Introduction

Following the U.S. Supreme Court’s invalidation of a counterpart U.S. patent in the same family for lack of enablement (21-757 Amgen Inc. v.  Sanofi (05/18/23) (supremecourt.gov)), the UPC has now rendered a decision on its European counterpart. Last year, the U.S. Supreme Court, in a unanimous opinion authored by Justice Neil Gorsuch, held that the patent “claims a lot, but enables only a little,” and stated the basis tenant of enablement to be: “[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class. In other words, the specification must enable the full scope of the invention as defined by its claims. The more one claims, the more one must enable.” Thus, in the United States, the Supreme Court set a precedent that functionally-defined antibody claims were subject to challenge for lack of enablement. 

We also note that, in 2023, a Japanese patent in the same family, JP5705288, was invalidated by the Japanese IP High Court for a lack of support; such a ruling was a reversal of the court’s own conclusion made some four years prior. JP Case No. 2021 (Gyo-ke) 10093. See Kluwer Patent Blog, May 2023.

Across the Atlantic, while enablement or lack of support were not at issue, the UPC’s first decision sets a precedent that claims directed to antibodies for a known target antigen are subject to challenge for lack of inventive step, thereby creating a global landscape fraught with risks from multiple lines of attack.

Just one year after it went into operation, the Central Division of the UPC, a patent tribunal made up of 17 member states of the European Union, issued its first revocation – in the first case ever lodged before it.  Sanofi-Aventis v Amgen (CFI 1/2023). Both Sanofi and Regeneron challenged the patent in question, EP Patent No. 3,666,797 B1 (the EP ‘797 patent), which covers Amgen’s Repatha cholesterol drug product. The claimants, who market Praluent, a competing antibody product, asserted that the EP ‘797 patent lacked inventive step, among other grounds.

In the July 16 ruling, a three-judge panel of the UPC Central Division in Munich revoked the EP ‘797 patent in its entirety, for all UPC contracting states, as invalid for lack of inventive step. The court’s opinion is described in greater detail below, and should draw the attention of many carefully watching the early happenings before this new patent tribunal.

Patent Family and Background

The challenged EP ‘797 patent claims priority to a PCT family including PCT/US2008/074097, and issued from a divisional application filed from now-granted EP 2,215,124 B9. The family’s earliest priority dates back to August 22, 2008. Like its parent application, which recites the antibodies by amino acid sequence, the EP ‘797 patent is directed to evolocumab (the active ingredient of Repatha), but recites the antibodies instead by functional limitation – namely, antibodies or antigen-binding fragments which bind the catalytic domain of PCSK9 and prevent or reduces the binding of PCSK9 to LDLR. The EP ‘797 patent granted in May of 2023 with eleven claims; the lone independent claim is reproduced below:

1.  A monoclonal antibody or an antigen-binding fragment thereof for use in
treating or preventing hypercholesterolemia or an atherosclerotic disease related to elevated serum cholesterol levels;
or for use in reducing the risk of a recurrent cardiovascular event related to elevated serum cholesterol levels;
wherein the monoclonal antibody or the antigen-binding fragment thereof binds to the catalytic domain of a PCSK9 protein of the amino acid sequence of SEQ ID NO: 1, and prevents or reduces the binding of PCSK9 to LDLR.

The EP ‘797 patent at issue – and this patent family at large – are thus related to marketed cholesterol-lowering antibody drugs, specifically proprotein convertase subtilisin type 9 (PCSK9) inhibitors. PCSK9 is a serine protease involved in regulating the levels of the low-density lipoprotein receptor (LDLR) protein. EP ‘797 patent at [0002]. Experiments with mice have shown that increasing PCSK9 protein levels decreases levels of LDLR protein in the liver. Id. The LDLR removes so-called “bad cholesterol” (LDL) from the blood in the liver; thus, in a non-regulated stated, PCSK9 binds LDLR and causes its degradation, preventing removal of “bad cholesterol” from the blood. By targeting PCSK9, and preventing the binding of PCSK9 to LDLR, the claimed antibodies regulate levels of LDLR and, therefore, of “bad cholesterol”. See generally id; [0067]; Opinion at 5.1. The specification of the EP ‘797 patent also discloses that purified PCSK9 is made up of two species, which become relevant in the court’s decision: (a) the pro-domain (17 Kd); and (b) the catalytic plus C-terminal domains (65 Kd). Opinion at 5.15.

While the EP ‘797 patent did not explicitly set out a problem to be solved, the court “deduced from the Patent description as a whole that the aim of the Patent is to provide a treatment or prevention of hypercholesterolemia or atherosclerotic disease associated with elevated serum cholesterol levels or for use in reducing the risk of recurrent cardiovascular events associated with elevated serum cholesterol levels targeting PCSK9 to regulate levels of LDLRs (and thereby LDL).” Opinion at 5.16.

