Patents - Akebia Therapeutics Inc v Fibrogen, Inc,
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Vadadustatt Structure
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Jane Lambert
Patents Court (Lord Justice Arnold) Akebia Therapeutics Inc v Fibrogen, Inc [2020] EWHC 866 (Pat) (20 April 2020)
This was a claim by Akebia Therapeutics Inc.(“Akebia”) and Otsuka Pharmaceutical Co. Ltd. (“Otsuka”) to revoke 6 patents held by FibroGen Inc. ("FibroGen"). The reason why they sought the revocation of those patents is that they wished to market their own product vadadustat. FibroGen's exclusive licensee, Astellas Pharma Inc (“Astellas”) brought quia timet infringement proceedings against Akebia, Otsuka and FibroGen. The proceedings came on before Lord Justice Arnold between 2 and 19 March 2020. His lordship delivered judgment on 20 April 2020.
The Patents
The patents in suit were as follows:
The Causes of Action
Akebia and Otsuka contended that the patents in Family A were obvious over an article by A.C.R. Epstein and others entitled, C. elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases that Regulate HIF by Prolyl Hydroxylation, Cell, 107, 43–54 (5 October 2001) (“Epstein”) and that the patents in Family B were obvious over Family A. They also argued that all the patents were bad for insufficiency. Astellas claimed that Akebia and Otsuka threatened and intended to infringe their patents. FibroGen also applied to amend its patents, some conditionally and others unconditionally.
The Family A Patents
The Inventions
At paragraph [110] of his judgment, Lord Justice Arnold said that WO997 relates to methods for increasing endogenous erythropoietin, ex vivo and in vivo, and to compounds that can be used in those methods.
i) EP 823: relates to medicaments for increasing endogenous erythropoietin in the prevention, pretreatment or treatment of anaemia, and to compounds that can be used in the methods;
ii) EP 531: relates to compounds for use in the treatment or prevention of anaemia; and
iii) EP 301: relates to compounds for use in the treatment or prevention of anaemia associated with kidney disease.
Erythropoietin is a glycoprotein cytokine secreted mainly by the kidney in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. The adjective "endogenous" in this context means produced internally (that is to say, by the body) as opposed to introduced externally.
Obviousness
S.72 (1) (a) of the Patents Act 1977 provides that one of the grounds upon which a patent may be revoked is that the invention for which the patent is granted is not a patentable one. S.1 (1) sets out the conditions for patentability one of which is that the invention involves an inventive step. S.3 provides that an invention shall be taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art by virtue only of s. 2 (2) of the Act. In Actavis Group PTC EHF and others v ICOS Corporation and another [2019] UKSC 15, [2019] Bus LR 1318 the Supreme Court approved at paragraph [60] the following test to determine whether a claim was obvious over the prior art which has been developed by the Court of Appeal in Windsurfing International Inc v Tabur Marine (Great Britain) Limited [1985] RPC 59, [1985] FSR 59 and Pozzoli Spa v BDMO SA and another [2007] EWCA Civ 588, [2007] Bus LR D117, [2007] BusLR D117, [2007] FSR 37:
“(1) (a) Identify the notional ‘person skilled in the art’;
(b) Identify the relevant common general knowledge of that person;
(2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;
(3) Identify what, if any, differences exist between the matter cited as forming part of the ‘state of the art’ and the inventive concept of the claim or the claim as construed;
(4) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?”
While approving the Pozzoli/Windsurfing test, Lord Hodge who delivered the Supreme Court's judgment in Actavis warned against applying the test in a mechanistic way. He said that the test was a gloss on s.3 of the Patents Act 1977 and did not require a literalist approach to the wording of the claim in identifying the inventive concept.
Obviousness over Epstein
While Lord Justice Arnold did not refer expressly to Actavis, Windsurfing or Pozzoli it would appear that he followed the Windsurfing/Pozzoli test. It was common ground that the "person skilled in the art" would be a team consisting of
Obviousness over Epstein
While Lord Justice Arnold did not refer expressly to Actavis, Windsurfing or Pozzoli it would appear that he followed the Windsurfing/Pozzoli test. It was common ground that the "person skilled in the art" would be a team consisting of
- a pre-clinical researcher involved in the investigation of anaemia associated with renal disease;
- a clinical nephrologist (a medical practitioner specializing in kidney care and involved in the treatment of patients with kidney disease); and
- a medicinal chemist involved in the development of new pharmaceuticals.
