Since the America Invents Act (“AIA”) established a new venue for hearing patent disputes, the Patent Trial and Appeal Board (“PTAB”), much ink has been spilled regarding the impacts of this forum on patent litigation and the overall intellectual property strategies employed by both patentees and challengers. The Promoting and Respecting Economically Vital American Innovation Leadership (“PREVAIL”) Act was recently sent to the Senate from the Committee of the Judiciary after an 11-10 vote, and it proposes regulations that could significantly change the ways that PTAB proceedings are conducted. What follows is a summary of the Act’s most substantive proposals.

The Act would implement a standing requirement for petitioners in line with what is required to bring a declaratory judgement action for invalidity in Article III courts. The Act also sets forth regulations that would estop challengers from raising arguments that were previously asserted in another PTAB proceeding or Article III court against the same patent; and challengers would no longer be able to assert invalidity against the same patent in both forums at the same time. The Act would also broaden the PTAB’s standard for determining the real parties in interest to a dispute. 

In addition to new standing requirements and procedural definitions, the Act would raise the burden of proof at the PTAB to match that of an Article III court, i.e, a challenger would have the burden to prove patent invalidity by a clear and convincing standard, rather than a preponderance of the evidence. 

Proponents of the PREVAIL Act argue that it is necessary to restore fairness to the PTAB by preventing multiple challengers from working together to bring separate or repeated challenges against a single patent or patent owner. Those in support of the Act also argue that it is necessary to harmonize the laws applied at the PTAB and Article III courts. Senator Coons, who introduced the bill, provided the following explanations for how the Act would solve problems with PTAB trials:

Problem:  Currently, anyone can challenge a patent in the PTAB, even if they are not facing a lawsuit or the threat of a lawsuit. Multiple parties can also work together to bring separate or repeated challenges against a single patent or patent owner—including small businesses or independent innovators with limited resources.  

Solution:  Require standing for PTAB challengers and limit repeated petitions.  The PREVAIL Act requires challengers to have been sued or threatened with a patent infringement lawsuit before filing a PTAB challenge. The bill also limits multiple PTAB challenges against the same patent by prohibiting any entity financially contributing to a PTAB challenge from bringing its own challenge.  

Problem: Although a party must file a PTAB challenge within one year of being sued for infringement, a loophole allows a time-barred party to challenge patents after the PTAB filing deadline expires by joining a PTAB proceeding brought by another party.  

Solution: Close the loophole.  The PREVAIL Act establishes a rebuttable presumption against joinder for a time-barred party and prohibits such a party from maintaining the proceeding after the original challenger settles.

Problem: Currently, the same party can file multiple petitions against the same patent, allowing challengers to paper over weaknesses in their case and increasing costs for patent owners defending their rights.

Solution: Require a party to raise all arguments in one challenge to protect a patent owner’s right to “quiet title” over the invention. The PREVAIL Act limits serial petitions by applying estoppel at the time the challenge is filed, rather than after a PTAB final written decision.

Problem: When validity of a patent is challenged in district court, “clear and convincing” evidence is needed to invalidate the patent. But at the PTAB, a petitioner need only show invalidity by a “preponderance of the evidence” standard. Further, until recently, the PTAB interpreted patent claims under a different standard than the district court. These differences often lead to inconsistent results between the two tribunals.

Solution: Harmonize PTAB claim interpretation and burden of proof with federal district court. The PREVAIL Act requires the PTAB to find a patent invalid by “clear and convincing” evidence and requires the PTAB to interpret claims using the same “plain and ordinary meaning” standard used in federal district court.  

Problem: Some aspects of PTAB proceedings lack transparency. For example, no rules prevent the Director from meddling in a PTAB panel’s decision.  

Solution: Increase transparency. The PREVAIL Act requires the USPTO Director to issue separate written opinions when rehearing PTAB decisions to increase transparency and reduce concerns that the Director unfairly influences PTAB decisions. The bill also prohibits the Director from influencing PTAB panel decisions and requires the Director to establish a code of conduct for PTAB judges.   

