overall, the position was that there was no information upon which to reason that the cyclobutyl was a better fit, other than the fact that the cyclobutyl had been adopted in RD37 and retained.

Having considered all three of these points made by Prof Ward and the cross-examination on them, I find it difficult to avoid the conclusion that Prof Ward was, at times, engaged in a process of trying to find or generate arguments against obviousness.

However, the mere fact that Prof Ward was so engaged does not mean the Claimants’ arguments succeed.

The next part of Astellas’ case I must consider involves their attacks on the Claimants’ primary evidence and their contentions that the Claimants’ case changed as the trial progressed. This requires me to focus in more detail on the Claimants’ primary evidence of obviousness, as set out in the evidence of Prof Westwell.

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.

The relevant context for the Poster was as follows:

Although I did not understand that the Claimants abandoned their primary evidential ‘immediately obvious’ case, it is true, as Astellas pointed out, that the Claimants did seek to develop a supplementary case: that it was ‘obvious to do a SAR’. It is possible that the Claimants had already anticipated the need to develop this prior to Prof Westwell’s cross-examination, but it is tolerably clear that the challenge made in his cross-examination cemented that perception.

Although Astellas, through Prof Ward, ran a case that the Skilled Team would simply take RD162 forward, another equally obvious route is that Skilled Team would conduct some analysis (i.e. their own SAR starting from RD162), not least to develop their own molecule. What was in dispute was what would then happen.

Although, as I have indicated, Prof Ward suggested that the Skilled Team would investigate modifications to the right-hand ring (the implication being only there), the Claimants suggested that Prof Westwell had agreed with this. They relied on this passage from one of his answers to a question I put to him:

“..it seems that swapping groups out of that right-hand aryl ring, largely, based on the limited evidence we have here, you retain activity. So long as you have that rigid phenyl group and you decorate it with different substituents, albeit a limited group, you are largely retaining the activity as an antagonist in that hormone refractory model” [T2/201_8-16].

In context, Prof Westwell was clearly talking about what appeared in the Poster. Later in the same answer, he did say this, but again, in my view, he was referring to what is shown in the Poster:

‘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.’

So in their closing, Astellas tried to paint the picture that the Skilled Team would take one of two routes:

In his cross-examination, it was put to Prof Westwell that when he had discussed the steps he had said were obvious over the Slides, he had not mentioned that the Skilled Team would do a SAR. His responses were that (1) SARs were discussed in the CGK section and (2) a medicinal chemist would do SAR – that is the nature of medicinal chemistry, an answer which appears in this important passage of the transcript at [T2/158-160]:

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:

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.

Astellas nonetheless submitted that it was clear from his written reports that Prof Westwell’s analysis was infected with hindsight. The basis for this suggestion was the following. One starts with the agreed CGK that at the start of a drug discovery project the Skilled Medicinal Chemist and the Skilled Cancer Biologist would agree a TPP (see [97] above). In cross-examination, Prof Westwell agreed that what the Skilled Medicinal Chemist would do would be conditioned on the TPP to be discussed with the Skilled Cancer Biologist, although there may be considerable variation in the amount of knowledge about the starting molecule. The SAR would progress to identify a front runner molecule, whereupon modifications are likely to become more focussed on improving that front runner, although you are also building up a model of the chemical structure requirements for binding to the desired target. The SAR progresses to identification of a lead molecule which has a range of properties across the board, giving the Skilled Team confidence to progress to more advanced testing. Problems may be encountered leading to alteration, substitutions and further research directed at trying to overcome them. It is also prudent to develop back-up compounds, designed to mitigate a potential issue with the lead compound.

Overall, Prof Westwell agreed that a SAR is quite a wide umbrella term since what needs to be done in the SAR depends on how much is known at the outset, what the goal is, how much testing has been done and so on. He also agreed that that was very much the work of the Skilled Medicinal Chemist ‘to have that understanding of the issues that you have just outlined, and to design a programme of optimisation of structural activity study to hopefully overcome any challenges..’

