Biopharmaceutical company Akebia Therapeutics and healthcare company Otsuka Pharmaceutical brought an action before the UK High Court to revoke six European patents (UK) owned by FibroGen. The patents related to inhibitors of the enzyme hypoxia inducible factor-prolyl hydroxylase (HIF-PHIs) for treating anaemia and related disorders. Akebia and Otsuka are in partnership to develop and commercialise the small molecule vadadustat, a HIF-PHI that is in phase III clinical development for the treatment of anaemia associated with chronic kidney disease (CKD). The companies sought revocation of the patents in order to market vadadustat in the UK.
Pharmaceutical company Astellas Pharma and biopharmaceutical company FibroGen are also in partnership to develop and market roxadustat, a different small molecule HIF-PHI for treating similar therapeutic applications to vadadustat, in the U.S., Europe, Japan and China. Astellas (as the exclusive licensee of the six FibroGen patents) brought a cross-claim against Akebia and Otsuka for threatened infringement of the patents for intending to market vadadustat in the UK.
Arnold LJ referred to Akebia and Otsuka collectively as “the Defendants” and to FibroGen and Astellas collectively as “the Claimants”. The patents were grouped into two families of three patents, each family deriving from a common international (PCT) application, designated “Family A” and “Family B” as shown below.
Determine whether the disclosure of the patent, read in the light of the common general knowledge of the skilled team, makes it plausible that the invention will work across the scope of the claim.
If the disclosure does make it plausible, does the evidence establish that the invention cannot be performed across the scope of the claim without undue burden?
For the first step, Arnold LJ considered it would not have been plausible to the skilled person that the invention worked across the scope of the claims. A key determinant was the claims were predicted to cover 10183 different compounds, whereas the specification only demonstrated that five compounds (Compounds C, E, F, J and K) had the claimed therapeutic effect . There was also a lack of disclosure of a structure-function relationship in the patents that would have otherwise enabled a prediction that substantially all the claimed compounds had the therapeutic effect. The Claimants counter-argued the claims only covered compounds which had the therapeutic effect by reference to the functional language of the claim (and therefore not all 10183 compounds), but this argument was rejected by Arnold LJ, who explained that the language of the claims implied substantially all the compounds falling under the structural definition of the claims had the therapeutic effect3.
Arnold LJ also evaluated the second step of the test recited above in case it was later found he had erred on the first step. Arnold LJ considered that, even though the skilled medicinal chemist would be successful in identifying some of the compounds of Formula I that had the claimed therapeutic effect, it would constitute a “substantial undertaking” to identify all of the claimed compounds, which would represent an undue burden for the skilled person [394, 399]. The claims of EP 823 and EP 301 were therefore held to lack sufficiency by virtue of Biogen insufficiency.
Furthermore, the claims of EP 823 and EP 301 were also found to lack inventive step by virtue of AgrEvo-type obviousness4 for the same reason that the claims were found to lack plausibility in the assessment of sufficiency.
Sufficiency of Family B Patents
All the claims in issue of the Family B Patents, with the exception of claim 36A (formerly claim 27) of EP 333, were held to be invalid by virtue of a lack of sufficiency (and lack inventive step by virtue of AgrEvo-type obviousness) for the same reasons as the Family A Patents (see above).
In view of the above, all the claims in issue of EP 823 and EP 301 (Family A) and those of Family B were held to be invalid. Claim 17A of EP 531 (Family A) was the only claim in issue that was held to be valid and therefore became relevant for the determination of infringement.
Infringement of Family A claims by vadadustat
There was no dispute that claims 8A and 24A of EP 823 and claim 4 of EP 301 were infringed by vadadustat had they been valid, which was not surprising given their broad scope. Arnold LJ also held that vadadustat infringed claim 19A of EP 823 and claim 2 of EP 301, which contained Formula I [261-288].
As shown above, claim 17A of EP 531 is directed to:
A compound for use in the treatment or prevention of anemia associated with kidney disease, wherein the compound is Compound C.
The claimants argued that, even though claim 17A of EP 531 was not infringed by vadadustat under normal interpretation (since vadadustat is not covered by Compound C in the literal sense) the claim was still infringed by virtue of the doctrine of equivalents. As expected, Arnold LJ set out the reformulated Improver questions from Actavis v Eli Lilly5:
Notwithstanding that it is not within the literal meaning of the relevant claim(s) of the patent, does the variant achieve substantially the same result in substantially the same way as the invention, i.e. the inventive concept revealed by the patent?
