November 22, 2021
FibroGen Inc owns six EP (UK) patents that it licenses exclusively to Astellas Pharma Inc, all relating to the use of medicines known as HIF-PH inhibitors for the treatment of anaemia. There are two kinds of anaemia, CKD (Chronic Kidney Disease) anaemia and ACD (Anaemia of Chronic Disease). The patents form two families of three patents each. Broadly speaking, the claims of the Family A patents all relate to a class of compounds defined in structural and functional terms for use in the treatment of CKD, while the claims of the Family B patents relate to the same compounds, but for the treatment of ACD.
Akebia Therapeutics Inc has a rival HIF-PH inhibitor called vadadustat, which is in clinical trials for anaemia.
Akebia issued proceedings against FibroGen for revocation of the patents on the grounds of lack of inventive step (obvious over the prior art) and insufficiency. The insufficiency claim contended that all the claims of both Family A and Family B patents were invalid on the grounds of excessive claim breadth due to a lack of plausibility and to undue burden. Astellas, as exclusive licensee, then brought a claim for quia timet infringement against Akebia, contending that the launch of vadadustat would infringe the Family B patents.
At first instance, Lord Justice Arnold, sitting as a judge of the High Court, held that the Family A patents were not obvious over the prior art but that all the relevant claims of Family A lacked plausibility and could not be performed across their scope without undue burden. He found that they were therefore invalid for insufficiency. On infringement, Arnold LJ found that vadadustat was within the relevant chemical definition (Formula I). Therefore, the Family A claims would be infringed on a normal construction if they were valid. Arnold LJ also found the relevant claims of the Family B patents insufficient for the same reasons as Family A, and that the Family B patents were obvious over the prior art. Finally, on quia timet infringement, there was no current threat to infringe the Family B patents even if they were valid.
On appeal FibroGen challenged the conclusions on insufficiency in relation to both patent families. FibroGen also appealed the conclusion that Family B was obvious over the prior art, arguing that the conclusion was inconsistent with the findings made while rejecting the quia timet infringement case. Akebia challenged the conclusion that vadadustat was within Formula I.
Taking two claims in the Family A patents as examples, broadly speaking, Birss LJ found that they consisted of structural features grouped into classes of compounds, which were infinitely large as they could include any compound that had the right kind of heterocyclic carboxamide in it and could have any other sort of chemical structure attached to it. There then followed two functional limitations, which were that the compound must inhibit HIF-PH, and increase endogenous erythropoietin, followed by a claim where the disease to be treated (i.e., CKD anaemia) was defined. Both claims were identical up until this point. An important feature of one of the claims was the inclusion of an extra final feature, which was a further structural limitation by means of a chemical formula called Formula I.
A critical question in the case was which compounds were within the claim? Was the patent directed to each and every heterocyclic carboxamide of the claimed structure and then, by the functional feature, asserting that they would be inhibitors of HIF-PH? Or was the patent only claiming those heterocyclic carboxamides of the structural features that were themselves inhibitors of HIF-PH?
Giving the lead judgment, Lord Justice Birss noted that under the Patents Act 1977, to be valid the patent specification must disclose the invention “clearly enough and completely enough for it to be performed by a person skilled in the art”.
Arnold LJ had approached the question of insufficiency using a two-stage test: (i) plausibility; and (ii) undue burden.
On plausibility, Arnold LJ had found that the patent implicitly promised that, substantially, all compounds that satisfied just the structural definitions in the claims would have the therapeutic efficacy. However, that was not plausible, i.e., the skilled person would have no reason to make a reasonable prediction that substantially all the compounds in the structural features of the claim would be effective in treating anaemia. Therefore, Arnold LJ had concluded that the claims were insufficient for want of plausibility.
On undue burden, Arnold LJ had found that it would require a substantial research project to identify any compounds other than those specifically identified in the specification, which met the criteria for efficacy, and success would not be guaranteed. The skilled medicinal chemist would be able to identify some compounds falling within the structural features that were effective, but they would not be able, “even in many lifetimes of sustained effort”, to make and test more than a tiny fraction of such compounds.
Birss LJ noted that in Regeneron v Genentech  EWCA Civ 93, Kitchin LJ had referred to the concept of “reasonable prediction” when considering plausibility, finding that it must be possible to make a reasonable prediction that the invention will work with substantially everything falling within the scope of the claim. In other words, the assertion that the invention will work across the whole scope of the claim must be plausible or credible.
As for undue burden, Kitchin LJ had said that where a claim is limited by function, it must still be possible to perform the invention across the whole scope of the claim without undue effort. This is a question of degree and depends upon all the circumstances including the nature of the invention and the art in which it is made.
