Bayer v Teva: Drug formulation patent found "the result of standard and routine considerations" ([2021] EWHC 2690 (Pat))

The recent decision of the English High Court in Bayer v Teva [2021] EWHC 2690 (Pat) is another example in which the UK courts have found a pharmaceutical invention to be the obvious outcome of routine drug development. In the Supreme Court decision Actavis v ICOS the court found a drug dose selection obvious in view of what was considered to be the obvious route that the skilled person would take through the drug development decision tree. The High Court in Bayer v Teva followed a similar reasoning to find the clinical formulation of Bayer's cancer drug, sorafenib, obvious in view of the preliminary phase I clinical trial results for the drug.   

In Bayer v Tevathe patent in question EP (UK) 2305255 was directed to the salt form of sorafenib and its use in the treatment of cancer. The particular claim in contention related to sorafenib tosylate salt. Sorafenib tosylate (NEXAVAR) is approved in the US and EU for the treatment of various types of cancer. The SPCs for the basic patent covering sorafenib expired earlier this year. Teva brought revocation proceedings against Bayer's sorafenib formulation patent (which had an expiry date of Dec 2022) across Europe, including the UK and Germany. 

Motivation to develop a drug in view of a clinical trial disclosure

Following Windsurfer/Pozzoli ([2007] EWCA Civ 588) the team skilled in the art in Bayer v Teva was found to include a person skilled in drug formulation: "the Skilled Formulator". The closest prior art was identified as a journal article disclosing the preliminary results of a phase I clinical trial for sorafenib (Lyons). Whilst Lyons predominantly discusses mouse models of cancer, the authors also point to some preliminary findings from a clinical trial for orally administered sorafenib ("Preliminary clinical data is encouraging, as at least 37% of patients in this initial study had stable disease lasting longer than 12 weeks"). In terms of the drug product itself, Lyons referenced the dose and chemical structure of the drug. The salt form of sorafenib used in the trial was not disclosed.  There was particularly no suggestion in Lyons that sorafenib tosylate might be the appropriate salt form of sorafenib to use. 

For the judge (Mr Justice Mellor), the question in view of Lyons was "what would the Skilled Team do next? (para. 124). Importantly, Lyons was seen by the judge as providing "a strong (but not irresistible) motivation to investigate [sorafenib] with a view to identifying a formulated drug" (para. 126). The analysis then became whether, in a standard programme of drug development, sorafenib tosylate would have been tested and selected for the clinical formulation. 

Decision tree

To arrive at sorafenib tosylate, the skilled team would have had to characterise the free base form of sorafenib. In doing so, they would have found that the free base was insoluble (and therefore not suitable for oral administration). According to the expert witness for the patentee, the skilled person would have found overcoming the very low solubility of sorafenib "to be an extremely challenging project" (para. 127). The judge, however, considered this to be an exaggeration, given that at the priority date working with new drugs with low solubilities "was neither unusual nor unexpected". 

Crucially, the judge found that the clinical trial results in Lyons would have reassured the skilled person that a sufficiently soluble formulation of sorafenib was possible, given that such a formulation must have been used in the clinical trial. The skilled person, the judge reasoned, would therefore have been motivated to carry out a salt screen in order to find a soluble salt form of sorafenib. The critical question then became whether the skilled person would have included the counterion tosylate in such a screen. 

Hindsight works both ways

The judgement contains a detailed comparison of the evidence from the opposing expert witnesses on the question of whether the Skilled Formulator would have tested tosylate in the salt screen for sorafenib or not. The judge was not convinced by the patentee's expert witness's evidence that tosylate would not have been included. Whilst there were reasons from the common general knowledge not to have included tosylate, the judge was not convinced that these would have been enough of a red flag for the skilled person to have left tosylate out of the screen:

It is far more likely that they would have said to themselves 'we cannot make any firm theoretical predictions, so let's get on and make a selection of salts and test them'

In a reversal of the usual objection that hindsight has been used to find an invention obvious, the judge found the expert to be using hindsight in their argument that the invention was not obvious. The question thus became not whether the invention had been "obvious to try", but whether there were sufficient reasons for the invention not to have been tried (equivalent to the EPO "could versus would" approach, see EPO Guidelines for Examination, G-VII-5.3). 

