US and UK law of Patent Enablement – Clear Divergence: The Fibrogen and Amgen decisions

Introduction

On 15 December 2023, the pending appeal to the UK Supreme Court (“UKSC”) in the case of Fibrogen v Akebia was withdrawn. The UKSC had granted permission to appeal on 3 October 2022 from the decision of the Court of Appeal (“EWCA”) (Birss LJ leading) handed down in August 2021[1]. That decision was itself an appeal from the decision of Arnold LJ sitting as a judge in the High Court (Patents Court) (“EWHC”) dated 20 April 2020 [2].

The relevant claims were for a broad class of compounds, defined by structure and function, to be used for treating specified types of anaemia. Arnold LJ in the EWHC had held under a narrow approach that the claims were invalid for insufficiency as lacking plausibility and imposing an undue burden on the skilled addressee. The EWCA overturned this decision and laid down a three-part test combining structural and functional aspects of the claim in the assessment of insufficiency.

Then, on 18 May 2023 the US Supreme Court (“SCOTUS”) handed down its decision in Amgen v Sanofi [3] the most recent instalment of the global battle between Amgen and Sanofi over the cholesterol lowering drug Praluent. The Court upheld the decision of Federal Circuit Court of Appeals (“CAFC”) [4], finding two of Amgen’s patents (US 8829165 and US 8859741) were invalid for lack of enablement. The SCOTUS decision provides an interesting illustration of the narrow approach taken to enablement or sufficiency of disclosure on the other side of the Atlantic and provides a note of caution to patentees seeking functionally limited claims covering broad families of compounds.

In this discussion, we will contrast the current approaches to broad functionally limited claims in the US and UK.

Sufficiency of functional claims – the UK approach

FIBROGEN v AKEBIA

FibroGen v Akebia (“Fibrogen”) remains the leading case in the UK on the validity of broad functionally limited claims, such as those at issue in Amgen v Sanofi. Several other recent decisions in the UK have also considered sufficiency of disclosure in light of the Fibrogen decision [5]. In the case of Sandoz v BMS (concerning the drug apixiban) the EWCA decision (Arnold LJ) upheld the decision of Meade J at first instance, which found the BMS claim invalid on formal grounds of insufficiency in that the claim lacked plausibility [6]. Significantly, Meade J at first instance considered the EWCA decision in Fibrogen but observed that the context in Sandoz was quite different as the BMS invention was in identifying a single compound which, based on a known mechanism and known structural understanding, would treat a recognised kind of condition. As such, Meade J observed that there really was no useful analogy between the cases. On appeal, Arnold J likewise did not consider it necessary to apply Fibrogen.

Meade J subsequently highlighted the distinction between the Fibrogen and Sandoz lines of authority in his decision in Teva v Grunenthal [7], where he stated at [339] “the issue in Sandoz was about plausibility in respect of a single chemical compound rather than plausibility across the scope of a claim covering numerous possibilities; for the latter situation the key statement of the law is to be found in Fibrogen…”

In the UK, the requirement of enablement most closely aligns with that of sufficiency (although there is significant overlap with inventive step, where issues of plausibility are raised). The requirement for sufficient disclosure (and the closest equivalent of 35 U.S.C § 112) is found in s 72(1)(c) of the Patents Act 1977, which states a patent must “disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art”.

The EWCA in Fibrogen identified two requirements for a claim to a broad functionally limited class to be valid:

1. it must be possible for the skilled person, without undue burden, to identify some compounds beyond those named in the patent, which are within the claimed class; and
2. it must also be possible for the skilled person to work substantially anywhere within the whole claim. So, it must be possible for the skilled person, given any sensible compound within the structural class (or substantially any), to apply the tests without undue burden and work out if it is a claimed compound.

Importantly, the EWCA emphasised that it is not necessary for the skilled person to be able to identify a priori from the patent all (or substantially all) of the compounds which fall within the broadest scope of the claim for it to be valid. It must, however, be possible for the skilled person to make a reasonable prediction of whether the invention will work with any given compound within the claim. Importantly, what was meant by a “compound within the claim” was significantly narrowed. According to the EWCA, “compounds within the claim” were not merely those falling within the “staggeringly large” structural class but additionally, those that also had the functional characteristic of inhibiting the key enzyme (HIF-PH) [8]. Of this functionally narrowed class, the question for the skilled person was whether a reasonable prediction could be made that this narrower class would have the desired therapeutic effect – increasing Epo production/treating anaemia [9].