Against that background, Astellas point out that, when it comes to the evidence on obviousness, there is no mention of a TPP either by Prof Westwell or Prof Hickson, even though it is supposed to be agreed between the Skilled Medicinal Chemist and the skilled cancer biologist. Furthermore, in his written evidence Prof Westwell did not expressly mention conducting a SAR exercise – hence the cross-examination from which I quoted the key extract above. See in particular T2/158₁₇-159₁₂.

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 (this being a point which was put forcefully to Prof Ward). 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.

Prof Westwell acknowledged that he was familiar with the compound now known as enzalutamide from his own work in the field from 2014-2020, and that he was told to put out of his mind his personal knowledge acquired after March 2006 and he stated he was satisfied that his knowledge of enzalutamide had not affected his opinions.

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.

The ‘obvious to do a SAR case’ was enthusiastically developed in the cross-examination of Prof Ward with a number of approaches being suggested which I will now summarise. Some of the suggestions put were bizarre: ‘they may just have had plenty of cyclobutyl in the fridge’.

It was put to Prof Ward that a Skilled Team will not want to go with one of their competitors’ products, they would want to create their own novel products. This was based on the article he had written mentioned above setting out the process of drug discovery in which he had indicated that novelty was essential for hit, lead and candidate compounds. He agreed that if one had done a high throughput screen and obtained two lead series or two hit series and all other things were equal, a team would “naturally go for the one that had more novel structures in it than not” [T3/362_8-24]. He qualified what he had written on the basis that it is ‘a holistic judgment’ of all the properties. The Skilled Team is trying to understand what is the potential for turning the hit series into a candidate, it maybe that it is not novel but the team can see a very clear strategy to make it novel in terms of where they are going on their optimisation journey [T3/363₂-364₂].

It was put to Prof Ward that the patent department might ask the chemist to look for the next most suitable analogue, because the chosen candidate had been patented by someone else. Prof Ward’s initial reaction was “that is not a situation I have ever encountered”. As Astellas submitted, that is not a promising start for this attack, particularly since Prof Ward has considerable “real world” industry experience at Cerebrus and then GSK. Prof Westwell accepted that Prof Ward’s experience was far more industry focussed than his own [T2/98_20-23]. Astellas submitted that if anyone would have had instructions from a patent department to look for the next most suitable analogue for patent protection reasons, it would have been Prof Ward. Yet, he had never encountered this particular scenario.

Prof Ward explained that if the instructions had come from the patent department to make something new and protectable, the Skilled Team would be more likely to focus on something structurally diverse – in order to achieve something protectable [T4/451₉-452₄].

This led to the proposition becoming more extreme. He was then asked to assume that the patent department came and said “We do not care how close it is; it just has to be different to 162, as close as you like…”. Even on this basis, Prof Ward said he would not know what underlying patent application or applications had been filed by the authors, which would lead him to go further away structurally. At [T4/452₅-453₉] he explained:

This line of questioning based on instructions from the patent department was, in my view, plainly hindsight driven. If patenting considerations are to be taken into account, the patent department would consider it was highly likely that a patent application had been filed covering the research disclosed in the Poster which would feature a familiar cascade of claims, often initially claiming a Markush structure but then increasing in specificity to a claim to the preferred molecule. That is precisely what featured in the PCT application which led to the Patent. In fact (as often occurs) the wider claims were abandoned and the Patent claims only the single compound RD162’, in this case because of the prior publication of the Poster, but the patent department would not have known this at the relevant date.

Furthermore, the normal expectation of the Skilled Team would be that the widest possible patent protection would be in the process of being sought and that would normally indicate that the development of a novel (and protectable) molecule from the starting point of RD162 would require some significant modifications. So, if one strips out hindsight, the quest for novelty would take the Skilled Team much further away from RD162 than the change from cyclobutyl to dimethyl.

This was another route suggested in cross-examination of Prof Ward. It is the idea that a Skilled Team will look at the Poster, not proceed with RD162 or any optimisation of that, but will instead seek to undertake a SAR on RD7. Astellas submitted that the reason why the Claimants alight on RD7 is plain (it has a dimethyl) but also that there is no reason for a Skilled Team (without knowledge of the Patent) not only to suddenly start from RD7, but then to adorn it with the right-hand side substituents of the compound from where they had chosen not to start (RD162), and not change anything else. They contended this is another hindsight analysis.