Problem: Currently, at least 85% of PTAB proceedings have a co-pending proceeding in another forum, like federal district court. Challengers get several bites at the apple by raising the same or similar validity challenges at the PTAB and the other forum.

Solution: End duplicative patent challenges. The PREVAIL Act requires a party to choose between making its validity challenges before the PTAB or in another forum, such as federal court. The bill also requires a party that is already involved in a separate proceeding to agree not to pursue the claims in their PTAB petition in that court, or any other forum.   

Problem: Often, another forum, such as a federal district court, reviews a challenger’s validity challenge to a patent and enters a final judgment on validity before the PTAB completes its review. Instituting or maintaining a PTAB proceeding after the district court already has decided validity is duplicative, inefficient, and may lead to inconsistent decisions between both tribunals.

Solution: Prioritize prior patent validity decisions. The PREVAIL Act requires the PTAB to deny a petition or dismiss a proceeding if another forum—such as a federal court—has already upheld the validity of the patent at issue.  

Problem: A PTAB challenge or a reexamination request often will assert the same prior art or arguments that the USPTO already considered during another Office proceeding. Multiple proceedings asserting the same prior art and arguments are costly and inefficient.  

Solution: Limit duplicative challenges to a patent within the USPTO.  The PREVAIL Act requires the USPTO to reject a PTAB challenge or a request to reexamine a patent where the challenge or request includes arguments that were previously considered by the USPTO, absent exceptional circumstances.

Problem: Since 2010, approximately $409.8 million in user fees have been diverted from the USPTO.

Solution: Eliminate fee diversion. The PREVAIL Act ends the practice of diverting fees collected by the USPTO to other unrelated federal agencies and programs by establishing a new revolving fund in the U.S. Treasury to ensure the USPTO has the funding necessary for timely and quality examination.  

Problem: Small businesses do not always have the resources they need to navigate the patent system.  

Solution: Support innovative small businesses. The PREVAIL Act supports small businesses by requiring the Small Business Administration to draft two reports examining the impact of patents and abusive demand letters on small businesses.  The bill also expands access to patent-searching databases currently available only in-person at public search facilities. 

Critics of the PREVAIL Act are concerned that it would tilt the balance too far in favor of patentees, potentially undermining the goals of the patent system to promote innovation and fair competition. Among many others, critics are concerned about the impact the Act’s standing provisions would have on individuals who currently have the right to challenge patents at the PTAB (e.g., non-practicing entities), but may lose that ability under the Act’s more restrictive criteria, potentially limiting access to this important mechanism for addressing questionable patents. Others argue that the Act would raise consumer drug prices by making it harder for patient advocacy groups and generics manufacturers to increase competition by challenging wrongfully issued drug patents. Further, critics argue that by restricting access to PTAB proceedings, the Act could reduce the number of challenges brought against questionable patents, allowing invalid patents to remain unaddressed and creating barriers to competition. In addition, critics contend that the provisions could shift patent litigation to federal courts, where proceedings are often more costly and time-consuming than PTAB reviews, which could disproportionately burden smaller businesses and startups with fewer resources. Also, while the PTAB has been touted as a tool in combating abusive practices by “patent trolls” by providing a relatively efficient and cost-effective means of invalidating overly broad or weak patents, critics argue that limiting access to the PTAB could embolden these entities to assert low-quality patents more aggressively. Overall, critics believe the Act would erode the effectiveness of the PTAB, increase litigation costs, and shift the balance of the patent system in a way that harms competition and innovation. They argue that reforms should focus on improving patent quality and accessibility rather than limiting the avenues for challenging questionable patents.

In sum, the PREVAIL Act would change how patent challengers and patent owners proceed before the PTAB. We will continue to monitor and report on the Act as it moves through the Senate. In the meanwhile, potential challengers and patent owners should assess their litigation strategies and planned timing in light of potentially significant changes in PTAB trials.

