Approved in 2017 by the U.S. Food and Drug Administration (FDA) to treat diabetes, Novo Nordisk’s Ozempic® is often prescribed off-label for weight loss. Novo Nordisk formulated another version of Ozempic®, Wegovy®, which was approved by the FDA in 2021 specifically for weight loss. According to Novo Nordisk’s 2022 annual report, worldwide net sales of Ozempic® in 2022 were approximately $8.4 billion.
With all the buzz and popularity surrounding these drugs, challenges have ensued. This article highlights a few of those challenges.
Ozempic® Issues at the Federal Trade Commission (FTC)
On April 30, 2024, the FTC sent warning letters to 10 companies and notified the FDA that it disputed more than 300 patent listings as being improper or inaccurate in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (commonly known as the Orange Book), including Ozempic®.
The Orange Book identifies drug products approved on the basis of safety and effectiveness by the FDA under the Federal Food, Drug, and Cosmetic Act and related patent and exclusivity information. Improper Orange Book patent listings can delay cheaper generic alternatives from entering the market, keeping brand name drug prices high. According to FTC chair Lina M. Khan, “[b]y challenging junk patent filings, the FTC is fighting these illegal tactics and making sure that Americans can get timely access to innovative and affordable versions of the medicines they need.”
When the patent listing is disputed, “the FDA will send the dispute to the branded drug manufacturer who will then have 30 days to withdraw or amend the listing, or certify under penalty of perjury that the listing complies with applicable statutory and regulatory requirements.”
This, however, has not been the only challenge to GLP-1 agonists.
Ozempic® Dispute at the Patent Trial and Appeal Board (PTAB)
On October 4, 2023, the PTAB granted an inter partes review (IPR) request by petitioner Mylan Pharmaceuticals Inc. of several claims of U.S. Patent No. 10,335,462 (’462 patent) entitled “Use of Long-Acting GLP-1 Peptides” and covering Ozempic®. The real parties in interest in the IPR included Mylan Pharmaceuticals Inc., Mylan Inc., and Viatris Inc.
During trial proceedings conducted by the PTAB, a challenger may petition for the institution of an IPR nine months after the grant or reissuance of a patent to review one or more claims on a patentability ground raisable under 35 U.S.C. § 102 or § 103 on the basis of prior art (e.g., printed publications or patents). The PTAB will institute this proceeding if the petition meets the threshold showing that there is a “reasonable likelihood” that the challenger will prevail with respect to at least one of the claims challenged. This burden never shifts to the patent owner, and an IPR results in a “final written decision with respect to the patentability of any [challenged] patent claim.”
In general, to show anticipation under § 102, each and every claim element, arranged as in the claim, must be found in a single prior art reference. A reference may also anticipate a claim even if it does not expressly teach all the limitations arranged or combined as in the claim “if a person of skill in the art, reading the reference, would ‘at once envisage’ the claimed arrangement or combination.”
A claim is unpatentable under § 103 if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. The question of obviousness is resolved on the basis of underlying factual determinations, including: (1) the scope and content of the prior art, (2) any differences between the claimed subject matter and the prior art, (3) the level of ordinary skill in the art, and (4) objective evidence of nonobviousness, if any. A party who petitions the PTAB for a determination of unpatentability based on obviousness must show that “a skilled artisan would have been motivated to combine the teachings of the prior art references to achieve the claimed invention, and that the skilled artisan would have had a reasonable expectation of success in doing so.”
The ’462 patent issued on July 2, 2019, and has an anticipated expiration date in 2033. It is directed to the “use of long-acting GLP-1 peptides in certain dosage regimes for the treatment of type 2 diabetes, obesity, etc.” The sole example provided describes administering semaglutide, “a unique acylated GLP-1 peptide with a half-life of 160 hours,” to “investigate HbA1c dose-response of once-weekly doses of semaglutide (five dose-levels) in subjects with type 2 diabetes. Safety, tolerability and pharmacodynamics of semaglutide versus placebo and open-label once-daily liraglutide were also investigated.” The ’462 patent concludes as follows:
Over 12 weeks, semaglutide dose-dependently reduced HbA1c and body weight. The effect of semaglutide 0.4 mg on glycemic control and body weight was comparable to that of liraglutide 1.2 mg, while semaglutide ≥0.8 mg appeared to bring more subjects to target and provided better weight loss than liraglutide 1.8 mg. No semaglutide safety concerns were identified. Dose escalation was not a major focus of this trial and it will be optimized in future clinical trials.