Astellas contended that the Claimants’ problem with this line of argument is that there is no reason to want to progress RD7 and no direction as to what would be done if it was progressed. I agree, for the following reasons which Astellas developed in their closing submissions.

On the face of the Poster, RD7 has worse activity than RD37 both in the in vivo assay on the right-side of the Poster and in the PSA level assay at the bottom. The clear evidence is that a Skilled Team would wish to progress the best compound. Prof Ward explained that “from my experience, you would have a team sitting together looking through the data. You just have so many assays. There will be a compound which is preferred from that set, and you would take that compound forwards.” [T4/380_8-11].

From the data in the Poster, that compound was RD37 which was optimised through RD131, RD161 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?

Apparently in an attempt to try to avoid this being branded as hindsight-driven, the case was put on the assumption that there is no material difference (although sometimes it was put as no difference: [T4/397₁₂-398₂₄]) between RD37 and RD7 (and sometimes between all RD compounds from RD6) due to the lack of any statistical significance in the absence of error bars.

There is no dispute that the lack of error bars means that the data have to be interpreted with some caution. The evidence on these is as follows:

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.

However, the Claimants never explained why a Poster at a conference would be expected to have error bars on it or information to enable the reader to make statistically sound conclusions. The Poster was just giving a gist of what has gone on. The gist here is that RD37 was the best antagonist to take forward to in vivo PK testing, but its half-life and steady state then proved to be poor. That then tells the story of the work done on the right-hand side of the molecule to improve the drug like properties.

Astellas submitted that the Claimants’ approach was to focus on that fact that the Poster does not permit a statistical conclusion to be drawn, and then seek to conclude from this that no conclusions can be drawn. The one does not follow from the other and it ceases to look at the teaching of the Poster as a whole.

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.

If all the compounds are treated essentially equally or even equally as advanced in cross-examination, that creates a number of problems for the Claimants’ case:

If the data in the Poster are to be ignored (or treated as meaning that all the RD compounds are basically the same), Astellas submitted that the Court has no idea which might be taken forward and what changes might be made. On this basis it might be RD6 but who knows what might be done with the azide group. It could be RD54 with different substituents building on the cyano group. It could be RD7 but it might not be and who knows what substitutions a Skilled Team might make.

Even if RD7 was selected, and was found (contrary to the indications on the Poster) to be the most active and so worthwhile pursuing, there is no reason at all to keep the entire right-hand side of RD162 identical, considering that the whole point of going to RD7 in the first place is because the Skilled Team did not want to proceed with RD162. As Astellas submitted, the Claimants’ case was circular. They posit a Skilled Team that does not want to progress RD162, who go to RD7 but then seek to make a very close analogue of RD162. Astellas submitted this makes no sense.

Finally, it was suggested that maybe RD162 would be progressed but RD162′ might be alighted upon as a back-up compound. Prof Ward explained this would be “super risky” [T4/465₁₀-466₁₇]. For similar reasons as explained above, Astellas submitted that nobody makes back-up compounds (the insurance for a rainy day with the main compound) with a goal of them being structurally similar to the candidate compound. The idea is to have something structurally diverse.

Before I reach any conclusions, I must finally consider three points on secondary evidence.

First, Astellas rely on evidence of what Professor Westwell himself did when faced with enzalutamide after the application date and their contention that there was no suggestion that the approach to SAR dramatically changed from 2006 to 2016, which was the date when Prof Westwell worked on enzalutamide after it was launched in 2012.

