The Federal Circuit heard oral argument on November 8, 2024, grappling with the issue of what patent claims may properly be listed in the Orange Book. In late 2023, Teva filed a complaint for patent infringement in response to Amneal’s ANDA filing seeking to make and sell a generic version of ProAir HFA (albuterol sulfate) Inhalation Aerosol (“ProAir”). Teva holds an approved NDA for ProAir in addition to five patents listed in the Orange Book as covering the product, all of which were asserted in the lawsuit. The patents claim variations of a metered dose inhaler and dose counter.

In its answer, Amneal asserted counterclaims requesting delisting of all five asserted patents in the Orange Book for failure to comply with the statutory requirements under the FD&C Act. Amneal cited 21 U.S.C. § 355(b)(1)(A)(viii), which governs new drug applications to the FDA. The statute states that among other things, applicants must include:

(viii) the patent number and expiration date of each patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug, and that—

(I) claims the drug for which the applicant submitted the application and is a drug substance (active ingredient) patent or a drug product (formulation or composition) patent; or

    (II) claims a method of using such drug for which approval is sought or has been granted in the application.

    (emphasis added).

    Amneal moved for partial judgment on the pleadings under Rule 12(c), arguing that none of the five asserted patents claims an active ingredient, drug product, or a method of using the drug and is therefore improperly listed. Teva responded that the patents are correctly listed because they cover drug products, relying on their NDA acceptance from the FDA and the definition of the word “drug” as defined in 21 U.S.C. § 321(g)(1):

    The term “drug” means (A) articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C).

    Notably, the FTC simultaneously but independently got involved, sending Teva a letter stating concerns that the asserted patents (among others) were improperly listed in the Orange Book. The FTC explained that its investigation was spurred by a lack of genetic competition among inhaler products, and asserted that improper listing of patents may undermine the competitive process and constitute illegal monopolization. The FTC was granted leave to file an amicus brief supporting Amneal at the district court and in the Federal Circuit appeal.

    In June 2024, the District Court of New Jersey found that the patents were improperly listed and ordered Teva to correct the Orange Book listings. The Court found that Teva’s inhaler patents were “directed to components of a metered inhaler device, but do not claim or even mention albuterol sulfate for the ProAir HFA.” Teva Branded Pharm. Prod. R&D, Inc. v. Amneal Pharms. of New York, LLC, No. CV 23-20964 (SRC), 2024 WL 2923018, at *7 (D.N.J. June 10, 2024). Therefore, the patent does not claim the drug for which the applicant submitted the application as required by the statute. Id.

    On appeal, Teva argued that the district court erred by failing to use the ordinary meaning of the word “claim” or the statutory meaning of the word “drug.” Teva further argued that removal of its patents from the Orange Book would in turn affect patents that claim inactive ingredients or a genus that generically includes the active ingredient. Specifically, Teva argued that in the asserted patents, there are a limited number of possible ingredients that may be contained in the inhaler’s medicament cannister, which is essentially equivalent to claiming a genus of active ingredients. As the claimed inhaler components are part of the approved drug product, they are listable patents in the Orange Book.

    Amneal maintained that adhering to the statute’s definitions and requirements means Orange Book listed patents must claim the drug for which the NDA request was submitted, rather than cover a potential drug that may be used (i.e., albuterol sulfate rather than another inhalant). Therefore, Amneal argued, the statutory definition of “drug” on which Teva relies is irrelevant because the only relevant drug is albuterol sulfate.

    The Federal Circuit panel consisted of Judges Taranto, Prost, and Hughes. Initially, the panel focused on identifying what can and cannot be considered a drug product under the FD&C Act and the Orange Book Transparency Act of 2020. The judges also pressed Teva on the practicality of the FDA’s inclusion of the inhaler as part of a drug product for ease of review as opposed to defining the inhaler itself as a drug.

    Turning to Amneal, the judges asked counsel to address Teva’s genus claims concern. Amneal agreed that a patent claiming albuterol sulfate among a list of other potential inhalants would be “closer” to a listable patent. Amneal maintained, however, that a patent generally claiming an active ingredient in a medicament cannister without naming an ingredient is not enough, nor can the ingredients be mentioned solely in the specification. To be listed, according to Amneal, the patent must recite the specific active pharmaceutical ingredient in the claims. Amneal added that companies would continue to enjoy patent protection for their genus claims; they simply would not benefit from the 30-month stay of FDA approval provided by the statute in connection with litigation of Orange Book listed patents.

    As the parties await an opinion, the case continues at the district court level. The Court recently issued a claim construction ruling on November 4th, finding that the asserted patents do not require the presence of an active drug. Teva Branded Pharm. Prod. R&D, Inc. v. Amneal Pharms. of New York, LLC, No. CV 23-20964 (SRC), 2024 WL 4664096, at *6 (D.N.J. Nov. 4, 2024).

    The Federal Circuit’s decision should bring much-needed clarity on the issue of whether pure device patents can properly be listed in the Orange Book. We will provide further updates as the case progresses.