The EWCA applied a three-part test to determine if a reasonable prediction could be made that the claim would work with a given compound:

1. identify what it is which falls within the scope of the claimed class (which may be defined by both structural and (step one) functional characteristics);
2. determine what it means to say that the invention works (i.e. what is the promised (step two) effect);
3. on the basis of (1) and (2) answer the question whether it is possible to make a reasonable prediction that the invention will work with substantially everything falling within the scope of the claim.

The EWCA therefore decided in a broad approach that patent claims for broad classes of compounds were not necessarily invalid for insufficiency even if they covered a potentially enormous number of compounds. Similarly, the test for undue burden was not the cumulative burden of identifying and testing for efficacy all the compounds covered by the structural formula and/or the functional requirements of the claim. The EWCA decision was highly encouraging to patent owners in the life sciences field, marking as it did a sea-change in the UK approach to insufficiency/undue burden and plausibility/reasonable expectation.

Following the withdrawal of the appeal to the UKSC, the three-part test laid down by the EWCA stands as settled law for the indefinite future, with no further cases considering this issue on the horizon.

Enablement of functionally defined genus claims – the US approach

AMGEN V SANOFI

Background

Both Amgen and Sanofi market monoclonal antibody drugs for the treatment of high cholesterol. Both drugs work by inhibiting a protein called PCSK9, which reduces the body’s ability to remove low density lipoprotein (“LDL”) cholesterol from the bloodstream. Both Amgen and Sanofi developed and patented specific antibodies which target PCSK9 and commercialised them under the brand names Repatha and Praluent respectively. Subsequently, Amgen also obtained two patents (US 8,829,165, “US165” and US 8,859,741, “US741”), which broadly claimed all antibodies which bind to specific amino acid residues on PCSK9 and block binding to LDL receptors.

Starting in 2014, US165 and US741 became the subject of litigation in various jurisdictions [10], with Amgen asserting infringement by Sanofi’s Praluent product. After protracted proceedings the US District Court found in 2019 that both patents were invalid for lack of enablement. This decision was upheld on appeal to the CAFC in February 2021. Amgen appealed this decision to the SCOTUS, which unanimously upheld the decision of the CAFC in May 2023.

Enablement

The enablement requirement in US patent law is found in section 112 of the Patent Act (35 U.S.C § 112) which requires a patent specification to include “a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art… to make and use the same.” In the recent decision, the SCOTUS started by emphasising that this requirement is central to the patent ‘bargain’ by ensuring the public has the full benefit of the invention following expiry of the patent. The key question is, of course, what level of disclosure is required to enable a skilled person to make and use the invention and perhaps more importantly, how to match the level of disclosure to the breadth of the claims.

Although the technology at issue has changed hugely over time, the Court noted that US caselaw back to the 19th century consistently emphasises that the “specification must enable the full scope of the invention as defined by its claims. The more one claims, the more one must enable.” This does not necessarily mean that a patent will be invalid either because it only provides limited examples or requires a “reasonable amount of experimentation” to implement. It is possible for broad claims to be enabled by one (or a few) examples where “some general quality… running through the class that gives it a peculiar fitness for the particular purpose.” is disclosed. However, the Court noted numerous examples where patents which claimed a broad class of materials, limited with reference to a particular function, were found to lack enablement because the disclosure did not match the breadth of the claim.

In the case of US165 and US741, the patents claimed a class of antibodies identified by a twofold functional requirement (1) that it binds to particular amino acid residues on PCSK9 and (2) that it blocks the binding of PCSK9 to LDL receptors. To support these claims, the patents contained details of 26 exemplary antibodies, identified by their amino acid sequences (including evolocumab, the active ingredient in Repatha). Sanofi conceded that the patents were enabled with respect to those 26 antibodies, but the Court noted the claims extended far beyond, to an entire class of antibodies (at least one million) which could bind to a particular region on PCSK9 and have the desired effect.

Beyond the 26 examples provided, Amgen argued the patents were sufficiently enabled, despite the breadth of the claims, because they described two methods for identifying antibodies within the claims – referred to as the “roadmap” and “conservative substitution”. The SCOTUS disagreed, concluding that the “roadmap” was little more than a trial-and-error process of preparing a large number of antibodies and screening them for binding to PCSK9. Similarly, the “conservative substitution” approach required substitutions to be made in the sequences of antibodies which were known to work to generate a number of candidates which could be screened for PCSK9 binding. The Court noted that whether a given antibody would bind PCSK9 was uncertain and the approaches suggested by the patents did not suggest any common quality shared by those which worked. As a result, the skilled person would be required to undertake painstaking experimentation to identify antibodies which met the functional requirements of the claims. Although the Court also emphasised that “enablement is not measured against the cumulative time and effort it takes to make every embodiment within a claim”, it agreed with the CAFC that the patents offered “little more than advice to engage in trial and error.” and as a result, were not sufficiently enabled.

