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

The Poster

The Poster is a poster by Samedy Ouk and others entitled “Development of Androgen Receptor Inhibitors for Hormone-refractory Prostate Cancer” presented at the Prostate Cancer Foundation Scientific Retreat at Scottsdale, Arizona on 29 September to 1 October 2005 (“the Retreat”). The Poster (also referred to in the evidence as “Ouk”) is shown below.

The judge set out what the Poster would disclose to the skilled team at [147]-[176]. This may be summarised as follows.

Under the heading is a yellow box 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. In the central blue box, it is explained that “Exploiting the existing knowledge such as crystal structure, binding affinity and homology modelling led to a rational design of non-steroidal compounds as potent antagonists for both HS [i.e. hormone-sensitive] and HR [i.e. hormone-refractory] prostate cancer”.

The Poster depicts a step-wise process of development undertaken by the authors. Starting from the two prior compounds shown in the white box in the middle, nilutamide (a well-known antiandrogen used at the time in the treatment of prostate cancer) and RU59063, they engaged in “Rational drug design & synthetic chemistry” to make the compound RD2 shown at the top. They then proceeded as shown schematically by the arrows. There were two stages in the process. First, “SAR studies” were undertaken. The most potent compound in these studies was RD37. Secondly, “PK-DM [i.e. pharmacokinetics-drug metabolism] optimisation” was performed to arrive at RD162. The medicinal 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.

SAR studies

The 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 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 to make a ring.

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

First, the authors have further expanded the size of the bottom ring (at position X) to a cyclopentyl. The medicinal chemist would understand the authors had made these modifications in RD37 and RD54 to investigate the impact of different sized groups in the binding pocket.  It is apparent that the dimethyl, cyclobutyl and cyclopentyl groups at this position are all consistent with antagonist activity.

Secondly, the methyl group on the phenyl ring (on the right) has been replaced by a cyano group (CN).

PK-DM optimisation

This features three 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. The medicinal chemist would appreciate that 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 medicinal chemist would consider this had likely been done to improve metabolic stability compared to RD161 (although the PK data for RD161 are not shown), since they would know that the phenyl ring might be susceptible to oxidation, a precursor to elimination of the drug metabolite and a measure of instability. Adding a fluorine was a common approach to preventing metabolic oxidation.

The cell-based data

The chart at the top right shows data from an antagonist assay on HS prostate cancer, and the chart at the bottom shows data from an antagonist assay on HR prostate cancer. These would both be understood to be cell-based assays, which are measuring relative PSA 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 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).

The in vivo data

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. It would be understood that the experiment probably 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. RD37 (pale blue line) appears to perform better than RD7 (yellow line), but there is nothing to indicate whether this difference is statistically significant.

The PK data

The chart in 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 (reproduced above) compares the IC₅₀, LogP and C_ss (steady-state concentration) of RD37, RD131 and RD162. The following is common ground:

Compared to bicalutamide, all three RD compounds are more potent antagonists (shown by their lower IC₅₀ values).

The IC₅₀ values for the three RD compounds are approximately the same.

Of the three RD compounds, RD37 is the most lipophilic (highest LogP), whilst RD162 is the least lipophilic (lowest LogP). Of the three RD compounds, the LogP value of RD162 is the most credible for a drug candidate. 

RD162 has a significantly better steady-state concentration than RD37 and RD131 and is comparable to bicalutamide, which is consistent with the data in the PK chart.