Astellas submitted that in none of his papers did he even once change the substituent at position X on the central ring. In one of his papers, the team of which he was a member sought to improve the antiproliferative properties of enzalutamide and looked at exploring the right-hand and left-hand rings, adding a 3,5-bis-triflouroumethyl group in ring B, a bulkier 3,5-tert- butyl was envisaged as well as adding further alternative substituents in ring A. Prof Westwell depicted the approach in fig. 1 of [XX-AW/8/103] set out below:

The compound at the top is enzalutamide and bottom right are his proposed changes to enzalutamide (bottom left is bicalutamide). No changes are made to position X on the central ring – the focus is on rings A and B. At no point in any of Prof Westwell’s papers do we see any change made to position X on the central ring. Astellas invite the conclusion that this entirely corroborates the opinion of Prof Ward, who would have optimised the right-hand ring. They suggest it is the opposite of the secondary evidence in Monsanto v Merck.

I do not propose to place any weight on this point because the context(s) for the later work done by Prof Westwell were different.

Second, in their opening, the Claimants sought to rely on a separate point which concerned how in fact the inventors came up with RD162’. I would not have referred to this topic at all (because it is completely irrelevant) but for the fact that Astellas sought to rely on some statements made in emails between some of the inventors as secondary evidence that the Skilled Team would not predict that the change to a dimethyl would not make a material difference.

The email from Dr Jung on 9 February 2006 explains that testing was being done on RD162′ and RD162′′ and he commented “let’s hope they both will have very similar activity and PK profiles to those of RD162”. In the earlier part of the same email chain of 6 February 2006, he had added a postscript: “PS. let’s hope RD162′ is as active as RD162!”

Astellas point out that the inventors were steeped in knowledge about the RD compounds but even they were uncertain as the effects of the changes featured in RD162’ and RD162”.

In the absence of any evidence from those involved, it is necessary to consider the relevant context in which these comments were made. The Poster (and the Slides – in so far as these actions are concerned) were made available to the public at the Prostate Cancer Foundation Scientific Retreat in Arizona that took place between 29 September to 1 October 2005. The filing date of the Patent was 29 March 2006. The emails were sent in early February 2006. By that time, it is a reasonable inference that the inventors had considerably more data about RD162 than had been published. When Chris Tran said ‘PS. I am curious as to why we are having a modified version of RD162. RD162 is really good already’, it is likely that the inventors already had full data on RD162 and had probably selected it as the molecule to take forward, but for this last-minute hiccup.

I consider this point is double-edged. On the one hand, one might say that the inventors chose to investigate RD162’ and RD162” precisely because they considered the changes which those molecules featured would not make any material difference to the activity and PK profile of RD162. Of course, that could not be guaranteed so the new molecules had to be made and tested.

On the other hand, Astellas may have a point here, but I am not persuaded I should take it into account. I am not convinced this scenario can be treated as a proper analogy to the scenario faced by the Skilled Team having read the Poster.

Third, Astellas developed some points in cross-examination based on particular compounds in the Tiers in the Patent. Various changes at position X away from cyclobutyl took certain compounds down into Tier 4 (no better than bicalutamide). I am not sure that Astellas actually sought to rely on these examples as secondary evidence that small changes can have a big impact. The Skilled Team would readily accept they can, but it depends on the circumstances. Furthermore, these points confuse two separate things: The first is a reasonable prediction which the Skilled Medicinal Chemist makes based on certain data. The second concerns the result(s) of the testing of the prediction which may or may not turn out to be accurate. Just because the results do not conform to the prediction does not mean that the prediction was unreasonable or that it was not worth testing.

I am acutely conscious that there is a lot riding on cases of this type which leads to the legal teams and their expert witnesses going to great lengths to establish their own case and to damage the case being presented by the other side. This can lead to over-complication and, in my judgment, it has done so in this case.

This is not entirely the fault of the parties. When an allegation of obviousness is made, the Court is obliged to adopt the viewpoint of the notional team of ordinary skill in the art, assess their common general knowledge and then decide the question of whether the step(s) from the prior art to the claim would have been obvious to that team, acting without hindsight. We are told that the notional Skilled Team should mirror teams in real-life, albeit with suitable adjustment to ensure the notional team is not inventive. The process is not automatically insulated from over-complication, but consideration of what would happen in real life can help to eliminate it.