Would it be obvious to the person skilled in the art, reading the patent at the priority date, but knowing that the variant achieves substantially the same result as the invention, that it does so in substantially the same way as the invention?
Would such a reader of the patent have concluded that the patentee nonetheless intended that strict compliance with the literal meaning of the relevant claim(s) of the patent was an essential requirement of the invention?
Importantly, question (i) above was evaluated by interpreting the inventive concept from the patent and then deciding whether the alleged infringement (the variant) achieves substantially the same result in substantially the same way as the invention as a matter of fact. Arnold LJ indicated that the burden of proof for establishing the latter part lies with the patentee . It was established that the inventive concept was the use of Compound C for treating renal anaemia associated with kidney disease but not the use of any compound for treating renal anaemia by inhibiting HIF-PH, as argued by the Claimants.
For question (i) above, Arnold LJ considered Compound C “has quite a different structure” to that of vadadustat and therefore the binding and specificity properties of the compounds would be expected to be quite different. It was therefore held that the answer to question (i) above was “no”. As a result, vadadustat did not infringe claim 17A of EP 531. However, Arnold JL went on to consider questions (ii) and (iii) on the basis that the answer to question (i) was later found to be “yes”. At , Arnold LJ explains there would rarely be a scenario where the answer to question (ii) is “no” if the answer to the question (i) is “yes”. Unsurprisingly, the answer to question (ii) above in this scenario was therefore also “yes”.
Lastly, Arnold LJ went on to evaluate the answer to question (iii) above (in the scenario that the answers to the first two questions were “yes”). In a comprehensive assessment, it was decided the answer to the last question was also “yes” [447-460]. There were various factors that led to this conclusion but one of the main reasons appeared to be that, although there was a number of different compounds disclosed in the patent, “a technical choice had been made” in deciding to limit the claims to Compound C. Arnold LJ also considered that a claim limited to Compound C should not encompass compounds that had previously been disclaimed from the application (by analogy to the jurisprudence of the German Federal Court of Justice6 ). It was also considered unjust by Arnold LJ for the extent of protection to cover compounds that would have been considered to lack sufficiency had the claim explicitly covered such compounds. Interestingly, Arnold LJ also considered the prosecution history by reference to paragraph  of the decision in Actavis v Eli Lilly. He held that, in this case, it would be contrary to public interest to ignore the prosecution history when the patentee had accepted a claim limitation to overcome a novelty objection during prosecution (resulting in vadadustat falling outside the claim scope in the literal sense) only to argue that the claim covered the compound falling within the original scope by virtue of the doctrine of equivalents.
Accordingly, all the Family A claims in issue other than claim 17A of EP 531 were found to be infringed by vadadustat had they been valid.
Infringement of Family B patents by vadadustat
The infringement case brought by the Claimants for the Family B patents was more complex than for Family A because the medical uses of the Family B claims were distinct from the medical uses the Defendants intended to market vadadustat for in the UK. Nevertheless, the Claimants argued the Summary of Product Characteristics (“SmPC”) for vadadustat evidenced that the drug would be used off-label for the medical uses covered by the Family B patents. The infringement action was therefore brought on the basis the Defendants were threatening to market vadadustat in circumstances where they knew, or it would have been obvious to a reasonable person in the circumstances, that vadadustat was suitable for putting and intended to put the claimed invention into effect in the UK (i.e. indirect infringement pursuant to section 60(2) Patents Act 1977). Since the Claimants did not bring an action for direct infringement of the Family B claims, Arnold LJ avoided a potentially complex assessment of “the mental element” required for infringement of medical use claims based on Generics (UK) Ltd v Warner-Lambert Co LLC  UKSC 56,  Bus LR 360.
In deciding on indirect infringement, Arnold LJ evaluated the viewpoint of the Defendants intending to market vadadustat and the intention of the downstream clinician who would prescribe the drug. Arnold LJ also reviewed the disclosure of the SmPC and clinical practice at the time for prescribing medicines for the uses claimed in the Family B patents, and decided that there was insufficient evidence to suggest that clinicians would prescribe vadadustat off-label. It was therefore held that there was no threat by the Defendants to infringe the Family B Patents. A key determinant of the decision appeared to be that there was no evidence to suggest vadadustat had any advantage over present medicines for the claimed medical uses, which meant it would be unlikely a clinician would change their prescribing practice.