Birss LJ said that to apply the reasonable prediction principle involved taking three steps: (i) identify what it is that falls within the scope of the claimed class; (ii) determine what it means to say that the invention works, i.e., what it is for; and (iii) consider whether it is possible to make a reasonable prediction the invention will work with substantially everything falling within the scope of the claim.
In terms of functional and structural limitations in claims, Birss LJ said that the structural limitation defines the class and is considered at the first step and the functional limitation defines the therapeutic effect and is addressed at the second step. The functional features can be tested by appropriate assays or animal models. The significance of the existence of inactive compounds within the formula will be a matter of fact and degree, but the fact that they might exist does not matter if it does not falsify the reasonableness of the prediction. Similarly, the fact that active compounds within the formula turn out to be unsuitable for reasons unrelated to efficacy itself, such as side effects profiles, is also unlikely to falsify the reasonableness of the prediction, depending again on this being a matter of degree. These issues also play a role in analysis of any undue burden.
On undue burden in claims that combine functional and structural features, as in these patents, Arnold LJ had concluded that the skilled person does not need to identify all compounds covered by the claim without undue burden, but that he/she must be able to identify “substantially all” compounds covered by the claim without undue burden. Birss LJ said that this test was wrong, since the claim could cover compounds that had not yet been invented. It was not necessary, simply because a claim contained functional features (or a mix of functional and structural features), to establish that the skilled person could identify all, or substantially all, the compounds which satisfied the test. It was sufficient for the skilled person, without undue burden, to identify some compounds beyond those named in the patent that are within the claimed class and therefore likely to have therapeutic efficacy.
Applying the three-stage test on reasonable prediction set out above, Birss LJ found that the compounds that fell within the scope of the claim, were those that satisfied both the structural features and the functional features. As for what it meant to say that the invention worked, it was to achieve the therapeutic effect and treat CKD anaemia. It was not relevant or necessary to ask whether it was plausible that compounds that had the structural features written in the claim would also satisfy the functional aspects. The question was whether it was possible to make a reasonable prediction that compounds that satisfied both the structural features and the functional features, would be useful to treat CKD anaemia. The answer was clear that this was indeed plausible. This was the essence of the invention as disclosed in the specification. The patent claimed that compounds that satisfied both the structural definitions and the step one functional features were the ones that would have the claimed therapeutic activity. The patent did not, as Arnold LJ had read it, implicitly promise that substantially all the compounds that satisfied the structural definitions would have the claimed therapeutic efficacy.
As for undue burden, Arnold LJ had in fact found that, although it would be a great deal of work, the skilled team would be able to find some compounds that were effective. He had not expressly stated that that result would be reached without undue burden, but in Birss LJ’s view, that was the “only answer”. It would take a great deal of work, but it would be routine for the medicinal chemist and iterative in nature.
As for uncertainty, Birss LJ agreed with FibroGen that, following Anan Kasei v Neo Chemicals  EWCA Civ 1646, there is a distinction to be drawn between a claim that is difficult to construe or has some room for doubt or fuzziness at the edge and one that is conceptually uncertain. The fact that reasonable experts might disagree about exactly where the boundary would lie between something which is and something which is not an inhibitor meant that there was a “fuzzy” boundary to the claim. The remedy for that would be that the patentee could not satisfy the court of infringement. However, to find the claim invalid in those circumstances would be a disproportionate response, which in Birss LJ’s view, the law did not require.
Obviousness and infringement
Birss LJ could see no error of principle, nor any finding of fact not open to the court on the evidence as it was. Therefore, he rejected the appeal on obviousness.
Birss LJ also rejected Akebia’s appeal that Arnold LJ had erred when construing the claim and that he had been wrong to find that vadadustat fell within Formula I on a normal construction. Analysing the medicinal chemistry, Birss LJ found that Arnold LJ’s reasoning could not be faulted.
Birss LJ allowed the appeal on the sufficiency of the Family A patents (both breadth of claim and uncertainty). Therefore, the patents were valid and would be infringed by vadadustat used to treat CKD anaemia.
Birss LJ dismissed the appeal on obviousness of the Family B patents. Therefore, even though the conclusion on sufficiency applied to those patents as well, they remained invalid for obviousness.
Finally, Birss LJ dismissed Akebia’s appeal seeking to overturn the finding below that vadadustat was a compound within Formula I. (FibroGen Inc v Akebia Therapeutics Inc  EWCA Civ 1279 (24 August 2021) — to read the judgment in full, click here).