Having identified differences between Epstein (the article mentioned above) and the relevant claim, the learned Lord Justice said at [316] that the issue of obviousness involved 4 questions. The first 2 lay in the province of the skilled nephrologist, the 4th in the province of the skilled medicinal chemist while the 3rd concerned both of them:
i) Would it be obvious to consider using a HIF-PHI (an enzyme called hypoxia inducible factor-prolyl hydroxylase) to treat or prevent anaemia associated with CKD (chronic kidney disease)?
i) Would it be obvious to consider using a HIF-PHI (an enzyme called hypoxia inducible factor-prolyl hydroxylase) to treat or prevent anaemia associated with CKD (chronic kidney disease)?
ii) If so, would the skilled person have a reasonable expectation of success, in the sense of satisfying the criteria for therapeutic efficacy discussed above?
iii) If so, would it be obvious to search for other compounds in addition to DMOG (dimethyl-oxalylglycine) to test?
iii) If so, would it be obvious to search for other compounds in addition to DMOG (dimethyl-oxalylglycine) to test?
iv) If so, would a routine search lead to the relevant compound?
The judge answered the first 3 questions in the affirmative but the last in the negative. It followed that the patents were not bad for obviousness.
The judge answered the first 3 questions in the affirmative but the last in the negative. It followed that the patents were not bad for obviousness.
Insufficiency of EP823 and EP301
At paragraph [347] the learned Lord Justice noted:
"A patent is invalid if 'the specification does not disclose the invention clearly and completely enough for it to be performed by a person skilled in the art' (section 72 (1) (c) of the Patents Act 1977 giving effect to Article 138 (1) (b) EPC). As I have observed in a number of previous judgments, although insufficiency is a single ground of invalidity, it embraces three distinct types of objection: where the invention cannot be performed at all without undue burden (sometimes called 'classical insufficiency'); where the invention cannot be performed across the breadth of the claim without undue burden (sometimes called 'Biogen insufficiency' and also referred to as 'excessive claim breadth'); and where the claim does not enable the skilled person to know 'whether they are within the claim or outside (previously called 'ambiguity' and recently re-named uncertainty”). In the present case the Defendants advance both of the latter types of objection against EP 823 and EP 301, but not the first."
“The specification must disclose the invention clearly and completely enough for it to be performed by a person skilled in the art. The key elements of this requirement which bear on the present case are these:
(i) the first step is to identify the invention and that is to be done by reading and construing the claims;
(ii) in the case of a product claim that means making or otherwise obtaining the product;
(iii) in the case of a process claim, it means working the process;
(iv) sufficiency of the disclosure must be assessed on the basis of the specification as a whole including the description and the claims;
(v) the disclosure is aimed at the skilled person who may use his common general knowledge to supplement the information contained in the specification;
vi) the specification must be sufficient to allow the invention to be performed over the whole scope of the claim;
(vii) the specification must be sufficient to allow the invention to be so performed without undue burden.”
When he reached the Court of Appeal, Lord Justice Kitchin added the following guideline in Idenix Pharmaceuticals Inc v Gilead Sciences Inc. [2016] EWCA Civ 1089 at [135]:
“The extent of the disclosure necessary to make the patent sufficient depends on the nature of the invention, the scope of the claims and the art in which the invention is made …”
At paragraph [351] of Akebia, Lord Justice Arnold said:
"The objection of excessive claim breadth concerns the requirement that the invention must be capable of being performed over the whole scope of the claim without undue burden (points (vi) and (vii) in Kitchin J’s summary quoted above). As will appear, this requirement must not be taken too far."
He noted at [352] that it is permissible for a claim to describe an invention in general terms provided it is plausible in the light of the disclosure and the common general knowledge that the invention will work with anything falling within the scope of those terms. He added at [353] that the court must undertake a two-stage enquiry. The first stage is to 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. At this stage, it is not permissible for either the patentee or the party attacking the patent to rely upon evidence which post-dates the patent. If the disclosure does make it plausible, the second stage is to consider whether the evidence establishes that in fact the invention cannot be performed across the scope of the claim without undue burden. At this stage, evidence which post-dates the patent is admissible.