    As a firm responsible for managing global portfolios for pharmaceutical companies, we closely follow and seek to stay abreast of developments regarding patentability in various jurisdictions.  We recently reviewed the Unified Patent Court (UPC) first decision – invalidating EP Patent No. 3,666,797 B1 – and provided a summary of that case. This analysis will focus on how the same patent disclosure has been evaluated before two courts – the U.S. Supreme Court and the UPC – and what applicants should consider, in view of the recent jurisprudence, when preparing patent applications.

    Please note that our firm specializes in U.S. patent law.  The analysis provided herein, including regarding the EPC Sanofi-Aventis v. Amgen decision, is for informational and educational purposes only.  We suggest that parties seeking guidance on European patent matters consult with a qualified European patent attorney for authoritative advice and/or representation.

    Background

    In May 2023, the U.S. Supreme Court invalidated U.S. Patent Nos. 8,829,165 and 8,859,741, holding that Amgen’s functionally claimed genus of monoclonal antibodies lack enablement, and stating, “[t]he more one claims, the more one must enable.” Amgen Inc. et al. v. Sanofi et al., 143 S. Ct. 1243 (2023).  Reinforcing the need for specific disclosures and leaving less room for “trial-and-error-discovery,” the Court reiterated the basic tenet 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.” Id. at 1254. 

    The Court did not close the door to all functional genus claims – the strict standard expressed by the Court is couched in the clarification that “it may suffice to give an example (or a few examples) if the specification also discloses ‘some general quality . . . running through’ the class that gives it ‘a peculiar fitness for the particular purpose.” 143 S. Ct. 1243, 1254 (quoting Incandescent Lamp, 159 U. S., at 475). That is, “[i]n some cases, disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset.” Id. Even so, the Court made it clear that, in evaluating enablement, “courts cannot detract from the basic statutory requirement that a patent’s specification describe the invention ‘in such full, clear, concise, and exact terms as to enable any person skilled in the art’ to ‘make and use’ the invention [under §112(a)].  Judges may no more subtract from the requirements for obtaining a patent that Congress has prescribed than they may add to them.” Id.  Though the Court did not evaluate obviousness of the claims, the decision nevertheless sent a shockwave through the patent law world by seemingly raising the threshold for satisfying the enablement required. 

    In July 2024, a three-judge panel of the UPC Central Division in Munich revoked EP Patent No. 3,666,797 B1 (the EP ‘797 patent) – a corresponding European patent to those contested in the U.S. – as invalid for lack of inventive step.  Sanofi-Aventis v Amgen (CFI 1/2023). In reaching this decision, the UPC held that “the skilled person … would have followed-up on the explicit suggestion in [lead reference] 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.

    We note that, 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 so-called “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 ultimately ruled they would have).  The UPC thus found 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.  The court did not, however, opine on the enablement of the claims at issue.

    One Disclosure, Two Standards

    Thus, in the span of just over a year, substantively similar claims of patents having the same disclosure were invalidated on distinctly different grounds. 

    The standards articulated by the US and EP courts create two competing – even contrasting – conditions to be met for patentability and for invalidating existing patents.  Taken at a high level, an applicant may be faced with a conundrum: cater to the U.S. enablement standard, and prepare a specification laden with working examples – and risk demonstrating obviousness, by showing the Examiner the myriad developmental, analytical, or otherwise preparatory steps that could theoretically lead to the claimed invention to be routine?  Or err on the side of unpredictability, highlight an unexpected technical effect and the difficulty of generating said invention – and risk limiting claim scope by enabling only a portion of the subject matter, severely limiting the functional breadth of the disclosure?

    To meet the heightened enablement standard of the U.S. Supreme Court decision, an applicant is incentivized to bolster the detailed description of the specification, including the inclusion of comprehensive, detailed examples, specific embodiments, and experimental data, where relevant, so as to avoid being considered “research assignments.”  Moreover, an applicant may wish to draw both narrow and broad claim scopes, wherein the broad claims are supported by detailed descriptions of the full scope of the invention, and the narrow claims relate back to specific embodiments.  Of course – and as was at issue in the U.S. Amgen decision – claims reciting functional limitations must be backed by sufficient guidance to achieve the claimed function across the full scope of the claims (“The more one claims, the more one must enable”).  Amgen, 143 S. Ct. at 1254.

    Meanwhile, to meet the inventive step standard recited in the UPC opinion, an applicant must show that the claimed invention is not obvious to one of skill in the art, considering the state of the art – that the invention involved a clear inventive step in response to an existing problem.  To meet this threshold, an applicant may want to highlight significant technical contributions (including, as considered in the UPC opinion, techniques which go beyond those which “the skilled person would have routinely employed”).  Opinion at 8.72.  An applicant may further wish to include comparative data, demonstrating the advantages and/or unexpected results of the invention, compared to prior art solutions, which the UPC acknowledged in that “[a] technical effect or advantage achieved by the claimed subject matter compared to the prior art may be an indication for inventive step,” but noted that a “feature that is selected in an arbitrary way out of several possibilities cannot generally contribute to inventive step.”  Opinion at Headnote 5.  In view of the UPC opinion echoing the EPO considerations for inventive step, an applicant may also want to frame the invention in the context of “problem-solution,” and in so doing clearly state the problem and the means by which the claimed solution differs from and improves upon existing technologies.

    What’s an Applicant to Do?