In this case, the over-complication has occurred because there was much theorising as to what the effects of certain mooted changes to RD162 would be. I have no doubt that real-life Skilled Teams would debate their theories of action – up to a point. However, in real-life teams, the theorising would quickly give way to action to test whether one or more of the theories had merit (assuming, of course, that pursuit of the theory was considered to have a reasonable expectation of success).

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:

On that primary case, I did not find persuasive any of the three points which Astellas advanced in their positive case of inventiveness. In my view, Prof Ward was trying too hard to generate points in favour of Astellas’ case.

I turn to consider the alternative case – it was obvious to do a SAR. Having read and considered the disclosure of the Poster with interest, I find the Skilled Team would have been motivated to do a SAR. I dismiss the idea that the Skilled Team would use any compound other than RD162 as their starting point. With RD162 as the starting point of the SAR, I also find the Skilled Team would have been motivated to develop a novel compound from that starting point. The real dispute lay in where that process would lead the Skilled Team.

As I mentioned, Astellas submitted there were only two options for the Skilled Team: take RD162 forward or do a SAR in order to develop a structurally distinct molecule. The Skilled Team starting on a SAR based on RD162 would wish to characterise RD162 i.e. to develop their own (and better) understanding as to how various parts of the molecule contributed to its properties. As Prof Ward put it: ‘…. I would characterise it, and not just characterise it to reproduce the data that are here, [i.e. in the Poster] I would characterise it to get a wider understanding of its potential …’.

This was the furthest that the evidence went on what would be done in the SAR. At best, it remained unclear whether the Skilled Medicinal Chemist would undertake a full SAR investigation (which would include making and testing RD162’) or whether s/he would accept some of the points indicated in the presentation in the Poster, and if so, which ones (which might result in RD162’ not being made or tested). As I mentioned at [290] above, Prof Westwell agreed that a SAR is quite a wide umbrella term since what needs to be done in the SAR depends on how much is known at the outset, what the goal is, how much testing has been done etc. For the SAR argument to succeed, it was necessary to spell out the goal and what testing would be planned, against the backdrop of RD162 as the starting point and the information in the Poster.

This alternative case depended on making and testing RD162’ not as the or one of the target molecules having conducted the SAR, but almost as a byproduct in the early stages of characterising RD162. It is possible to envisage that, on other evidence, that process could have led to a finding of obviousness. The problem for the Claimants is that one normally expects a true case of obviousness to be set out clearly in the evidence in chief of the party making the allegation. This argument was not set out by Prof Westwell at all. The evidence given by Prof Ward came very close but I was not satisfied that the target was established. Once again, I find the intense focus on the change from the cyclobutyl to the dimethyl was tainted by hindsight – the knowledge that RD162’ was the target.

In one sense, Prof Ward’s dogged resistance in cross-examination on the points I considered above might have favoured the Claimants’ case, but it cannot improve it largely because the cross-examination was itself driven by the focus on reaching the target. For the avoidance of doubt, I placed no weight on any of the secondary evidence.

In the circumstances, I reject the allegation that claim 1 was obvious over the Poster.

Save for one point, there was no real dispute as to what the Slides disclosed to the Skilled Team.

The Skilled Team would understand from the Slides that the authors were investigating compounds for use in the treatment of HRPC. They would further understand from the Slides that it was important for such compounds to be AR antagonists and not to act as agonists in HRPC.

It was common ground that the Skilled Team would consider the cross-referenced Chen paper on Slide 1. The material presented on Slides 2 and 3 regarding AR overexpression would be understood to be material taken from that paper.

Slides 5-7 describe the general approach of the authors in seeking compounds that were stronger antagonists of AR than bicalutamide, but without showing agonist activity in cells that overexpressed AR.

Slide 8 is a summary of “Design, Synthesis and SAR studies” that the authors have carried out. This was agreed to be a key slide.

It explains that certain design tools were used to initially arrive at the compound shown as RU59063. This has high AR binding affinity but agonistic activity. Prof Westwell described the structure of RU59063 by reference to circled parts shown in the figure below:

Slide 8 also shows a pharmacophore (shown below). As Astellas pointed out, a pharmacophore should not be confused with a Markush formula: instead, it provides an overview of the authors’ views of different interactions of a molecule within a binding site (in this case, the interactions of the molecules under study within the AR binding site). The targets for investigation are marked R, R₁ and R₂.