Applying these principles, the judge said at [376]that the patent implied that substantially all compounds which satisfy the structural definitions in the claims in issue would have the claimed therapeutic efficacy. Otherwise, the skilled team would be faced with a situation where the structural definition covered around 110183 compounds (or a little less or even more). The specification only demonstrated that 5 compounds, namely Compounds C, E, F, J and K, satisfied the criteria for therapeutic efficacy. That would amount to no more than an invitation to the skilled team to find the other compounds covered by the claim which work. He observed:
"It would not involve an inventive step, because it would not solve the technical problem of identifying compounds which have the desired activity, and it would not sufficiently disclose the invention, because it would leave most of the work to the reader."
He, therefore, concluded at [381] that all the claims in issue were insufficient for want of plausibility.
In case he was wrong the judge considered whether the invention could be performed across the scope of the claims in issue without undue burden. Taking all of the evidence into account, he concluded at [399] that the invention could not be performed across the scope of the claims in issue without undue burden. 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. Accordingly, the claims were bad for insufficiency.
"The objection of excessive claim breadth concerns the requirement that the invention must be capable of being performed over the whole scope of the claim without undue burden (points (vi) and (vii) in Kitchin J’s summary quoted above). As will appear, this requirement must not be taken too far."
He noted at [352] that it is permissible for a claim to describe an invention in general terms provided it is plausible in the light of the disclosure and the common general knowledge that the invention will work with anything falling within the scope of those terms. He added at [353] that the court must undertake a two-stage enquiry. The first stage is to 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. At this stage, it is not permissible for either the patentee or the party attacking the patent to rely upon evidence which post-dates the patent. If the disclosure does make it plausible, the second stage is to consider whether the evidence establishes that in fact the invention cannot be performed across the scope of the claim without undue burden. At this stage, evidence which post-dates the patent is admissible.
Applying these principles, the judge said at [376]that the patent implied that substantially all compounds which satisfy the structural definitions in the claims in issue would have the claimed therapeutic efficacy. Otherwise, the skilled team would be faced with a situation where the structural definition covered around 110183 compounds (or a little less or even more). The specification only demonstrated that 5 compounds, namely Compounds C, E, F, J and K, satisfied the criteria for therapeutic efficacy. That would amount to no more than an invitation to the skilled team to find the other compounds covered by the claim which work. He observed:
"It would not involve an inventive step, because it would not solve the technical problem of identifying compounds which have the desired activity, and it would not sufficiently disclose the invention, because it would leave most of the work to the reader."
He, therefore, concluded at [381] that all the claims in issue were insufficient for want of plausibility.
In case he was wrong the judge considered whether the invention could be performed across the scope of the claims in issue without undue burden. Taking all of the evidence into account, he concluded at [399] that the invention could not be performed across the scope of the claims in issue without undue burden. 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. Accordingly, the claims were bad for insufficiency.
Astellas's Claim against Akebia and Otsuka.
There was no dispute that vadadustat would have infringed some of the claims of the Family A patents upon what the Supreme Court called a normal construction in Eli Lilly and Co. v Actavis UK Ltd.[2017] RPC 21, [2017] Bus LR 1731, [2017] UKSC 48 had those claims been valid. Other claims would not have been infringed either on a normal or on an equivalence construction.
Amendment
The one amendment that was not agreed by the parties was allowed by the court at [463] for the following reasons:
"The only issue as to the allowability of the amendments to the Family A claims which remained live at the end of the trial concerns the amendments to granted claim 1 of EP 531 to produce amended claim 17A. On its face, these amendments amount to a drastic narrowing of the claim. Nevertheless, the Defendants contend that, if claim 17A is infringed by virtue of the doctrine of equivalents, then the amendments are not permissible because they extend the scope of protection of granted claim 1. If I am correct that vadadustat does not infringe claim 17A, this issue does not arise. If I am wrong in that conclusion, I do not consider the amendments are impermissible. Vadadustat would, on my construction of Formula (I), have fallen within the granted claim as well as the amended claim, and thus infringement would not demonstrate any extension of protection. The fact that the granted claim would, having regard to my conclusions on insufficiency, be invalid, whereas claim 17A is valid, does not mean that the scope of protection of the claim has been extended." The one amendment that was not agreed by the parties was allowed by the court at [463] for the following reasons:
The Family B Patents
The Inventions
The Lord Justice said at [465] that WO121 relates to methods and compounds for regulating or enhancing erythropoiesis and iron metabolism, and for treating or preventing iron deficiency and anaemia of chronic disease. The specification states:
“The invention provides various methods of regulating/enhancing iron processing and iron metabolism. In one aspect, the invention provides methods for increasing iron transport, uptake, utilization, and absorption in a subject, each of the methods comprising administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF). In particular embodiments, the invention provides methods for increasing transferrin expression, transferrin receptor expression, IRP-2 expression, ferritin expression, ceruloplasmin expression, NRAMP2 expression, sproutin expression, and ALAS-2 expression in a subject, each method comprising administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF). In other embodiments, the invention provides methods for decreasing hepcidin expression, the method comprising administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF). Methods for increasing heme synthesis in a subject by administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF) are also provided.”