Interestingly, the online database DrugBank predicts the solubility of the tosylate salt of sorafenib to be less than that of the free base. The expert witness for the patentee further pointed out that the actual solubility of sorafenib tosylate, as provided in the EMA regulatory documents for sorafenib tosylate, was even lower. A skilled person, it argued, would thus have had a very low expectation of success in formulating such a low solubility salt for oral administration.  

Crucially, however, the claim in question was construed to relate to the salt form per se, and not to its use for oral administrationThe judge therefore did not fully consider whether, having tested sorafenib tosylate, a skilled person would have selected it for use for oral administration. The judge also pointed out that the skilled person would not have been aware of the real solubility of sorafenib tosylate until the salt form had in fact been made and tested. As such, the judge argued, the evidence from the EMA regulatory documents necessarily involved hindsight. 

The judge further highlighted what he felt to be a particularly revealing exchange, in which the expert witness for the patentee admitted that the skilled formulator would not have been ‘fired or criticised’ for testing tosylate. But does the question itself reveal a certain use of hindsight? Perhaps a better form of the question would have been: Would have been fired or criticised if tosylate was found not to work? In reality, the question is more whether a skilled formulator, with limited resources and multiple options, could have convinced themselves and others that sorafenib tosylate was worth testing. 

Following a detailed comparison expert witness testimony, the judge concluded:

[i]f one compared a number or real skilled teams side by side....they would select different ranges or salts to test in a first or second tier [...] Some teams who found unpromising results in the first and second tier screen would continue past a second tier screen, others might not. I bear in mind that some real teams might never have selected the tosylate salt for inclusion (depending on their particular experience), but I am satisfied that most would. Above all, the inclusion of the tosylate salt would have been the result of standard and routine considerations. 

The claim to sorafenib tosylate was therefore found obvious in view of the prior art of the clinical trial disclosure. 

Final thoughts

The judge's reasoning in Bayer v Teva resembles the approach taken by the UK Supreme Court in Actavis v ICOS. In both cases, arriving at the invention required a multiple step drug development program, with a number of crucial decision points based on newly acquired data. In Actavis v ICOS the skilled person was found to have not only to have motivation to carry out dose-finding studies, but to interpret and take account of the surprising evidence that they would have found in such a study, in order to direct further dose-finding studies. Similarly, in Bayer v Teva, the selection of sorafenib tosylate would have required a whole development program, potentially with multiple tiers of salt screens. 

In cases such as Bayer v Teva it might be said that the patentee will always be on the back foot, however much effort is taken to avoid hindsight. The patent itself will always be evidence in the back of everyone's mind that the invention was tried. In this regard, innovators may at least take comfort in the guidance provided in Actavis v ICOS, in which Lord Hodge provided a non-exhaustive list of nine relevant factors to be considered in an analysis of inventive step. This list included not only whether the claimed invention was "obvious to try" or "routine", but also the burden and the cost of the research program and the existence of alternative or multiple paths of research. 

Bayer has been similarly unsuccessful in maintaining the German equivalent of the UK patent. It remains to be seen whether Bayer will seek appeal to the Court of Appeal in the UK. 

Bayer v Teva: Drug formulation patent found "the result of standard and routine considerations" ([2021] EWHC 2690 (Pat)) Bayer v Teva: Drug formulation patent found "the result of standard and routine considerations" ([2021] EWHC 2690 (Pat)) Reviewed by Rose Hughes on Sunday, November 28, 2021 Rating: 5

1 comment:

  1. The problem with this decision is that almost all research methodology is routine, it is the results of such routine research that are often surprising. So this case seems to be saying that if I run routine screens and discover that a tested compound cures all cancers, that discovery is not patentable because it is the result of routine research. Patents are intended to encourage research and that includes routine research that leads to unexpected results of value to the public at large.

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