The Skilled Medicinal Chemist would note the following about this figure:

Slide 9 shows the structure of RD37 and describes it as a potent antagonist in hormone sensitive LNCaP cells. Data is presented that shows RD37 reducing relative PSA levels in a dose dependent manner compared to bicalutamide and RU59063. RD37 exemplifies the pharmacophore of slide 8 in that:

Slides 10-15 present further data relating to RD37, setting out its benefits, including that it acts as an AR antagonist in HRPC cell lines without agonist activity (slides 10, 11), that it shows selectivity for AR (slide 12), that it has comparable binding affinity to bicalutamide (slide 13), and that it slows the growth of HRPC cell line in vivo compared to bicalutamide. Slide 15 provides some PK and PD data on RD37, showing that it has a short serum half-life and is cleared after around 6 hours.

Slide 16 presents the structures of 2 derivatives of RD37: RD131 and RD162. It also presents PK data relating to these compounds and also bicalutamide. This is materially the same as the data that is shown in the Poster (see [173] above), the only difference is that the text below the chart on slide 16 makes it clear that the serum concentrations were measured after IV dosing, whereas this is not stated in the Poster. This slide shows that RD37 has PK problems, with high logP values (too lipophilic) and its PK after dosing (shown in the graph as the light blue line at the bottom) is poor (almost all gone after 15 hours). No steady state value can be given.

The box on slide 16 indicates that the inventors had then tried a number of different compounds (the structures of RD131 and RD162 being shown) with RD162 having good IC₅₀ values, reasonable LogP and good steady state concentration, when compared to bicalutamide. Of the three molecules disclosed on this slide, RD162 performs by far the best in PK after IV dosing, where it shows promising performance as compared to bicalutamide.

Slide 17 shows how RD37, RD131 and RD162 perform in a cell-based assay mimicking HRPC, measuring relative PSA levels. RD37, RD131 and RD162 all show an antagonist-type dose response with increasing concentrations.

Slide 18 states the following conclusions:

‘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’

The experts were agreed that the first three conclusions summarise the key points from the preceding slides (even though the reference to ‘imine’ would not be understood).

Astellas suggested that the changes made to RU59063 might have assisted in improving the potency due to “inducing altered AR conformation” – in other words the changes made at R and R₁ and R₂ have potentially altered the conformation of the receptor leading to improved potency.

Prof Westwell thought that the greatest contributor to this improved potency was the installation of the rigid aryl ring, but he accepted that the change to cyclobutyl “is part of that. It has a role in binding.” and that “part of that is also to optimise the structure in the bottom left, the R1/R2” and “you would infer that both those changes [R₁/R₂ and R] in different parts of the molecule were contributory, yes” [T2/145₃-146₁₁].

The experts were also agreed that the ‘Further in vivo studies’ were in progress to optimise the PK properties of RD162, since there is no doubt that the most promising candidate identified in the Slides is RD162. In other words, the take home lead compound from the Slides (taking into account both activity and PK data) is RD162.

Astellas also pointed out that RD162 shares the structure of RD37 with different substitutions being made to the right-hand phenyl ring (a methylamide group directly attached to the ring with an added fluorine on that phenyl ring). As with the other compound depicted in the Slides (namely, RD131), RD162 retains the cyclobutyl on the central ring, a feature of RD37.

As before, what was in dispute was what the Skilled Team would do next, having read and considered the Slides with interest.

For various reasons, the Claimants’ case of obviousness over the Slides is different (to that over the Poster). It is, of course, necessary to assess it as if the case over the Poster did not exist. So I start with a summary of the Claimants’ case on the Slides.

At the relevant date there was a motivation to find treatments for HRPC. Applying Pozzoli:

Once again, in closing, the Claimants’ case was more nuanced, and they emphasised the following points:

As before, I will first set out the context in which Prof Westwell formed his opinion that claim 1 was obvious based on the Slides.