    Striking a balance between providing a sufficiently detailed disclosure and avoiding building a roadmap to an obvious invention is no easy feat.  A rich specification which provides copious details, examples, structures and data may inadvertently provide something – perhaps an allegedly routine method, or admission or evidence of motivation – which could be used to argue that the invention lacks inventive step before the UPC, especially if the description outlines potential variations and optimizations of said invention that could appear routine and within the general level of skill in the art.  All the while, a specification lacking such details and disclosures is at risk of heightened scrutiny in the U.S., especially in more complex arts, for while “a specification may call for a reasonable amount of experimentation to make and use a patented invention,” the Court reiterated that “[w]hat is reasonable in any case will depend on the nature of the invention and the underlying art.” 143 S. Ct. 1243, 1255.

    These differing standards could further conflict in the case of broad claims.  For example, in the U.S. a broad claim may be permissible if (as suggested by the Supreme Court) a diligent applicant layers the patent’s specification with examples and embodiments so as to enable a person skilled in the art to make and use the full scope of the claims.  However, such broad claims may face immediate challenge before the UPC, especially if each claim – however well supported – does not demonstrate am unexpected technical contribution over the prior art, with the examples and data serving as basis to allege a routine path for a skilled artisan motivated to create an alternative to the prior art. 

    In navigating the matrix created by the respective Amgen cases, patent applicants may want to consider various aspects of their patent applications. 

    • Scope of the Claims: In the past, many applicants aimed to obtain similar claim scope across various jurisdictions, from the same specification.  However, in the current legal landscape, there are different approaches to consider when evaluating claim scope, as follows:
      • US: Include broad and narrow claims alike, with independent claims of varying scope, and ensure that the broadest claims are supported by the detailed description, experimental data, and working examples. While not every claimed embodiment necessarily needs a corresponding example, the court has stressed that embodiments must be closely tied together by a general quality of a given class.  See Amgen, 143 S. Ct. at 1255, quoting The Incandescent Lamp Patent, 159 U.S. 465, 474 (1895) (“it may suffice to give an example (or a few examples) if the specification also discloses ‘some general quality … running through’ the class that gives it ‘a peculiar fitness for the particular purpose.’”)
      • UPC: Prioritize claims that clearly demonstrate or are supported by a technical advancement or effect (see UPC Opinion at 8.76-8.79, commenting on the lack of demonstrated technical effect for the limitation “[b]inds to the catalytic domain”).  Further, include language in the specification specifically supporting the problems solved by claims related to distinct improvements and explain the technical challenges that were overcome so as to distinguish inventive acts from routine acts of an alleged POSA at that time (see id. at 8.6, explaining that “[a]starting point is realistic if its teaching would have been of interest to a skilled person who, at the priority date of the patent at issue, was seeking to develop a similar product or method to that disclosed in the prior art which thus has a similar underlying problem as the claimed invention.”)
    • Specification: While each portfolio – and each invention – will be approached with a different strategy, it is possible that the “standard” practice of nationalizing a shared specification in multiple countries may need reconsideration.  That is, it may be helpful for applicants, under the right circumstances, to file different specifications, on the same day, in order to ensure proper support and avoid the myriad problems described above. An applicant may wish to consider whether to:
      • US: Draft a comprehensive and detailed description to meet the heightened enablement standard of Amgen, in particular emphasizing variations, alternatives, and differing examples to support each species of a genus (for example) – with the aim to meet the Court’s description that “[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.” Amgen, 143 S. Ct. at 1254.
      • UPC: Emphasize aspects of the invention that clearly step away from routine experimentation, and instead demonstrate a technological contribution, or distinct solution to a problem in an unexpected way.  Avoid extraneous details that could suggest a motivation or routine work in the field (See UPC Opinion at8.54 and 8.56, describing that “generating and selecting such antibodies was a matter of routine for the skilled person,” and that “the Defendant has not put forward any (technical) problems that the person skilled in the art would not have been able to overcome on the basis of their common general knowledge at the relevant date;” see also id. at 8.72, noting that “the Central Division is not convinced that the immobilisation techniques employed by Defendant go beyond techniques that the skilled person would have routinely employed at the relevant date.”)
    • Functional and Structural Language: As was at issue in the Amgen patents across both jurisdictions, claims which describe inventions functionally may need different treatment from those which describe inventions structurally. Practitioners must carefully consider the following issues:
      • US: A specification can recite functional language provided the specification provides sufficient detail to enable a skilled artisan to perform the function across the entire scope of the claim.  The court is wary of allowing broad “roadmaps” of functional limitations.   See Amgen, 143 S. Ct. at 1257 (“Through trial and error, imagine that an inventor finds and discloses 26 different successful lock combinations. But imagine, too, that the inventor tries to claim much more, namely all successful combinations, while instructing others to randomly try a large set of combinations and then record the successful ones. … Sure enough, that kind of ‘roadmap’ would produce functional combinations. But it would not enable others to make and use functional combinations; it would instead leave them to ‘random trial-and-error discovery.’”) (Internal citations omitted).  Structural claims seem less problematic, but should be supported by detailed descriptions, chemical structures, and/or amino acid or nucleotide sequences, where applicable, proportionate with the breadth of the desired claims.
      • UPC:  While functional claims can be used, recent case law makes clear that functional limitations must be backed by concrete embodiments demonstrating a non-obvious contribution or effect.  (See UPC Opinion at 8.67, stating that “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 the claim. In the present case, ending up with antibodies that fall under the scope of the claims of the Patent, including antibodies that bind to the catalytic domain of PCSK9, was obvious.”) With structural claims, reliance on specific feature-based limitations may help satisfy the inventive step requirement by clearly differentiating the invention from the known problem and existing solutions.