Comparison of approaches to functional claims

Although the approach of the EWCA in Fibrogen described above is substantially more granular than that applied by the US courts, the two cases appear to show a significant divergence in how sufficiency/enablement of functionally limited claims are considered on each side of the Atlantic.

An instructive way of comparing the two approaches is to consider how a UK court might have approached claim 1 of US165 using a Fibrogen analysis. Claim 1 of US165, claims:

An isolated monoclonal antibody,

wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of the following residues: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO:3, and

wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.

Considering the Fibrogen reasonable prediction principle, at step 1, the class of claimed antibodies, is only limited by function (i.e. any antibody which binds to a specified amino acid residue of PCSK9). The EWCA in Fibrogen noted that it is perfectly permissible to define a class of compounds in this way, without reference to any structural features [11]. Both the CAFC and SCOTUS noted that the US claims are limited only by function [12]  and that while, this is not necessarily precluded, it involves a high enablement threshold [13].

At step 2 of the Fibrogen analysis, the invention of US165 works if the antibody blocks binding of PCSK9 to LDL receptors [14]. The US courts also effectively considered the invention worked when binding of PCSK9 to LDL receptors was reduced.

The third Fibrogen question is whether the skilled person could make a reasonable prediction that substantially all antibodies which bind to the specified amino acid residues of PCSK9 protein would reduce binding of PCSK9 to LDL receptors.

Both the CAFC and SCOTUS concluded that the patents did not provide enough information for a skilled person to identify antibodies which met the functional requirements (i.e. binding to particular region of PCSK9 and preventing binding to LDL receptors). On the evidence, the US courts found that the 3D structure and binding properties of any given antibody was unpredictable and could not be determined from the amino acid sequence. Detailed information regarding the structure and binding was only provided for the 26 example antibodies and the two methods suggested for identifying additional antibodies which met the binding requirements amounted substantial research projects relying on trial and error. The SCOTUS reached this conclusion without separately considering each of the functional requirements, making it difficult to know whether the patents failed at step 1 or step 2 of the Fibrogen test. The CAFC considered that even the first functional limitation (binding to specific PSCK9 amino acid residues) alone would require undue experimentation [15].

The EWCA in Fibrogen also accepted that “Some step one functional features themselves can give rise to an undue burden on their own” [16]. The Court explained that relevant issues in assessing this included whether the test (e.g. to identify antibodies which bind to a certain region) is established in the art and how difficult it is to carry out, whether relevant compounds are known or if the skilled person has “been left to fish in an infinitely large ocean with each catch giving them no pointers to the next one” [17].

Although the principles identified by the US and UK courts appear similar, the difference in the focus of the analysis appears likely to lead to markedly different results. In the UK, the EWCA emphasised that it is not necessary to be able to identify substantially all of the compounds within the scope of the claim, but it must be possible to determine without undue burden whether any given compound falls within the claim. Both the SCOTUS and CAFC stressed that it was necessary for the patent to “enable the full scope of the invention as defined by its claims” without “undue experimentation”. The SCOTUS noted that “enablement is not measured against the cumulative time and effort it takes to make every embodiment within a claim” [18]; however, the CAFC (with which the SCOTUS agreed) stated that it is, instead, relevant to consider “the amount of effort needed to obtain embodiments outside the scope of the disclosed examples and guidance” and that the full scope of the claims be “predictably generated by the described methods”. This focus by the SCOTUS on whether substantially all the compounds within the scope of the claim could be identified, was an approach expressly dismissed by the EWCA in Fibrogen.

Rather than focusing on whether the compounds across the full scope of the claims could be generated, a UK court following Fibrogen would consider whether it was possible (without undue burden) to determine if any given antibody would bind to the specified regions of PCSK9 (as opposed to considering the totality of the claimed class of antibodies, which was the focus of the US courts). The evidence in the US cases suggest this may impose an undue burden, but, assuming the UK court considered testing antibody binding relatively routine, the next question would be whether an antibody which bound to those residues could be reasonably predicted to block binding of PCSK9 to LDL receptors. The amino acid residues identified in claim 1 of US165 are part of the so called ‘sweet spot’ region of PCSK9 and it was well established that antibodies binding to the sweet spot would result in a reduction of LDL receptor binding. As a result, a UK court would likely consider that a reasonable prediction could be made that any antibody binding to the residues specified in US165 (step 1) would block binding of PCSK9 (step 2). In this situation, provided the court considered step 1 did not cause undue burden, a UK court would likely have found US165 valid, contrary to the outcome in Amgen in the SCOTUS.