Having considered the disclosure of the Slides, the relevant context for his views on obviousness were set out in a new section entitled ‘Obvious steps to take in light of the Slides’. In the first paragraph of that section, he set out a similar three-fold reminder to that in [9.42]. In [10.28], he identified correctly the difference between the outcome from the Slides and claim 1 and then in [10.29] he used the same wording, mutatis mutandis, as in [9.47]. His reasons followed in [10.30]-[10.33]. Not surprisingly, these focussed on the pharmacophore shown in Slide 8.

In summary, his reasons were that RD162 would be identified by the Skilled Medicinal Chemist as the most promising compound in the Slides since slide 16 showed it was the only compound identified as having antagonist activity in vitro combined with useful PK properties. He continued as follows:

‘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.’

This reasoning is closely tied to material in the Slides. His 10.31 addresses the left-hand side and gives a reason why the Skilled Team would not want to make changes there.

In 10.32 he addresses the right-hand side, making it clear that the phenyl ring must be retained but also reasons to retain (and not interfere with) the methylamide and fluorine substituents because it is those substituents which have provided the much-needed antagonist activity, particularly over the starting point of RU59063. By reference to the pharmacophore on Slide 8, Prof Westwell was effectively saying that the Skilled Team would not want to interfere with where the investigation of position X had reached.

Then he turns to consider the only other area of investigation suggested in the pharmacophore – the R1 and R2 substituents at what I call position X. The pharmacophore shows very clearly that their role is ‘Hydrophobic interactions with AR’, as he says. He makes his point about wanting to avoid introducing a chiral centre by keeping R1 and R2 the same. Then he explains why, in his opinion, having R1 and R2 as methyl groups was obvious to the Skilled Team – I need not repeat his wording (set out above) because it is clear. It also seems entirely technically sensible. Indeed (and I will be corrected if I am wrong about this), the technical reasons he gave were not challenged.

As before, Astellas’ challenge was that this was all driven by hindsight. Their principal point, as I understand it was that R1 and R2 were marked for investigation in the pharmacophore on Slide 8, by reference to RU59063 which featured the gem-dimethyl at position X. Although this is not stated in terms, they say the clear inference is that substituents at position X were investigated, and one can see the outcome – the adoption of the cyclobutyl in RD37 which is retained in RD131 and RD162.

Astellas also attempted to characterise the Claimants’ case as nothing more than saying that because the pharmacophore shows that the group at R₁ and R₂ is involved in hydrophobic interactions, then it is obvious to try any hydrophobic substitution, including the dimethyl that has just been discarded (whilst at the same time, of course, using the specific right-hand group of RD162). This struck me as an exaggeration, but the issue remains as to whether it was obvious to investigate the dimethyl at position X.

Astellas submitted that is not an obvious thing to do, relying on the following:

In conclusion, Astellas submitted the Slides represent a disclosure which changes features of the existing art and says that the changes have brought benefits. The obviousness case is that it is obvious from this to change one of them back. Accordingly, Astellas submitted there is nothing obvious about it at all.

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.

As I discussed above, 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:

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.

The Patent is entitled “Diarylhydantoin compound”. Astellas does not maintain any claims to priority and so the relevant date is the filing date of the Patent, 29 March 2006.

The invention is said (at [0001]) to relate to “a diarylhydantoin compound and methods for synthesizing them and using them in the treatment of hormone refractory prostate cancer”. As both the medicinal chemistry experts point out, in fact the claimed compound is a diarylthiohydantoin (reflecting the presence of C=S rather than C=O), although nothing turns on this.

At [0002] to [0007] the Patent provides some background to prostate cancer including its prevalence and existing treatment pathways. Bicalutamide is identified at [0004] as the most commonly used anti-androgen. Two weaknesses of current antiandrogens are identified: their weak antagonistic activity and their strong agonist activity when AR is overexpressed in HR prostate cancer. At [0008]-[0009] it is stated that there is a need for new thiohydantoin compounds and specifically selective modulators of the AR, such as modulators which are non-steroidal, non-toxic, and tissue selective.