    It will be interesting to see how patent applicants and practitioners adapt and evolve in response to these recent decisions, as well as what ramifications these decisions will have globally.  Because certain patent offices in other jurisdictions closely follow EP decisions to set their own examination standards, while other jurisdictions follow US standards, and some jurisdictions have followed both US and EP standards, these decisions will have ramifications beyond just the US and Europe.  Undoubtedly, patent drafting and prosecution strategies will change and practitioners will need to stay vigilant to navigate the differing standards between the U.S. and UPC.

    Disclaimer: The information contained in this posting does not, and is not intended to, constitute legal advice or express any opinion to be relied upon legally, for investment purposes or otherwise. If you would like to obtain legal advice relating to the subject matter addressed in this posting, please consult with us or your attorney. The information in this post is also based upon publicly available information, presents opinions, and does not represent in any way whatsoever the opinions or official positions of the entities or individuals referenced herein.

    As a firm responsible for managing global portfolios for pharmaceutical companies, we closely follow and seek to stay abreast of developments regarding patentability in various jurisdictions. Thus, we reviewed the UPC’s first decision and provide a summary of the first revocation of a European patent by the new Unified Patent Court (UPC).

    Please note that our firm specializes in U.S. patent law. The analysis provided herein regarding the Sanofi-Aventis v. Amgen decision is for informational and educational purposes only. We suggest that parties seeking guidance on European patent matters consult with a qualified European patent attorney for authoritative advice and/or representation.

    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.

    Disclaimer: The information contained in this posting does not, and is not intended to, constitute legal advice or express any opinion to be relied upon legally, for investment purposes or otherwise. If you would like to obtain legal advice relating to the subject matter addressed in this posting, please consult with us or your attorney. The information in this post is also based upon publicly available information, presents opinions, and does not represent in any way whatsoever the opinions or official positions of the entities or individuals referenced herein.

    On November 17, 2023, Genentech, Hoffman-La Roche, and Biogen (collectively “plaintiffs”) filed a complaint in the federal district court for the District of New Jersey against Dr. Reddy’s Laboratories and Fresenius Kabi (collectively “defendants”) (DNJ No. 23-cv-22485). The plaintiffs allege that the defendants infringe or intend to infringe fifteen patents related to the biologic rituximab, which the plaintiffs sell as Rituxan.

    Rituximab is an anti-CD20 monoclonal antibody used for the treatment of various cancers and autoimmune diseases, including leukemia, lymphoma, and rheumatoid arthritis.[1] Rituxan (rituximab) was first FDA-approved in 1997.[2] There are currently three FDA-approved rituximab biosimilars on the market: Celltrion’s Truxima (approved in 2018), Pfizer’s Ruxience (approved in 2019), and Amgen’s Riabni (approved in 2020).[3] Dr. Reddy’s rituximab biosimilar is already approved and marketed as Reditux and Tidecron in India and several Latin American countries.[4]

    This is not the first BPCIA case the plaintiffs have filed over rituximab; complaints were filed against Sandoz in December 2017 and Celltrion in January 2018. Both complaints were also filed in D.N.J., and both cases were settled by the end of 2018. However, this is the first complaint filed since other rituximab biosimilars entered the market.

    [1] https://www.ncbi.nlm.nih.gov/books/NBK564374/

    [2] https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103705

    [3] https://www.goodrx.com/rituximab/biosimilars

    [4] https://www.gabionline.net/biosimilars/general/Biosimilars-of-rituximab

    As one BPCIA case came to a close in May[1], another got underway. On May 1, 2023, Amgen filed a complaint in the District of New Jersey, accusing Sandoz of infringing patents that relate to denosumab, the active ingredient in Amgen’s PROLIA and XGEVA. PROLIA is prescribed for a high risk of bone fracture in certain settings, for example, patients suffering from osteoporosis. XGEVA is prescribed to prevent skeletal-related events (e.g., fractures or spinal cord compression) in cancer patients whose cancer has spread to the bone, as well as to treat certain types of tumors.

    Back in February, the FDA accepted Sandoz’s FDA application for a proposed denosumab biosimilar. Now, Amgen is seeking a declaratory judgment of infringement and an injunction prohibiting the production and sale of the proposed biosimilar.

    Amgen v. Sandoz, 2:23-CV-02406 (D. N.J.), is one of three BPCIA cases we will continue to monitor and discuss. The other two cases are Regeneron v. Mylan, 1:22-CV-00061 (N.D. W. Va.) (Reference Product: EYLEA)[2] and Biogen v. Sandoz, 1:22-CV-1190 (D. Del.) (Reference Product: TYSABRI). Stay tuned to the Biosimilar Bulletin for updates on these cases and more.

    [1] On May 22, 2023, in Janssen Biotech v. Amgen, 1:22-CV-1549 (D. Del.), a joint stipulation of dismissal was filed due to settlement. https://www.biosimilarsip.com/2023/05/24/janssen-and-amgen-settle-stelara-bpcia-case/

    [2] The two-week trial scheduled in this case is currently proceeding in the Northern District of West Virginia. Updates to come.

    On Tuesday, May 23, 2023, Janssen and Amgen settled their case regarding Amgen’s proposed biosimilar to Stelara in Delaware district court.[1]

    Stelara, also known as ustekinumab, is an anti-IL-12/IL-23 antibody drug used to treat plaque psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis. Amgen has created a biosimilar of Stelara called ABP 654, which has the same amino acid sequence as ustekinumab. Amgen reportedly is conducting clinical studies to support interchangeability of ABP 654 with Stelara.[2] Janssen filed their complaint in November of 2022.

    Prior to settlement, the parties were in the midst of completing briefing for a preliminary injunction hearing, initiated by Janssen in an attempt to prevent Amgen from launching their biosimilar product. According to the amended complaint, Amgen provided its Section 8A 180-day notice of commercial marketing on November 7, 2022, and disclosed its aBLA to Janssen in early December 2022.[3] However, the case settled before Amgen filed its answering brief in opposition to the preliminary injunction. The terms of the settlement were not disclosed.

    [1] Ord. of Dismissal with Prejudice, 1, Janssen Biotech, Inc., v. Amgen Inc., No. 22-1549-MN (D. Del. May 23, 2023).

    [2] See First Amended Complaint ¶ 30, Janssen Biotech, Inc., v. Amgen Inc., No. 22-1549-MN (D. Del. May 23, 2023).

    [3] First Amended Complaint ¶¶ 40, 47, Janssen Biotech, Inc., v. Amgen Inc., No. 22-1549-MN (D. Del. May 23, 2023).

    Artificial Intelligence (AI) has long been associated with science fiction movies about dystopian futures, leading to fear among the general public about its potential impact. This is especially the case today for those in academia who have graded countless papers written by ChatGPT. However, the truth is far from what we see in the movies. In fact, one industry where AI is making significant progress is the biosimilar industry. AI offers many possibilities, including optimizing process design and process control, smart monitoring and maintenance, and trend monitoring to drive continuous improvement. Recently, the FDA has participated in discussions around AI and biotechnology.

    The FDA has already played an important role in the integration of AI in the biotechnology field. It has authorized more than 500 AI/ML-enabled medical devices, but last month, the FDA made two big contributions to the conversation. The first is its publication of a discussion paper on artificial intelligence in drug manufacturing to help proactively prepare for the implementation of AI in the field.[1] The second is an article the FDA published disclosing the implementation of AI-based modeling to analyze protein aggregation in therapeutic protein drugs.[2]

    1. FDA Discussion Paper – Artificial Intelligence in Drug Manufacturing

    In its discussion paper, the FDA requests public feedback to help inform its evaluation of the existing regulatory framework involving AI in drug manufacturing. The FDA suggests a number of areas for consideration.

    One such area is standards for developing and validating AI models. The FDA admits that there are limited industry standards and FDA guidance available for the development and validation of models that impact product quality. The lack of guidance is a concern since AI has such great applicability during drug manufacturing. AI can be used in applications to control manufacturing processes by adapting process parameters based on real-time data, or in conjunction with interrogation of in-process material or the final product to: (1) support analytical procedures for in-process or final product testing, (2) support real-time release testing, or (3) predict in-process product quality attributes.

    The FDA also notes the challenge applicants have in defining standards that validate an AI-based model and sustaining the ability to explain the model’s output and impact on product quality. As AI methods become more complex, it becomes more challenging to explain how changes in model inputs impact model outputs.

    Another area for consideration is how continuously learning AI systems that adapt to real-time data may challenge regulatory assessment and oversight. AI models can evolve over time as new information becomes available. The FDA states that it may be challenging to determine when such an AI model can be considered an established condition of a process. It also may be challenging to determine the criteria for regulatory notification of changes to these models as a part of model maintenance over the product lifecycle. Applicants may need clarity on: (a) the expectations for verification of model lifecycle strategy, and (b) expectations for establishing product comparability after changes to manufacturing conditions introduced by the AI model.

    Comments on these and other issues can be sent to the FDA at the link below.[3]

    2. FDA’s AI/Machine Learning Modeling to Ensure Safety and Demonstrate Biosimilarity

    Despite the limited guidance the FDA has for AI-based technologies, it recently published a study utilizing AI for characterizing protein aggregation, which will provide a more effective means of demonstrating biosimilarity and improve safety in therapeutic protein drugs.

    One major challenge that biosimilar developers face with therapeutic protein drugs is characterizing these products in order to compare them with a reference product. Characterization is particularly an issue because of protein aggregates that can create subvisible particles with a wide variety of sizes, shapes, and compositions from a variety of stress conditions. Although a small fraction of the total protein, these aggregates may increase the risk of undesirable immune responses.