In the IPR, the petitioner challenged claims 1–10 of the ’462 patent, of which claim 1 is representative: “1. A method for treating type 2 diabetes, comprising administering semaglutide once weekly in an amount of 1.0 mg to a subject in need thereof.” The petitioner asserted two grounds of anticipation for claims 1–3 and three grounds of obviousness for claims 1–10. Specifically, the petitioner asserted that Patent Cooperation Treaty (PCT) Publication No. WO 2011/138421 A1 (WO ’421) anticipated claims 1–3 of the ’462 patent under § 102(a) and (e), and a review of clinical data by Lovshin anticipated claims 1–3 of the ’462 patent under § 102(b). The petitioner additionally asserted that certain combinations—(1) WO ’421 and U.S. Patent Application Publication No. 2007/0010424 A1 (’424 publication), (2) Lovshin and PCT Publication No. WO 2006/097537 A2 (WO ’537), and (3) the ’424 publication, clinical trial NCT657, and clinical trial NCT773—rendered claims 1–10 obvious under § 103(a).
Regarding the single nonfinal office action that was issued in the ’462 patent on July 23, 2018, the petitioner asserted the following:
The Examiner’s single rejection—considering claims differing significantly from those that ultimately issued—never considered, let alone applied, [WO ’421], [WO ’537], the ’424 publication, NCT773 or Lovshin. And with respect to NCT657—the only primary reference the Examiner considered—the Examiner materially misapprehended it.
[WO ’421] and Lovshin both disclosed ranges of once-weekly doses of 0.1–1.6 mg that encompass the 1.0 mg dose now claimed. NCT773 disclosed a clinical trial using once-weekly doses of semaglutide with a maximum dose of 1.2 mg. [WO ’537] disclosed details regarding semaglutide and specified methods of using it more broadly than NCT657. And the ’424 publication disclosed formulation components not detailed in NCT657.
The Examiner’s single rejection of the claims concerning semaglutide focused on anticipation by NCT657 in view of post-priority date pharmacokinetic parameters. The Examiner never considered [WO ’421] or Lovshin, let alone analyzed their disclosed range of doses as related to anticipation.
The patent owner responded that WO ’421 and WO ’537 were listed on an information disclosure statement, which the examiner considered, and that the remaining references relied on by the petitioner were cumulative of previously presented references. The petitioner responded that the U.S. Patent and Trademark Office (USPTO) “never applied any of the Petition’s prior art combinations during prosecution of the [’462 patent].”
Though the PTAB disagreed with the patent owner that the ’462 publication and NCT773 were cumulative of prior art previously presented to the USPTO, the PTAB found that the same art and arguments previously before the USPTO were presented in the petition, namely, a teaching of administering semaglutide once weekly in a dose range of 0.1–1.6 mg that includes a dose of 1.0 mg.
The patent owner asserted that the PTAB should exercise its discretion to deny institution of the IPR under 35 U.S.C. § 325(d) and § 314(a). After review, the PTAB determined that the petitioner had sufficiently demonstrated a material error on the part of the examiner: the examiner’s statement that NCT657 “does not teach or disclose a higher amount of 1 mg semaglutide” was incorrect and failed to consider the teachings of the dosing ranges of WO ’421 and Lovshin, and the maximum dose of 1.2 mg of semaglutide taught in NCT773. As such, the PTAB declined to deny institution of the IPR under § 325(d). Moreover, the PTAB found nothing that would warrant the exercise of the PTAB’s discretion to deny institution of the IPR based on § 314(a).
After reviewing the remainder of the petitioner’s and the patent owner’s arguments, the PTAB found that the petitioner had shown a reasonable likelihood that it would prevail in establishing that at least one claim of the ’462 patent was unpatentable. Specifically, the PTAB noted that the petitioner had shown that WO ’421 and Lovshin each expressly disclosed “a method for treating type 2 diabetes,” treatment “comprising administering semaglutide,” and administration of semaglutide “once weekly in an amount of 1.0 mg.” Further, although WO ’421 related to a combination therapy of a GLP-1 receptor agonist and a DPP-4 inhibitor, the PTAB agreed with the petitioner that the transitional term “comprising” in claim 1 “allow[ed] for administration of additional therapeutics along with semaglutide.”
The PTAB found the petitioner’s argument persuasive that the narrow once-weekly dosing range of 0.1–1.6 mg for semaglutide would anticipate a 1.0 mg once-weekly dose because the range provided a relatively finite number of doses, including 1.0 mg, and the evidence suggested that all of these doses would provide treatment for type 2 diabetes as defined by the ’462 patent. The PTAB further explained that the record did not support a finding that the 1.0 mg dose was critical.
Since the PTAB found that the petitioner had established a reasonable likelihood that it would prevail in demonstrating that at least claim 1 was anticipated by each of WO ’421 and Lovshin, the PTAB instituted review of all claims challenged on all grounds set forth in the petition.
Petitioner Dr. Reddy’s Laboratories, Inc. and Dr. Reddy’s Laboratories Ltd. also requested an IPR of claims 1–10 of the ’462 patent. Specifically, the petitioner asserted anticipation of claims 1–3 of the ’462 patent by each of WO ’421 and Lovshin individually under § 102(b). The petitioner also asserted obviousness of claims 1–10 of the ’462 patent by the combination of each of: (1) WO ’421 and the ’424 publication, (2) WO ’537 and Lovshin, and (3) NCT657, NCT773, and the ’424 publication under § 103.