The invention is said to be the compound RD162’. The structure of RD162’ is given at [0011] and at [0010] it is said to have strong antagonistic activity with minimal agonistic activity against AR and to inhibit growth of HR prostate cancer. A method of synthesis of RD162’ is given at [0017].

The detailed description includes an extensive section (at [0053]-[0217]) detailing the synthesis of diarylhydantoin and diarylthiohydantoin compounds. The synthesis of the claimed compound (RD162’) is described as Example 56 (at [0195]-[0201]). The closely related compounds RD162 and RD162’’ are described as Examples 52 and 57 respectively.

The pharmacological examination of the compounds begins at [0218]. A series of assays are described and some (but not all) of the RD compounds are tested in various in vitro and in vivo models.

At [0219] the compounds are said to have been subjected to tests using a human prostate cell line that had been engineered to over-express AR (LNCaP), which is described as showing features of HR prostate cancer.

The antagonist activity of a number of RD compounds was measured using the method described at [0220]. The resulting IC₅₀ values are reported in Table 1.

The agonistic activity of those compounds was measured as described at [0222] and the results reported in Table 2. An alternative assay to measure agonist activity is described at [0226]. The results are reported in Table 3, and are said to be consistent with those reported in Table 2.

The effect of some of the RD compounds on AR mitochondrial activity by MTS assay (said to be a surrogate for growth) was also described at [0228]-[0231]. The results are shown at Figs 3, 4 and 5. A second MTS study is described at [0234] in which hormone sensitive (rather than HR) LNCaP cells are used. Both RD7 and RD37 are said to inhibit the growth of these cells.

The inhibitory effect on HR prostate cancer xenograft tumours is described at [0232]-[0233] by measuring the size of human-derived tumours implanted into immunocompromised mice. RD37 is said to have strongly inhibited the growth of LNCaP-AR derived and LAPC4 derived tumours in this model. In a similar experiment described at [0235], RD162 was reported to be effective to prevent tumour growth and even to cause shrinkage.

A pharmacokinetic (PK) study on bicalutamide and three RD compounds (RD37, RD131 and RD162) is described at [0236]-[0240] and the results reported in Fig 13 and Table 4. Figures 15A and 15B also show these results. In addition to the IC50 and LogP values for RD131 and RD162, Table 4 reports the steady state plasma concentrations for bicalutamide, RD131 and RD162 in mice plasma.

The description continues (from [0241]) by ranking the synthesised compounds into six tiers. The concept of ranking into tiers was introduced at [0054] in which it was said that the compounds in Tiers 1-3, 4 and 5-6 were expected to be “superior to”, “comparable to” and “worse than” bicalutamide respectively for the treatment of prostate cancer. At [0241] it is stated that the classification of compounds to particular tiers was based on consideration of the available in vitro, in vivo and PK data previously described as well as additional data not disclosed in the Patent. It is also explained that not all compounds were tested in each assay and a degree of judgment was applied in ranking the compounds relative to each other in terms of their expected utility in treating prostate cancer.

The only data provided in the specification in respect of RD162’ is that at [0245] (in the discussion of the Tier 1 compounds) and Figure 21. The Claimants point out that:

Figure 21 is described (at [0043]) as “a graph representing PSA absorbance associated with LN-AR cells treated with various concentrations of RD162, RD162’, RD162’’, and RD170 and vehicle solution”. At [0245] it is stated that “Figure 21 shows that under treatment with RD162, RD162’, RD162", RD169, and RD170 at doses of 100, 200, 500, and 1000 nM, PSA levels of LN-AR cells decreased. Moreover, the higher the dose, the lower the PSA level.”

Notwithstanding the terminology of ‘treatment’ and ‘dose’, it would be clear to the Skilled Team (not least from [0043]) that the data in fig.21 are from a cell-based assay rather than in vivo. The experts agree that fig. 21 shows the results of two different experiments.

Fig. 21 (as supplemented by Prof Clarke) is shown below. I will briefly explain the coloured lines added by Prof Clarke in his reply report: