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16 May 2022

Patently Obvious? The English High Court Considers Drug Development Practices in Teva v Bayer

On 8 October 2021, Mr. Justice Mellor handed down his judgment in (1) Teva Pharmaceutical Industries Limited (2) Teva UK Limited v Bayer Healthcare LLC [2021] EWHC 2690 (Pat). The decision follows existing case law to find that the chemical formulation of a drug developed by Bayer (a salt form of sorafenib, sorafenib tosylate, used in the treatment of cancer) was the obvious outcome that would result from the routine drug development by the hypothetical Skilled Team (comprising individuals skilled in the art). This follows the previous Supreme Court decision in Actavis v ICOS¹, in which the Court arrived at a similar conclusion.

While there were other claims for the use of sorafenib tosylate salt orally, or the use for the treatment of cancer, claim 12 of the patent in suit, EP (UK) 2305255 (Patent), was for the chemical formulation for the sorafenib tosylate salt per se.

Obvious actions for the Skilled Team

Would the Skilled Team attempt to formulate a soluble form of sorafenib?

In Teva v Bayer, the closest prior art was an article about sorafenib in the journal Endocrine-Related Cancer, entitled “Discovery of a novel Raf kinase inhibitor”, written by authors from Onyx, Bayer, and Chiron. The judgment refers to this article as “Lyons” (after one of the principal authors); Lyons was published prior to the priority date of the Patent.

Lyons disclosed the preliminary results of phase I clinical trials for sorafenib. Lyons referenced the dosage and chemical structure of the drug (and that it had been successful for oral administration in humans), but did not disclose that sorafenib tosylate salt was the salt form of sorafenib that was used. Indeed, Lyons did not mention which salt form of sorafenib had been used in the trials.

In para. 126, Mellor J. found that: “Lyons provided the Skilled Team with a strong (but not irresistible) motivation to investigate this chemical entity with a view to identifying a formulated drug, preferably for oral administration to humans. The point is that from the starting point of Lyons, the Skilled Team (and the Skilled Formulator in particular) had their CGK routine tests, considerations and analysis to work with.”

Consistent with the tests set out in Windsurfing² and Pozzoli³, the Skilled Team was held to include a person skilled in drug formulation (the Skilled Formulator). Accordingly, the crucial question to be answered was: In the standard course of drug development, would the Skilled Team have tested and selected sorafenib tosylate for clinical formulation? If so, then sorafenib tosylate per se would be obvious.

Given that Lyons disclosed to the Skilled Formulator that a sufficiently soluble formulation of sorafenib was possible, the judge was not persuaded by the defendant’s expert’s suggestion that the Skilled Team would have found overcoming the low solubility level of sorafenib to be “an extremely challenging project” (para. 127) and that this would have meant that seeking to identify a suitably soluble sorafenib salt would not have been obvious. The Skilled Team would know that a soluble salt form of sorafenib must exist, because an orally administered tablet was used in the clinical trials described in Lyons. The Skilled Formulator, Mellor J. concluded, would therefore have been motivated to carry out a salt screen to identify and find that suitably soluble form.

Would the Skilled Team have used the tosylate salt in its salt screen?

This is the question at the heart of this case (as confirmed by the judge at para. 129). Mellor J. paid close attention to each party’s expert, and quoted each at length in his judgment; he eventually concluded that it was likely that the Skilled Team would have tested tosylate as part of its salt screen. While the prior art would have raised some concerns over the use of the tosylate, the judge found that this alone was not a sufficient reason for the Skilled Team not to have tested such. He said that:
“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” (para. 165).

As mentioned above, the patent claim in question was for sorafenib tosylate per se. Therefore, if the hypothetical Skilled Team knew that a soluble form of sorafenib existed, and they would have included tosylate in their salt screen to find such, then the sorafenib tosylate was obvious.

The judge made it clear that it is not certain that a Skilled Team might not choose to include tosylate in its salt screen, but it is likely that most Skilled Teams would have done so:

“I am quite sure if one compared a number of real skilled teams side by side, having read Lyons and faced with sorafenib, they would select different ranges of salts to test in a first or second tier, albeit with considerable overlap. 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. For all the reasons set out above, I find claim 12 of the Patent invalid for obviousness. Teva’s claim succeeds.”

Hindsight is a wonderful thing

The judge was very insistent that illegitimate hindsight should not be a factor in this analysis:

“I remind myself however that the Skilled Team, when selecting the salts to include in their salt screen, would not have focussed on tosylate in particular, either to include it or to exclude it, and such focus carries a very distinct risk of introducing illegitimate hindsight into the analysis.” (para. 100).

In this case, each side accused the other of relying on hindsight – either looking for reasons that the Skilled Team would have included tosylate in the salt screen or looking for reasons that it would have been excluded. Taking into account the evidence of both experts, the judge found that, even without hindsight, to the Skilled Team reading Lyons, the Patent claim was obvious and thus invalid.

Be careful what you publish

It might be said that Bayer’s difficulties in the matter were of its own making, having published Lyons; had the paper not been published ahead of the priority date of the Patent, then the evidence relied upon at trial would not have been sufficient information for the hypothetical Skilled Team to seek out the sorafenib tosylate, and the obviousness arguments would have failed.

Obviousness is in the details

The Supreme Court in Actavis⁴ set out a list of factors as to whether certain steps (such as the testing of sorafenib tosylate in Teva v Bayer) were obvious. These include:

  1. Whether something was “obvious to try”;
  2. Whether the research was routine in nature;
  3. The burden and cost of the research programme;
  4. The necessity for and the nature of value judgments during a research programme;
  5. The existence of alternative or multiple paths of research;
  6. The motivation of the Skilled Person to undertake certain tasks;
  7. Whether the results of the research were unexpected or surprising;
  8. The need to avoid hindsight;
  9. Whether the feature of the claimed invention is an added benefit in the context in which the claimed invention is obvious for another purpose; and
  10. The fact that there is no blanket prohibition on dosage regime patents, but that there has been relaxation in the rules in relation to the assessment of the inventive step of these patents.

The Court was faced with an assertion by Bayer that Teva sought to place outsized reliance on the decision of Birss J. (as he then was) in Hospira v Genetech⁵ as a means to avoid strict adherence to the Actavis analysis. Mellor J. concluded that the approaches in those cases were not at odds with one another, as the obviousness analysis should not be applied in a mechanical way, but rather that each case should be treated in accordance with the facts at hand, taking into account, inter alia, the factors set out above.

Authored by Robert Peake