Inventive Step – Base Reference (Lagace)

Against this technical backdrop, the court delved into the patentability, and particularly the alleged inventive step, of the ‘797 patent (the court also evaluated written description, priority, and novelty, but invalidated the patent solely on inventive step grounds, which will be the focus of this summary). First, the UPC clarified that “[i]n order to assess whether or not a claimed invention was obvious to a skilled person, it is first necessary to determine a starting point in the state of the art.  There has to be a justification as to why the skilled person would consider a particular part of the state of the art as a realistic starting point … In general, a claimed solution is obvious if, starting from the prior art, the skilled person would be motivated (i.e. have an incentive[]) to consider the claimed solution and to implement it as a next step … in developing the prior art.” Opinion at 8.6-8.8 (emphasis added). Both parties agreed that the primary reference, Lagace, Thomas A., et al. “Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.” The Journal of clinical investigation 116.11 (2006): 2995-3005 (“Lagace”), was at least a “realistic starting point” for the evaluation of inventive step. Opinion at 8.12.

Lagace is directed to understanding the relationship between PCSK9 and LDLR, and more specifically that “secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels.” Lagace at Abstract; Opinion at 8.15. Lagace disclosed that a known mutant form of PCSK9 (D374Y) had been shown previously to be associated with severe hypercholesterolemia, and provided in vivo and in vitro experimental data showing, for example:

• the number of cell surface LDLRs declined after incubation with PCSK9 in a concentration dependent manner;
• PCSK9 uptake in wild-type cells was high and was markedly reduced in the LDLR-/- mice that did not produce LDLR;
• PCSK9(D374Y) binds to LDLRs with higher affinity than does wild-type PCSK9, a finding that correlates with the enhanced ability of the mutant PCSK9 to destroy LDLR; and
• In mice modified to express human PCSK9 (“TgPCSK9 mice”), the LDL-R protein was essentially undetectable in livers of wild-type mice after they were parabiosed with TgPCSK9 mice, indicating that PCSK9 was active in mouse plasma.

Opinion at 8.17-25 (emphasis added and internal citations omitted). From the teachings of Lagace, the court stated, a skilled artisan “would have realised that Lagace was interested in finding out more about the mechanism by which PCSK9 reduces the number of LDLR.” Opinion at 8.26.

Obviousness

With Lagace established as a jumping-off point, the court ruled that “[t]he the skilled person having the aim to … provide a treatment [for the claimed conditions] associated with elevated serum cholesterol levels targeting PCSK9 to regulate levels of LDLRs (and thereby LDL), would as a next step have pursued the route of developing antibodies that block the interaction between PCSK9 and LDLR as explicitly suggested by Lagace.” Opinion at 8.31. In its defense, Amgen argued that PCSK9 was only one of many targets, and that it was not a “validated” target, but the court found that “the relevance of and significant (commercial) interest in PCSK9 as a target for the treatment of hypercholesterolemia had been well established and was generally accepted at the relevant date.” Opinion at 8.32-33.

Indeed, the court stated that “in cannot be concluded that the skilled person at the relevant date would have serious doubts about whether PCSK9 indeed acts (at least also) extracellularly in vivo as taught by Lagace, at least not doubts that were of such a nature that these would have dissuaded the skilled person from pursuing an antibody approach to block the interaction between PCSK9 and LDLR as suggested by Lagace.” Opinion at 8.50. Thus, having established that Lagace established suitable background for one of skill in the art, the court ruled that a skilled artisan would not be dissuaded from proceeding with experimentation using PCSK9 as a primary therapeutic target.

Reasonable Expectation of Success & Reaching the Claimed Invention

Moving beyond the PCSK9 antibody target itself, the court found a reasonable expectation of success for one armed with the teachings of Lagace, and stated “[t]he uncertainties raised by the Defendant would not have prevented the skilled person from taking the obvious next step, i.e. developing PCSK9/LDLR inhibiting antibodies to treat hypercholesterolemia and related disorders, due to insufficient prospects of success.” Opinion at 8.56.

Regarding whether a skilled artisan would reach the claimed antibodies under the teachings of the prior art, the court reiterated that “it is not the question whether the skilled person would inevitably arrive at the same result (falling within the scope of the claim or not). Rather, it is sufficient (but also necessary) for denying inventive step that the skilled person would without inventive contribution arrive at a result which is covered by a claim.” Opinion at Headnotes; emphasis added; see also Opinion at 8.67. From the record, the court established the known antibody generation protocols of the time, and the ability of a skilled scientist to express and purify antibody domains, and stated that “[a]ccording to the Defendant, the entire PCSK9 protein can be used as an antigen to immunize the transgenic mice as demonstrated. Accordingly, the skilled person would have used the whole PCSK9 protein as an antigen to obtain anti-PCSK9 antibodies in following Lagace´s suggestion to develop antibodies against PCSK9 that block the interaction between LDLR and PCSK9.” Opinion at 8.69.