Sources:

https://www.congress.gov/bill/118th-congress/senate-bill/2220/text

https://ipwatchdog.com/2024/11/21/prevail-act-narrowly-moves-forward-despite-concerns-drug-pricing-impact/id=183421/

On December 20, 2024, the U.S. Court of Appeals for the Federal Circuit issued a significant ruling in the Teva v. Amneal case following oral arguments before the Federal Circuit, which we discussed in our previous article. The Federal Circuit affirmed the district court’s decision that Teva’s patents were improperly listed and must be removed from the Orange Book.[1] The ruling clarifies that the statutory framework for Orange Book listings require listed patents to claim the active ingredient of the approved drug.[2] Patents claiming solely device components of a combination product are not listable in the Orange Book.[3]

Background of the Dispute

The case arose over Teva’s ProAir® HFA, a metered-dose inhaler containing albuterol sulfate, a medication used to treat bronchospasm.[4] Teva had listed nine non-expired patents in the FDA’s Orange Book relating to the ProAir® HFA.[5] The five asserted patents claim physical components of an inhaler, and not the active ingredient (albuterol sulfate).[6]

When Amneal filed an Abbreviated New Drug Application (ANDA) with a paragraph IV certification, Teva sued Amneal for patent infringement under the Hatch-Waxman Act.[7] In response, Amneal filed several counterclaims, including a claim seeking an order requiring Teva to delist the five asserted patents from the Orange Book.[8] The district court concluded that the asserted patents are not directed to the active ingredient—albuterol sulfate—but rather to the metered inhaler device and rejected Teva’s arguments that (1) under the Hatch-Waxman Act a patent claims a drug if the approved drug infringes the patent and (2) the asserted patents are Orange Book listable because the claimed articles are intended for use as a component of ProAir® HFA.[9] The district court ordered Teva to remove the challenged patents from the Orange Book, which the Federal Circuit has now affirmed.[10]

The Court’s Reasoning

  1. Statutory interpretation

    The Federal Circuit explained that a patent that “claims the drug for which the applicant submitted the application” in 21 U.S.C. § 355(b)(1)(A)(viii)(I) does not mean that “the claim could somehow be interpreted to read on the drug.”[11] The Federal Circuit rejected Teva’s argument that a patent claims a drug if the approved drug would infringe the patent.[12] The Federal Circuit clarified that “[w]hether Teva’s [New Drug Application (NDA}] infringes Teva’s patents is separate from the issue of whether those patents actually claim the drug for which Teva submitted the application.”[13] Moreover, the Federal Circuit noted that, contrary to Teva’s assertions, this decision aligns with earlier rulings, such as Apotex and United Food.[14] The Federal Circuit concluded that “Teva’s argument does not acknowledge that claiming and infringement have separate statutory bases and that the listing provision identifies both as separate requirements.”[15] It held that determining whether a patent is properly listed involves considerations of both claiming the drug and reasonably asserting infringement.[16] The Federal Circuit further noted that interpreting the statute provision according to Teva’s interpretation would create statutory redundancy.[17] In this case, the Federal Circuit found that Teva’s patents, which were directed to the inhaler’s device components, did not meet these statutory requirements.[18]

    1. Orange Book Listable Patents

      Turning to the issue of which patents are Orange Book listable, the Federal Circuit dismissed Teva’s argument that these patents were properly listed because they covered the ProAir® HFA device.[19] The Federal Circuit clarified that a patent must specifically claim the active ingredient or its formulation, or an approved method of using the drug, in order to be eligible for listing in the Orange Book.[20] This conclusion is based on the drug regulatory approval pathway, which focuses on the active ingredient.[21] In contrast, the Federal Circuit noted that devices have a distinct approval pathway.[22] 