    The FDA’s study characterized aggregate protein particles using flow imaging microscopy (FIM). This imaging technique can record multiple images of a single subvisible particle from a single sample. Although these image sets are rich in structural information, manual extraction of this information is cumbersome and often subject to human error, meaning that most of the information is underutilized.

    To overcome the shortcomings of current optical image analysis, the FDA applied convolutional neural networks (CNNs), a class of artificial neural networks proven helpful in many areas of image recognition and classification. This AI/ML approach enables automatic extraction of data-driven features (i.e., measurable characteristics or properties) encoded in images. These complex features (e.g., fingerprints specific to stressed proteins) can potentially be used to monitor the morphological features of particles in biotherapeutics, and enable tracking the consistency of particles in a drug product.

    CNNs can be trained with input data using supervised learning or a fingerprinting approach. For supervised learning, the AI model is trained using estimations of the most discriminatory parameters defined using images that are correctly labelled as either stressed or unstressed. Once trained, the CNN can predict which pre-defined labels best apply to a new image. The fingerprinting approach, on the other hand, is optimized to reduce the dimension of the spatially correlated image pixel intensities, resulting in a new lower dimensional (e.g., 2D) representation of each image. These lower dimensional representations can be used to analyze complex morphology encoded in a heterogeneous collection of FIM images since the full images can readily be mapped to a lower dimensional representation by the CNN.

    The FDA found that flow microscopy combined with CNN image analysis could be applied to a range of products and will provide potential new strategies for monitoring product quality attributes. Such technology will enable processing of large collections of images with high efficiency and accuracy by distinguishing complex “textural features” which are not readily delineated with existing image processing software.

    *            *            *

    As AI becomes more advanced and more of those in the biosimilar industry utilize this technology, the more guidance the FDA will have to provide, and the sooner the better. These two contributions from the FDA indicate that it is well aware of this need and is even looking to promote AI’s use across the pharmaceutical and biopharmaceutical fields.

    [1] https://www.fda.gov/media/165743/download

    [2] https://www.fda.gov/drugs/regulatory-science-action/artificial-intelligencemachine-learning-assisted-image-analysis-characterizing-biotherapeutics?utm_medium=email&utm_source=govdelivery

    [3] https://www.regulations.gov/  Docket No. FDA-2023-N-0487

    After the Supreme Court invited the Solicitor General to file a brief expressing the views of the United States regarding Teva Pharms USA, Inc. v. GlaxoSmithKline LLC, et al., the Solicitor General filed its brief amicus curiae on March 29, 2023. The Solicitor General urged the Supreme Court to grant Teva’s petition for a writ of certiorari. The Solicitor General indicated that even after an outcry of amici in response to the Federal Circuit’s initial decision, the Federal Circuit’s holding that a reasonable jury could view petitioner’s carved-out labeling as evidence of intent to induce infringement of respondents’ method-of-use patent further exacerbated the practical concerns raised by the court’s initial opinion. Specifically, the Solicitor General warned that under the Federal Circuit’s holding, a generic manufacturer that follows the Hatch-Waxman Amendments by marketing an FDA-approved label that carves out the brand-name indications claimed by a method-of-use patent can still be liable for intent to induce infringement.

    Additionally, the Solicitor General echoed Judge Prost’s dissent,[1] noting that “[t]he section viii pathway cannot function properly if FDA and generic manufacturers cannot rely on an NDA holder’s representations to the agency regarding which portions of the brand-name drug’s labeling teach patented methods of use.” Under the governing statutes, the FDA cannot authorize a generic drug that would infringe a patent, but it also lacks both the expertise and the authority to review patent claims. As such, it is the brand-name manufacturer’s responsibility to identify the portions of the approved labeling that correspond to the method of use claimed by the patent. Additionally, a generic manufacturer is not free to omit additional portions of the brand-name labeling beyond the omissions approved by the FDA. This uncertainty will deter generic manufacturers from invoking the section viii pathway, which may threaten the availability of lower-cost drugs. Further, the Solicitor General found that the Federal Circuit’s holding that “when a label instructs or teaches a patented use, it can be considered evidence of intent to encourage that use” as inappropriate here, as Teva’s labeling was driven by FDA regulatory requirements and GSK’s own identification of the indication that should be excised.

    Finally, in response to the Federal Circuit’s description of Teva’s marketing efforts, catalogs, and press releases that contributed to the finding of intent to induce infringement, the Solicitor General noted that this literature presented to doctors advised the doctors to read the labels and prescribe the drug as indicated by the labels. The Solicitor General stated, “Absent independent evidence that petitioner understood its carved-out labeling to encompass patented uses, proof that petitioner expected and encouraged doctors to rely on the labeling cannot support an inference of intent to induce infringement.”

    In light of the Supreme Court’s request that the Solicitor General file its brief amicus curiae, and the Solicitor General’s recommendation that the Supreme Court grant Teva’s petition for a writ of certiorari, it appears that the Supreme Court may agree to hear this case.  We will provide additional updates on this case if this happens.

    [1] GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., 7 F.4th 1320, 1342-1361 (Fed. Cir. 2021) (Prost, J., dissenting).