Finally, Arnold LJ held that claim 36A of EP 333 (the only claim in Family B found to meet the requirement of sufficiency) was not infringed by vadadustat on the basis of the doctoring of equivalents, for similar reasons to claim 17A of EP 531 (see above).
Accordingly, all the Family B claims in issue were found not to be infringed by vadadustat had they been valid.
In what is likely to be the last patent court trial held in person this year, this landmark 640-paragraph judgment delivered by one the UK’s most renowned IP judges did not disappoint, contemplating a range of important and complex patent law issues and Nobel Prize-winning technology.
There are several important lessons to be learnt from this judgment in relation to protecting broad chemical formulae when the therapeutic effect of the compounds covered by the chemical formulae is explicitly included in the claims. Firstly, caution must be taken when drafting broad claims that cover a large number of compounds and only a relatively small fraction of these are demonstrated in the patent application to possess the claimed therapeutic effect. The patentee must make sure compounds falling within the structural definition of the claims possess the claimed functional features (or there is at least evidence the effect is plausible across the scope of the claims), otherwise the claims risk being invalidated by virtue of a lack of inventive step (AgrEvo-type obviousness) and/or sufficiency (Biogen insufficiency). As the Claimants discovered, explicitly including a functional feature in a claim is not a substitute for removing compounds falling under the structural definition of the claim that do not possess the functional feature, since there is a risk the court will construe the claim to imply that all compounds possess the functional feature (and therefore the claim may be considered to lack sufficiency). Interestingly, this approach is different to that typically taken by the EPO, where the inclusion of such a feature during prosecution would generally be considered to exclude non-working embodiments from the claim.
Secondly, when contemplating potential infringers, it is important to know exactly where the technical part of the invention lies, which highlights the balance between a fair scope of protection for the patentee and the extent of disclosure of a technology to the public. Overly broad claims will encompass compounds that do not possess the technical feature(s) and overly narrow claims (such as those limited to the specific examples) will not capture competitor compounds that possess the technical feature(s) of the invention but fall outside the scope of the claims under normal interpretation (i.e. “variants”). As we have seen from this case, it is not enough to rely on the doctrine of equivalents to catch infringers, especially when the scope of the claims has been narrowed during prosecution such that the variant no longer infringes. Knowing exactly where the technical part of the invention lies can often be difficult due to the lack of data available during prosecution, and there is usually not enough time to fully characterise the invention before the application is filed. However, a detailed disclosure of the invention in the application is key to meeting the requirement of the first Improver question, since it concerns the inventive concept of the patent. In the present case, Arnold LJ may have reached a different conclusion to the first Improver question had the patent disclosed experimental evidence showing that Compound C and vadadustat worked in substantially the same way (or at least a structure-function relationship that allowed such a prediction).
Thirdly, timing is key. The Claimants decided to bring the infringement action before the Defendants had even started marketing Vadadustat in the UK and so the court was forced to consider threatened indirect infringement, which meant making predictions on how the drug would be prescribed. There may have been a different outcome had the Claimants waited until vadadustat had been marketed in the UK and there was evidence that vadadustat was being prescribed off-label for the claimed medical use (or at least stronger evidence it was known from a clinical perspective the drug had advantages compares to existing medications, making it likely that it would be used for the claimed medical use). However, it is likely the Claimants acted early in order to prevent vadadustat from an initial launch in the UK.
Although FibroGen and Astellas will no doubt be disappointed by the outcome of the decision, there will still be an opportunity to bring a further infringement action against Akebia and Otsuka if circumstances change in the future. At the time of writing, there does not appear to be evidence of the decision being appealed. In the meantime, the validity of all six patents are currently under threat from pending opposition/appeal proceedings before the European Patent Office. It will be interesting to see whether the patents survive the same invalidity attacks as the present case.
If you would like to have a word with Oliver, Tom or Kristina about this article or matters related to the subject of this article, don’t hesitate to get in touch.
This is a shortened version of the original article. The original article has been submitted for publication in EIPR
1Akebia Therapeutics Inc v Fibrogen, Inc  EWHC 866 (Pat) (20 April 2020).
2Biogen Inc v Medeva plc  RPC 1.
3Citing Idenix Pharmaceuticals Inc v Gilead Sciences Inc  EWCA Civ 1089.
4Idenix Pharmaceuticals Inc v Gilead Sciences Inc  EWCA Civ 1089.
5Actavis UK Ltd v Eli Lilly and Co  UKSC 48,  Bus LR 1731.
6BGH Case X ZR 16/09 - Okklusionsvorrichtung (Occlusion Device)