“The invention provides various methods of regulating/enhancing iron processing and iron metabolism. In one aspect, the invention provides methods for increasing iron transport, uptake, utilization, and absorption in a subject, each of the methods comprising administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF). In particular embodiments, the invention provides methods for increasing transferrin expression, transferrin receptor expression, IRP-2 expression, ferritin expression, ceruloplasmin expression, NRAMP2 expression, sproutin expression, and ALAS-2 expression in a subject, each method comprising administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF). In other embodiments, the invention provides methods for decreasing hepcidin expression, the method comprising administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF). Methods for increasing heme synthesis in a subject by administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF) are also provided.”
Obviousness over WO997
Again, there was no reference to Windsurfing, Pozzoli or Activas but it is clear that Lord Justice Arnold applied the Windsurfing/Pozzoli test. It was noted at [519] that it was common ground that the skilled team for Family B was the same as for Family A. However, there was a dispute as to what was their common general knowledge. In identifying the inventive concept, he read the citations in the Family B patents between paragraphs [544] and [548] and construed the relevant Family B claims between [549] and [553]. Finally, be considered the differences between the inventive concept and propr art between [549] and [574]. He found all those claims were obvious over WO997.
Insufficiency of Family B
The issues were the same as for Family A and the judge dealt with them briefly. The relevant claims were insufficient for implausibility [576], undue burden [577] and uncertainty [578].
Infringement
Infringement
Although vadadustat would have fallen within the scope of the Family B claims had they been valid there was no evidence that Akebia or Otsuka would have threatened or intended to market their drug in those circumstances.
Summary
Lord Justice Arnold summarized his findings at [640]:
"i) the Family A Patents are not obvious over Epstein, and since this is the only attack on the validity of claim 17A of EP 531 that claim is valid (subject to the allowability of the amendment);
Summary
Lord Justice Arnold summarized his findings at [640]:
"i) the Family A Patents are not obvious over Epstein, and since this is the only attack on the validity of claim 17A of EP 531 that claim is valid (subject to the allowability of the amendment);
ii) all the claims in issue of EP 823 and EP 301 both lack plausibility and cannot be performed across their scope without undue burden, and therefore are invalid for insufficiency;
iii) claim 24A of EP 823 and claim 4 of EP 301 are uncertain, and therefore invalid for insufficiency;
iv) all the Family A claims in issue other than claim 17A of EP 531 would be infringed by vadadustat if they were valid;
v) claim 17A of EP 531 is not infringed by vadadustat on the basis of equivalence, and the same goes for claim 36A of EP 333;
vi) the amendments to produce claim 17A of EP 531 are permissible;
vii) all the claims in issue of the Family B Patents are obvious over WO 997;
viii) all the claims in issue of the Family B Patents except for claim 36A of EP 333 are invalid on the grounds of insufficiency for the same reasons as the Family A Patents; and
x) even if the claims in issue are valid, there is no threat by the Defendants to infringe the Family B Patents."
Further Information
iv) all the Family A claims in issue other than claim 17A of EP 531 would be infringed by vadadustat if they were valid;
v) claim 17A of EP 531 is not infringed by vadadustat on the basis of equivalence, and the same goes for claim 36A of EP 333;
vi) the amendments to produce claim 17A of EP 531 are permissible;
vii) all the claims in issue of the Family B Patents are obvious over WO 997;
viii) all the claims in issue of the Family B Patents except for claim 36A of EP 333 are invalid on the grounds of insufficiency for the same reasons as the Family A Patents; and
x) even if the claims in issue are valid, there is no threat by the Defendants to infringe the Family B Patents."
Further Information
As his lordship said at paragraph [6], this was a case of considerable complexity. Astellas's written closing submissions ran to 434 paragraphs and Akebia and Otsuka's to 537. Both sides referred to further material in their respective opening skeleton arguments. I have had to omit most of the technical details to make this note manageable and comprehensible. Anyone wishing to discuss it is welcome to send me a message through my contact page. I shall be happy to respond by phone, Skype or Zoom.
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