      The Federal Circuit rejected Teva’s arguments that (1) this interpretation is inconsistent with the statutory definition of a drug as a component for use in an article to treat disease, and (2) its ProAir® HFA inhaler—a combination product containing both drug and device components—should allow the device-related patents to be listed in the Orange Book.[23] The Federal Circuit noted that “the fact that the FDA approved Teva’s ProAir® HFA combination product as a drug does not make the inhaler’s device parts a drug. They are still devices, just ones present in the product that was approved, in a single application, under the NDA pathway.”[24] Therefore, the Federal Circuit concluded that patent claims directed only to a product device feature, such as the inhaler’s dose counter mechanism, is insufficient.

      Lastly, The Federal Circuit dismissed Teva’s request for a remand for the district court to construe the claims of its patents, arguing that they did claim an active ingredient. [25] The Federal Circuit found no need for a Markman hearing in this instance because, even under Teva’s proposed construction, the claims of the asserted patents do not satisfy the statutory requirement of claiming the active ingredient as Teva’s proposed construction merely would require reading the presence of “an active drug” into the claims.[26]  The Court explained that a claim requiring “an active drug” is far too broad to particularly and distinctly claim the drug approved in Teva’s product.

      Implications for the Pharmaceutical Industry

      The decision is significant for both innovator and generic pharmaceutical companies. For innovator companies, the ruling serves as a reminder to carefully review which patents are included in the Orange Book to ensure compliance with the Hatch-Waxman Act’s requirements.

      For generic drug manufacturers, this decision provides an opportunity to challenge improper listings that may delay their market entry. Generic drug manufacturers may seek delisting of patents that do not directly claim the active ingredient of a drug to expedite FDA approval as part of their overall strategy for bringing their products to market.

      In 2023-2024, the Federal Trade Commission (“FTC”) sent warning letters to numerous pharmaceutical manufacturers for improper or inaccurate listings of patents in the Orange Book, and notified the FDA that it disputes more than 300 Orange Book patents listings across 20 different brand name products.  Immediately upon release of the Federal Circuit’s decision, the FTC issued the following statement:

      We are pleased the court agreed with the FTC that these improper inhaler patent listings must be wiped from the Orange Book. Removal of junk patent listings is critical to ensuring drugmakers can fairly compete to offer generic drugs at a lower price for consumers. This decision is important not only for lowering asthma inhaler costs, it also sets the stage for removal of junk listings on a range of other critical medications where junk device listings impede competition.

      The Federal Circuit’s ruling in Teva v. Amneal clarifies the requirements for Orange Book patent listings under the Hatch-Waxman framework and marks a victory for generic drug developers.  In view of the decision and the numerous patents that have been flagged by the FTC, it will be interesting to see if pharmaceutical manufacturers that are on notice will now remove patents from the Orange Book or continue to maintain their listings and await litigation or Federal enforcement actions.

      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.

      [1] Teva Branded Pharm. Prods. R&D, Inc. v. Amneal Pharms. of New York, LLC, No. 2024-1936, 2024 WL 5176737 (Fed. Cir. Dec. 20, 2024).

      [2] Id.

      [3] Id.

      [4] Id. at 5.

      [5] Id. at 6.

      [6] Id. at *7.

      [7] Id.

      [8] Id.

      [9] Id.

      [10] Id.  As of December 23, 2024, all five of Teva’s patents that are the subject of this decision remain listed in the Orange Book.

      [11] Id. at 12.

      [12] Id. at 11.

      [13] Id.

      [14] See id. at 11-12; Apotex, Inc. v. Thompson, 347 F.3d 1335 (Fed. Cir. 2003); and United Food & Commercial Workers Local 1776 v. Takeda Pharmaceutical Co., 11 F.4th 118 (2d Cir. 2021).

      [15] Id. at 12.

      [16] Id.

      [17] Id. at 9.

      [18] Id.

      [19] Id. at 13.