    Biosimilars are becoming increasingly important in healthcare as they offer a lower-cost alternative to biologic drugs, which can be expensive for patients, governments, and insurers.  These biologic medicines, which are highly similar to existing biological products and are designed to be as effective and safe as the brand name drugs, offer the potential to provide more affordable treatment options to patients. However, the regulatory landscape for biosimilars is still evolving, and there are legislative efforts to address several perceived impediments to biosimilar approvals and marketing.  To address some of the perceived impediments, various bills have been introduced since Congress passed the Biologics Price Competition and Innovation Act (BPCIA) in 2010. In this article, we will explore the latest updates in biosimilar legislation and their potential impact on patients, healthcare providers, and the pharmaceutical industry.

    One impediment is that various states and insurers will not allow pharmacists to substitute a biosimilar unless the FDA declares it to be “interchangeable.” Acquiring interchangeable status requires the product to undergo switching studies whereby participants must alternate between the biologic and the biosimilar. These studies can cost millions of dollars and further delay market access.  In November 2022, Sen. Mike Lee (R-Utah) introduced the Biosimilar Red Tape Elimination Act. The Bill aims to reduce health care costs and increase access to biosimilar drug products by eliminating switching studies as a requirement to obtain an “interchangeability” designation from the FDA. The interchangeability designation allows pharmacists to substitute the reference product for the biosimilar without requiring physician permission. Under Sen. Lee’s proposed Bill, corporations could more easily establish interchangeability, and therefore, patients could more easily obtain their biologic medications at a lower cost.  

    In January 2023, the biosimilar landscape saw the emergence of three new Bills that could have significant implications for the future of biologic medicines. Sen. Amy Klobuchar (D-MN) introduced the Stop STALLING Act and the Preserve Access to Affordable Generics and Biosimilars Act. Sen. John Cornyn [R-TX] introduced the Affordable Prescriptions for Patients Act of 2023.

    Another impediment is that some drug manufacturers have submitted numerous or baseless citizens petitions so that the FDA would delay competing manufacturers’ biosimilar or generic approvals.  The Stop STALLING Act seeks to deter branded pharmaceutical companies from filing what it claims is a “sham” citizen petition with the FDA in order to interfere with the regulatory approval process for competitors’ generics and biosimilars. Such delays prevent patient access to affordable medication. The Bill would give the FTC enhanced authority to take action against companies that file these sham petitions to delay market entry. The FTC could “commence a civil action to recover a civil penalty and seek other appropriate relief in a district court of the United States against any person that submitted or caused to be submitted” a petition (e.g., a “citizens petition”) if the FTC has reason to believe it is a “sham” petition.

    Pay-for-delay deals, the practice in which drug companies use pay-off agreements to delay the introduction of cheaper substitutes, is another impediment.  The Preserve Access to Affordable Generics and Biosimilars Act would prohibit anticompetitive “pay-for-delay deals” that prevent or delay the introduction of affordable generics. The bill targets “reverse payment” settlement agreements which are categorized as “allow[ing] a branded company to share its monopoly profits with the generic company as a way to protect the branded company’s monopoly” and “unduly delay the marketing of low-cost generic drugs contrary to free competition, the interests of consumers, and the principles underlying antitrust law.” These deals increase the cost of prescriptions and impose significant costs on our health care system.

    Finally, Sen. Cornyn’s Affordable Prescriptions for Patients Act would curb drug companies’ abuse of patents through “product hopping,” where companies extend exclusivity by switching patients to a new, slightly changed, version of the branded drug while the older version succumbs to generics. Some examples of this behavior include destroying the inventory of the old drug, pulling it from the market, aggressively raising its price, badmouthing the old drug, or even diminishing its safety. As a result of this conduct, patients are stuck paying more for a drug that is substantially similar to the old one. 

    Relatedly, on February 22, 2023, Sen. Elizabeth Warren along with Sen. Bernie Sanders and Representatives Katie Porter and Pramila Jayapal sent a letter to Kathi Vidal, director of the United States Patent and Trademark Office (USPTO), arguing that Merck’s development of a subcutaneous version of the biologic drug Keytruda® (pembrolizumab) appears to be an example of anti-competitive business practices, including double-patenting, patent thicketing, product hopping, and evergreening.

    Thus, while biosimilars are increasingly important in reducing healthcare costs and increasing patient access to lifesaving medicines, there are various perceived impediments to biosimilar approvals and marketing that will need to be addressed. It is clear that the regulatory landscape for biosimilars is evolving, and we can expect to see more legislation in the coming years as the biosimilar industry continues to grow.

    The United States Patent and Trademark Office (USPTO) issued updated guidance on the duty of candor and duty to disclose in relation to submissions made to other government agencies, particularly the Food and Drug Administration (FDA). The Notice did not constitute new rule making and instead aims to clarify the obligations of patent applicants and attorneys to disclose all relevant information to the USPTO. However, in light of the Notice, patent applicants and patent owners should expect to see an increase in the number of patent examiner requests for further documents and information, and invalidity or unenforceability challenges from third parties based on a failure to disclosure or for alleged inconsistent statements made to other governmental regulatory agencies such as the FDA.

