Delivery Device Patents on GLP-1 Receptor Agonists

Abstract

This study analyzed the US Food and Drug Administration–listed patents on glucagon-like peptide 1 (GLP-1) receptor agonists to determine their claim characteristics and the potential barriers they pose to generic entry.

Nearly all glucagon-like peptide 1 (GLP-1) receptor agonists approved by the US Food and Drug Administration (FDA) for type 2 diabetes and weight management are drug-device combinations containing active ingredients sold together with delivery devices. Manufacturers have secured long periods of market exclusivity on these products, in part by listing numerous device patents with the FDA, creating large patent thickets (ie, many patents directed toward the same product).¹ These patent listings can delay competition by precluding the FDA from approving generic versions for marketing until the patents expire or face successful challenge, which can be time-consuming and costly.²

Courts and regulators have recently raised concerns that many patents on drug-device combinations have been impermissibly listed with the FDA. In 2020, the US Court of Appeals for the First Circuit found that Sanofi had wrongfully listed a patent on a mechanical subpart of its insulin glargine pen because the patent did not mention insulin, and only patents on drugs may be listed with the FDA.³ The Federal Trade Commission recently identified 110 potentially improperly listed patents, most of which covered inhaler and epinephrine pen delivery devices without mentioning active drug ingredients.⁴ We analyzed FDA-listed patents on GLP-1 receptor agonists to determine their claim characteristics and the potential barriers they pose to generic entry.

Methods

We identified all patents listed on GLP-1 receptor agonists using annual editions of the FDA’s Approved Drug Products With Therapeutic Equivalence Evaluations (Orange Book) from 2006 to 2023. For each patent, we used Google Patents to extract claims, which define the subject matter covered by the patent. Two authors (R.A. and W.B.F.) independently determined whether patents were obtained on delivery devices vs other aspects of the products and then, for each device patent, searched the claims for any mention of active ingredients or other prespecified terms linking the device patent to the product (eMethods in Supplement 1). We used Lex Machina to identify litigation related to patent challenges, and we calculated the proportion of litigated patents covering delivery devices. Analyses were completed in Excel, version 16 (Microsoft).

Results

Manufacturers listed a total of 188 patents on 10 FDA-approved drug-device combinations containing GLP-1 receptor agonists, including 107 device patents (57%) and 81 nondevice patents (43%) (Table 1). No device patents contained claims mentioning their active ingredients, chemical structures, or therapeutic classes. Only 1 patent (listed on 3 different products in the cohort) mentioned an indication (diabetes). Removing these device patents from the Orange Book would reduce the size of patent thickets on GLP-1 drug-device combinations from a median of 20.5 (IQR, 9.0-25.8) patents to a median of 6 (IQR, 5.3-6.8) patents and, in 2 cases, would reduce the duration of expected patent protection by 1.5 and 2.6 years, respectively.

Table 1. FDA-Approved GLP-1 Receptor Agonist Drug-Device Combinations Listed in the Orange Book.