Having determined a motivation, the court turned to whether one would reach he claimed result without inventive contribution, and stated that “[a]fter generating antibodies against PCSK9 using any of the above methods (whereby the Central Division reiterates that the claims are not limited to any particular method of generating antibodies), the next step will be to screen antibodies to confirm binding to PCSK9.” Opinion at 8.70. Critically, after weighing the evidence of both sides, the court emphasized that “even if it were accepted in favour of the Defendant that the inventors of the Patent took a non-routine approach and obtained the results (functional antibodies) included in the Patent, this does not mean that the skilled person would not arrive at an antibody falling under the scope of the Patent claims using routine methods of antibody generation and selection.” Opinion at 8.72-73. In so ruling, the court set aside Amgen’s arguments regarding failure of alternative methods and arguments regarding failure of others, and stated “an objective approach to inventive step must be taken. It is only relevant what the claimed invention actually contributes to the prior art.” Opinion at 8.74-75.

Claim Limitation (Catalytic Domain)

The last point addressed by the court is a specific limitation of claim 1: “binds to the catalytic domain.” Amgen argued that said binding is non-obvious, whereas the claimants argued that the term is arbitrary and without useful technical effect. Opinion at 8.76. The court agreed with the claimants, and held that the feature of binding to the catalytic domain – because it does not have a causal connection to the effect of reducing binding of PCSK9/LDLR – cannot contribute to the inventive step. Opinion at 8.78. More specifically, the court ruled that “[e]specially in view of the interpretation of the term “catalytic domain”, which requires the antibody to bind to at least one amino acid residue that lies within the catalytic domain … and which term is not limited to antibodies that bind exclusively (or even predominantly) to amino acid residues that lie within the catalytic domain, the so generated antibodies would in all likelihood encompass antibodies that ‘bind to the catalytic domain’ … As long as the anti-PCSK9 antibodies block the interaction between the LDLR and PCSK9, as suggested by Lagace, they would “pass the screen” and would meet the functional requirements of the claim.” Opinion at 8.78. Thus, the court concluded that, “[t]here would have been no technical reason for the skilled person to (include or) exclude any (functional, inhibiting) antibodies based on their binding location.” Id.

Conclusion

In summary, the Central Division revoked all of the claims as obvious and reasoned that “the skilled person … would have followed-up on the explicit suggestion in Lagace and would have developed anti-PCSK9 antibodies as a treatment for hypercholesterolemia and – doing so – would have arrived at the (uses of) antibodies as claimed . . . .  The unknowns and uncertainties that were brought forward by the Defendant, none of which are clearly voiced in the many prior art documents relied upon in this case, in any event do not outweigh the clear incentive provided by Lagace to develop anti-PCSK9 antibodies that block the interaction between PCSK9 and LDLR for treatment.” Opinion at 8.81-8.82.

While this is the first invalidation ruling to issue from the UPC, the court presented its analysis in a manner echoing that of the EPO’s “problem-and-solution” approach, including identifying the closest prior art document (Lagace), considering the underlying problem (in short, providing a treatment for hypercholesterolemia or related conditions by targeting PCSK9 to regulate levels of LDLRs, and thereby LDLs), evaluating whether the claimed solution would have been obvious (which the court ruled it was on a theory that where the target antigen is known, producing antibodies that bind the target is routine and not inventive), and considering whether the skilled person would have had a reasonable expectation of success (which the court ruled they would have). The court’s finding – that, starting from the teachings of Lagace, a skilled artisan would have pursued antibodies blocking the PCSK9/LDLR interaction without the need for an inventive step – will undoubtedly be closely scrutinized by those seeking to protect antibody therapeutics in Europe.

UPC Opt-Out

By default, all European national patents granted by the EPO, with an effect in UPC-member countries, are subject to the jurisdiction of the UPC. Applicants in UPC-member countries can reversibly opt-out of UPC proceedings, however, via an administrative filing with the EPO at any point prior to the filing of a UPC action.

The window to file an opt-out will run during a transitional period of seven years from the opening of the court in 2023 (and may be extended by an additional seven years; thus, the transitional period will run either through the end of May 2030, or else the end of May 2037). It will be interesting to see whether the EPO and other European courts follow the UPC’s rationale in assessing antibody claims going forward.