    Each individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability. Specifically, 37 CFR 1.56(a) and 1.555(A) state that the duty to disclose applies to “[e]ach individual associated with the filing and prosecuting of a patent application” and “[e]ach individual associated with the patent owner in a reexamination proceeding.” Fed. Reg. Vol. 87, No. 145 at 45765. Specifically, this announcement was designed to remind current or would be applicants that this duty to disclose extends to statements made to other governmental agencies, such as the FDA, in order to obtain licensing or regulatory approval. “If a party to a USPTO proceeding discovers that an earlier position taken in a submission to the USPTO or another Government agency was incorrect or inconsistent with other statements made by the party, the party must promptly correct the record.” Id. The USPTO particularly noted that “when examining a claim directed to a process of manufacturing a particular drug product that was effectively filed more than one year after FDA approval of the drug product, an examiner may appropriately require an applicant to submit to the USPTO information submitted to the FDA (e.g. in a New Drug Application or Biologics License Application) on how the drug product was manufactured.” Id. at 45766.

    This announcement was made in direct response to President Biden’s July 2, 2021 Executive Order on Promoting Competition in the American Economy, which, among addressing other issues, expressed concern that “too often, patent and other laws have been misused to inhibit or delay—for years and even decades—competition from generic drugs and biosimilars, denying Americans access to lower-cost drugs.” Id. at 45764 (quoting 86 FR 36987). Following Biden’s executive order, Senators Patrick Leahy and Thom Tillis drafted a letter to Andrew Hirshfeld, then Under Secretary of Commerce for Intellectual property and Director of the USPTO, to “take steps to reduce patent applicants’ making inappropriate conflicting statements in submissions to the [USPTO] and other federal agencies,” specifically noting inconsistent, and at times conflicting, statements made to the FDA and the USPTO Id. at 45764-65.

    Although, this notice “clarifies the ’duty of disclosure’ and ‘duty of reasonable’ inquiry owed to the USPTO and American public,” it should be noted that this has always been the rule. Id. at 45765. The updated guidance from the USPTO includes several examples to help clarify the duties of candor and disclosure. Belcher Pharmaceuticals, LLC v. Hospira, Inc., 11 F.4th 1345 (Fed. Cir. 2021) (failure to disclose to USPTO inconsistent statements to FDA invalidated patent claims); Bruno Independent Living Aids, Inc. v. Acorn Mobility Services, Ltd., 394 F.3d 1348 (Fed. Cir. 2005) (finding failure to disclose inconsistent was an “exceptional case” and awarding attorney fees).

    What must be disclosed to the USPTO?

    1. Any information that is material to patentability (including but not limited to: prior art, prior sales, prior offers for sale, positive or negative testing data, FDA submissions, third party documents).
    2. Third party documents may include, for example, paragraph IV notices, patent dance documents, third party submissions to the applicant or PTO in other application/proceeding, or patent office in another country.
    3. Must correct any incorrect or inconsistent positions taken in a submission to the USPTO or to another Government agency.

     “A duty of reasonable inquiry may exist based on circumstances known to the party presenting the paper to the USPTO.” See Fed. Reg. Vol. 87, No. 145 at 45766. This duty includes reviewing documents that are submitted to or received from other Government agencies, including the FDA. Bruno independent Living Aids, Inc. v. Acorn Mobility Services, Ltd., 394 F.3d 1348 (Fed. Cir. 2005) (prior art “equivalent” submitted in FDA docs was not disclosed to PTO: unenforceable and “exceptional” case with attorney’s fees). Failing to inquire “when the circumstances warrant it” could result in sanctions or other adverse action. This duty also includes inquiring about and disclosing prior offers for sale or sales. GS Cleantech Corp. v. Adkins Energy LLC, 951 F.3d 1310 (Fed. Cir. 2020) (offer for sale more than one year prior to filing, patent prosecutor withheld it from PTO, unenforecable). Other situations may include patent prosecutors consulting with litigation teams and foreign patent counsel to ensure that third party documents from such proceedings are disclosed to the USPTO.

    The Notice is a valuable reminder that applicants should immediately implement reasonable procedures to maintain open lines of communication between U.S. patent prosecution counsel and personnel involved in communications with FDA (or other relevant government agency), as well as litigation and foreign patent counsel in relevant situations. Such open lines of communication will reduce risks of a failure to disclose material information. Further, such communications can reduce the risk of inconsistent statements being made to government agencies, and, in the event a seemingly inconsistent statement is made, allow the patent applicant to attempt to promptly correct the record.

    Patent counsel can provide an invaluable service to companies concurrently seeking patent protection and FDA approval. Given that patent counsel is already deeply familiar with the patentability issues and trained in spotting material information, consulting with patent counsel can efficiently prevent a failure to comply with the duty of disclosure and avoid submission of inconsistent statements that violate the duty of candor. Moreover, given that drug development often involves complex partnering relationships between two or more companies, patent counsel can play an integral role in preserving privilege in such situations.

    Disclaimer: The information contained in this posting does not, and is not intended to, constitute legal advice or express any opinion to be relied up legally, for investment purposes or otherwise. If you would like to obtain legal advice relating to the subject matter addressed in this posting, please consult with us or your attorney. The information in this post is also based upon publicly available information, presents opinions, and does not represent in any way whatsoever the opinions or official positions of the entities or individuals referenced herein.