Product and version	Active ingredient	FDA approval date	Total No. of patents	Device patents, No. (%)a
Byetta
300 μg/1.2 mL	Exenatide	4/28/2005	8	0
600 μg/2.4 mL	Exenatide	4/28/2005
Victoza, 6 mg/mL	Liraglutide	1/25/2010	12	6 (50)
Bydureon
2 mg/vial	Exenatide	1/27/2012	39	8 (21)
2 mg (pen)	Exenatide	2/28/2014
2 mg/0.85 mL (BCise)	Exenatide	10/20/2017
Saxenda, 6 mg/mL	Liraglutide	12/23/2014	28	22 (79)
Adlyxin
0.05 mg/mL	Lixisenatide	7/27/2016	16	10 (63)
0.1 mg/mL	Lixisenatide	7/27/2016
Xultophy, 100 units/mL; 3.6 mg/mL	Insulin degludec/liraglutide	11/21/2016	25	19 (76)
Soliqua, 100 units/mL; 33 μg/mL	Insulin glargine/lixisenatide	11/21/2016	26	19 (73)
Ozempic
2 mg/1.5 mL	Semaglutide	12/5/2017	25	21 (84)
4 mg/3 mL	Semaglutide	4/9/2019
8 mg/3 mL	Semaglutide	3/28/2022
2 mg/3 mL	Semaglutide	10/6/2022
Wegovy
0.25 mg/0.5 mL	Semaglutide	6/4/2021	5	0
0.5 mg/0.5 mL	Semaglutide	6/4/2021
1 mg/0.5 mL	Semaglutide	6/4/2021
1.7 mg/0.75 mL	Semaglutide	6/4/2021
2.4 mg/0.75 mL	Semaglutide	6/4/2021
Mounjaro
2.5 mg/0.5 mL	Tirzepatide	5/13/2022	4	2 (50)
5 mg/0.5 mL	Tirzepatide	5/13/2022
7.5 mg/0.5 mL	Tirzepatide	5/13/2022
10 mg/0.5 mL	Tirzepatide	5/13/2022
12.5 mg/0.5 mL	Tirzepatide	5/13/2022
15 mg/0.5 mL	Tirzepatide	5/13/2022

Abbreviation: FDA, US Food and Drug Administration.

^a Manufacturers listed a total of 107 device patents on glucagon-like peptide 1 (GLP-1) receptor agonists in the Orange Book. Of these device patent listings, there are 65 distinct patents because some patents are listed on more than 1 product.

Brand-name manufacturers filed 30 lawsuits against generic firms alleging patent infringement relating to 5 of 10 GLP-1 drug-device combinations. Fifty-seven percent (40 of 70) of patents included in these lawsuits were Orange Book–listed device patents making no mention of active ingredients (Table 2).

Table 2. Litigated Patents on GLP-1 Receptor Agonist Drug-Device Combinations.

Product	No. of lawsuits	No. of patents involved in lawsuitsa	No. (%) of device patents involved in lawsuits
Byetta (exenatide)	2	8	0
Victoza (liraglutide)	13	8	4 (50)
Saxenda (liraglutide)	5	25	18 (72)
Ozempic (semaglutide)	8	24	18 (75)
Wegovy (semaglutide)	2	5	0
Total	30	70	40 (57)

^a Whenever a firm seeks US Food and Drug Administration approval for a generic version of a brand-name drug with active patents listed in the Orange Book, the generic firm must certify that all patents are invalid, unenforceable, or not infringed by their product (paragraph IV certification). The brand-name firm may then sue the generic firm for patent infringement following a paragraph IV certification. This column lists all patents included in litigation by brand-name firms against generic firms following paragraph IV certifications. Note that a single patent counts more than once if litigated by brand-name firms on more than 1 glucagon-like peptide 1 (GLP-1) receptor agonist.

Discussion

Brand-name manufacturers of GLP-1 receptor agonists list dozens of device patents with the FDA that are disconnected from active drug products. These patents contribute to large patent thickets that serve as a basis for litigation against potential generic GLP-1 manufacturers.

Such reliance on disconnected device patents goes beyond what has been observed for other drug-device combinations: 23% of distinct FDA-listed device patents on inhalers⁵ and 15% on insulin pens⁶ mention the products’ active ingredients in their claims compared with no such mentions among device patents on GLP-1 receptor agonists.

A limitation of this study is that the extent to which device patents on these products may delay future generic competition cannot be precisely predicted. In addition, brand-name firms can still litigate patents that do not appear in the Orange Book. Nonetheless, removal of these patents may substantially reduce barriers to generic entry by decreasing the number of patents that generic firms must contest ahead of FDA approval. Without effective generic competition, prices for GLP-1 receptor agonists will remain high for many years, reducing access for patients and raising health care costs.

Section Editors: Kristin Walter, MD, and Jody W. Zylke, MD, Deputy Editors; Karen Lasser, MD, Senior Editor.

Supplement 1.

eMethods

Supplement 2.

Data Sharing Statement