      [20] Id.

      [21] Id. at 14.

      [22]  Id. at 13-14.

      [23] Id. at 15.

      [24] Id. at 16.

      [25] Id. 17.

      [26] Id.

      On December 3, 2024, Bristol Myers Squibb announced a collaboration agreement with three-year-old startup AI Proteins.[1] According to its founder, Chris Bahl, PhD, AI Proteins uses “AI, synthetic biology, and laboratory automation to rapidly design and optimize novel miniproteins with ideal drug-like properties.”[2] The end goal of this collaboration is likely biologic products incorporating AI-generated proteins. This is the latest in a long series of signs that the pharmaceutical industry is continuing to invest in the use of artificial intelligence in drug discovery.[3]

      On February 13, 2024, the United States Patent and Trademark Office (USPTO) released guidance on AI-assisted inventions.[4] This guidance was drafted in light of President Biden’s October 30, 2023, Executive Order on AI[5] and the Federal Circuit’s 2022 decision in Thaler v. Vidal, which determined that an AI system cannot be an inventor.[6] The USPTO explained that use of an AI system in inventing does not per se render an invention unpatentable, but, in the view of the USPTO, a natural person must have contributed in “some significant manner” to the invention to qualify as an inventor under the Pannu factors.[7] This view has been criticized[8], and it is unclear whether the Federal Circuit will follow the USPTO’s position.   

      Because the law around AI inventorship is still emerging, patent prosecutors in the biologic space and biosimilar litigators should keep a close eye on the law as it develops. It remains to be seen whether Bristol Myers Squibb’s collaboration with AI Proteins—or any other use of AI—will result in any marketed biologic product. However, if we do eventually see a proliferation of AI designed biologics, inventorship may become a major issue in future biosimilar litigation.

      For now, would-be biologic innovators should keep these issues in mind, lest their patent portfolios be weakened from the inception.[9] Pharmaceutical companies investing in AI discovery tools should ensure that natural persons are still making significant contributions. Meanwhile, would-be biosimilar manufacturers should watch closely should this issue arise in BPCIA or other patent litigation.

      [1] Kevin Dunleavy, AI Proteins lands $400M drug discovery deal with Bristol Myers, Fierce Biotech (Dec. 3, 2024).

      [2] Id.

      [3] See Carrie Arnold, Inside the nascent industry of AI-designed drugs. 29 Nat Med 1292–1295 (2023) https://doi.org/10.1038/s41591-023-02361-0; Three ways AI is changing drug discovery at AbbVie | AbbVie.

      [4] Inventorship Guidance for AI-Assisted Inventions, 89 Fed. Reg. 10043 (Feb. 13, 2024) Federal Register: Inventorship Guidance for AI-Assisted Inventions.

      [5] Exec. Oder No. 14110 (Oct. 30, 2023) Executive Order on the Safe, Secure, and Trustworthy Development and Use of Artificial Intelligence | The White House.

      [6] Thaler v. Vidal, 43 F.4th 1207 (Fed. Cir. 2022).

      [7] Pannu v. Iolab Corp., 155 F.3d 1344, 1351 (Fed. Cir. 1998) (“All that is required of a joint inventor is that he or she (1) contribute in some significant manner to the conception or reduction to practice of the invention, (2) make a contribution to the claimed invention that is not insignificant in quality, when that contribution is measured against the dimension of the full invention, and (3) do more than merely explain to the real inventors well-known concepts and/or the current state of the art.”).

      [8] ABA-IPL Comment Letter to USPTO Inventorship Guidance for AI Assisted Inventions (May 14, 2024) https://downloads.regulations.gov/PTO-P-2023-0043-0051/attachment_1.pdf

      [9] See Annelise Gilbert et al, AI Helps Pharma Find New Drugs But Imperils Lucrative Patents, Bloomberg Law (Apr. 4, 2024).

      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.

      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.

      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.  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.

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      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