On April 25, 2024, the PTAB granted a motion for joinder between IPR ’724 and IPR ’009.
When compared to IPRs, other adversarial post-grant proceedings such as post-grant review (PGR) and covered business method (CBM) review allow for a broader range of legal challenges, including grounds addressing subject matter eligibility, enablement, indefiniteness, and written description support. A PGR proceeding reviews the patentability of one or more claims in a patent on any ground that could be raised under 35 U.S.C. § 282(b)(2) or (3) and may be instituted upon a showing that it is more likely than not that at least one claim challenged is unpatentable.
The CBM review process was “transitional,” opening on September 16, 2012 (one year after AIA enactment) and becoming inactive or “sunsetting” on September 16, 2020, while still being applicable to any CBM petition filed before September 16, 2020. CBM review limited qualified petitioners to persons or their privies who had been sued or charged with infringement of a “covered business method patent,” allowing for any and all “grounds of patentability” to be raised in a CBM review.
Considering that between October 1, 2022, and September 30, 2023, approximately 98% of petitions filed before the PTAB were IPRs, leaving only 2% of petitions being PGRs, and between September 16, 2012, and September 30, 2020, only 5% of post-grant challenges before the PTAB were CBM reviews, it is likely that IPRs will continue to be in the forefront of challenges to GLP-1 agonists and related patents.
Litigation Involving Ozempic®
Consolidated litigation involving the ’462 patent to which Dr. Reddy’s Laboratories, Inc. and Dr. Reddy’s Laboratories Ltd. are defendants includes: (1) Novo Nordisk Inc. v. Mylan Pharmaceuticals Inc., No. 22-cv-01040-CFC (D. Del. filed Aug. 8, 2022); (2) In re Ozempic (Semaglutide) Patent Litigation, No. 22-md-3038-CFC (D. Del. filed Aug. 5, 2022); and (3) Novo Nordisk Inc. v. Mylan Pharmaceuticals Inc., No. 22-cv-00023 (N.D. W. Va. filed Mar. 18, 2022).
Moreover, on January 27, 2023, Novo Nordisk Inc. and Novo Nordisk A/S filed suit against Viatris Inc. and Mylan Pharmaceuticals Inc. in the U.S. District Court for the District of Delaware and in the U.S. District Court for the Northern District of West Virginia. The petitioners assert patent infringement after the defendants submitted Abbreviated New Drug Application (ANDA) No. 217705 seeking approval of a generic version of Novo Nordisk’s pharmaceutical product Wegovy® prior to the expiration of U.S. Patent Nos. 8,129,343, 8,536,122, 9,764,003, 10,888,605, and 11,318,191, which cover Wegovy® and its use.
An ANDA contains data that is submitted to the FDA for the review and potential approval of a generic drug product. A generic drug product is comparable to an innovator drug product “in dosage form, strength, route of administration, quality, performance characteristics, and intended use.” Generic drug applications are deemed “abbreviated” since they generally are not required to include preclinical and clinical data to establish safety and effectiveness. Instead, applicants of generic drug products must demonstrate that their product performs in the same manner as the innovator drug product. Once the ANDA is approved, an applicant can manufacture and market the drug product to provide a safe, effective, and lower cost alternative to the innovator drug it references. All approved innovator and generic drug products are listed in the FDA’s Orange Book.
Additional litigation concerning the ’462 patent includes: (1) Novo Nordisk Inc. v. Aurobindo Pharma USA, Inc., No. 1:22-cv-00295 (D. Del. filed Mar. 4, 2022) (dismissed Mar. 28, 2022); (2) Novo Nordisk Inc. v. Rio Biopharmaceuticals, Inc., No. 1:22-cv-00294 (D. Del. filed Mar. 4, 2022); (3) Novo Nordisk A/S v. Sun Pharmaceutical Industries Ltd., No. 1:22-cv-00296 (D. Del. filed Mar. 4, 2022); (4) Novo Nordisk Inc. v. Zydus Worldwide DMCC, No. 1:22-cv-00297 (D. Del. filed Mar. 4, 2022); (5) Novo Nordisk Inc. v. Dr. Reddy’s Laboratories Ltd., No. 1:22-cv-00298 (D. Del. filed Mar. 4, 2022); and (6) Novo Nordisk Inc. v. Alvogen, Inc., No. 1:22-cv-00299 (D. Del. filed Mar. 4, 2022).
Unpredictability Ahead
With disputes and challenges across federal bodies, agencies, and courts, the future of Ozempic® is uncertain—and this uncertainty may reflect on other GLP-1 agonists.