Conclusion

As the UKSC has not had an opportunity to consider whether to maintain the broad approach of the EWCA decision, or (re)adopt the narrow approach as per the UKHC in Fibrogen and per SCOTUS in Amgen, a clear difference has now emerged in approach between the US and UK courts in respect of a key issue that underlies many patents in the life sciences/pharma/biotech field. Such differences in approach are clearly undesirable in the context of an increasingly globalised life sciences industry.

Although some aspects of the approach to sufficiency of claims with functionally limited classes of compounds are similar both in the US and UK, the decisions in Amgen v Sanofi and Fibrogen highlight how relatively subtle differences in analysis can lead to dramatically different results for validity. Following the withdrawal of the appeal to the UKSC in Fibrogen, it appears this divergence in approach is here to stay, at least for immediate future and it will be interesting to see how patentees adapt to the different sufficiency requirements on each side of the Atlantic.

1. FibroGen, Inc v Akebia Therapeutics Inc & ors [2021] EWCA Civ 1279 (24 August 2021).
2. Akebia Therapeutics Inc & ors v FibroGen, Inc [2020] EWHC 866 (Pat) (20 April 2020).
3. Amgen Inc. et al. v Sanofi et al. 598 U.S. (2023).
4. Amgen Inc. et al. v Sanofi et al. 987 F. 3d (2021).
5. See e.g. Gilead Sciences Inc v NuCana Plc [2023] EWHC 611 (Pat); Sandoz Ltd v Teva Pharmaceutical Industries Ltd [2022] EWHC 822 (Pat); [2023] EWCA Civ 472. The EPO Enlarged Board of Appeal in G0002/21 (Reliance on a purported technical effect for inventive step (plausibility)) also commented on sufficiency of disclosure, but limited to the context of assessing the plausibility of second medical use claims.
6. Arnold LJ in Sandoz also noted that EPO Enlarged Board decision G1/21 contained nothing which would disturb the leading UK authority on plausibility – Warner Lambert v Generics [2018] UKSC 56.
7. Teva Pharmaceutical Industries Limited v Grünenthal GmbH [2023] EWHC 1836 (Pat).
8. Described by the EWCA as the “step one functional feature”.
9. Described by the EWCA as the “step two functional feature”.
10. Parallel proceedings have also been ongoing in the UK and European Patent Office (“EPO”) in relation to a European counterpart of US165 and US741 (EP 2, 215, 124), which was opposed for lack of novelty, obviousness and insufficiency amongst other grounds. After a long period of opposition, EP124 was finally maintained in amended form in December 2020.
    In the UK, Amgen sued Sanofi for infringement of EP124 in 2016 and Sanofi counterclaimed for invalidity. These claims did not significantly progress, with the parties agreeing to a stay in December 2016, pending the outcome of the EPO opposition. The stay was lifted in October 2020, however, no further action was taken.
    Another European counterpart, EP 3, 666, 797 was recently granted and almost immediately became the subject of the first revocation action filed in the UPC and an infringement action against Sanofi shortly afterwards.
11. Referring particularly to Lilly ICOS v Pfizer [2000] EWHC Pat 49 and Regeneron Pharmaceuticals Inc v Genentech Inc [2013] EWCA Civ 93 as examples.
12. See Amgen Inc. et al. v Sanofi et al. 598 U.S. (2023) at 16 and Amgen Inc. et al. v Sanofi et al. 987 F. 3d (2021) at 5.
13. Amgen Inc. et al. v Sanofi et al. 987 F. 3d (2021) at 11.
14. Note that the corresponding European Patent EP767 included an additional therapeutic functional limitation “for using in treating or preventing hypercholesterolemia or an atherosclerotic disease related to elevated serum cholesterol levels or reducing the risk of a recurrent cardiovascular event related to elevated serum cholesterol levels”. So the question would be slightly more complex in the UK.
15. Amgen Inc. et al. v Sanofi et al. 987 F. 3d (2021) at 12.
16. FibroGen Inc v Akebia Therapeutics [2021] EWCA Civ 1279 at [63].
17. Ibid.
18. Amgen Inc. et al. v Sanofi et al. 598 U.S. (2023) at 13.