Insulin Delivery Device Patents Prolong Market Exclusivity

Insulin manufacturers are extending brand-name market exclusivity by filing multiple new patents on their products’ delivery devices, a new analysis suggests.

The data come from the publicly available US Food and Drug Administration’s (FDA’s) Approved Drug Products With Therapeutic Equivalence Evaluations, dubbed the “Orange Book,” along with Google patents, on all insulin products approved in the United States from 1986 to 2019. During that time, the FDA approved 56 brand-name originator insulin products. The median duration of expected patent protection is 16.0 years.

Of the 33 that were drug-device combinations, 63% of those patents were related to the delivery devices rather than the insulin itself. Sanofi’s Lantus (glargine) Solostar, for example, had 18 patents following glargine approval, all for the device.

“Insulin manufacturers have employed several strategies to extend periods of market exclusivity on brand-name insulin products, particularly filing patents after FDA approval and obtaining a large number of patents on delivery devices,” write Anders Olsen, MD, of Brigham and Women’s Hospital, Boston, and colleagues. The study was published November 16 in PLOS Medicine.

Regarding the filing of multiple patents, known as “thickets,” lead author William B. Feldman, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, told Medscape Medical News, “Whenever those patents are listed in the Orange Book, it has historically made it harder for competitors to enter the market.”

In turn, “that makes things more expensive for healthcare systems and higher out of pocket costs for patients…. These patent games that manufacturers play have direct effects on costs, which can have direct effects on patient adherence,” Feldman added.

Asked to comment, Simeon I. Taylor, MD, of the University of Maryland, Baltimore, told Medscape Medical News that the patent on the device protects the device but not the insulin once that patent has expired. Moreover, he noted, pharmacy benefit manufacturers (PBMs), acting on behalf of insurance companies, dictate which product a patient’s insurance will cover based on their own profit motive.

“After expiration of the patent covering the active pharmaceutical ingredient, such as glargine, competitors can pair that insulin molecule with any device of their choice. The PBMs can provide more favorable reimbursement for whichever product they prefer, thereby forcing the patient to use it, even if that insulin product is not packaged in a patient’s favorite device. In general, PBMs are more likely to be motivated by the size of the rebates they receive from each manufacturer rather than by patient preferences, patient welfare or which product has the lowest list price,” Taylor said.

Taylor also noted that manufacturers could benefit from patents on the devices while the insulin is still under patent. “Even if a patent on a device would not extend marketing exclusivity, a superior device could be an advantage for a proprietary product before the patent on the insulin had expired.”

But Olsen and colleagues point out that thus far, even the “follow-on” competition has been dominated by the big three insulin manufacturers, including Lilly’s basaglar (glargine) for Sanofi’s originator Lantus (glargine) and Sanofi’s admelog (lispro) for Lilly’s brand-name Humalog (lispro). They note that uptake of these has been limited.

Prior to 2020, insulin was categorized as a small-molecule drug rather than a biologic, meaning that competitors couldn’t pursue abbreviated new drug applications for generic approvals or abbreviated biologics licensing applications for biosimilar approval. After the FDA change, insulins would be deemed “interchangeable” with the branded products. It also meant that insulin products would no longer be listed in the Orange Book but rather in the “Purple Book,” for which manufacturers are not required to list all key patents.

“This may make it difficult for biosimilar manufacturers to challenge new insulin products in the coming years…. Requiring biologic manufacturers to list all key patents with the FDA, as some have proposed, would help address this problem,” the authors write.

Feldman told Medscape that even though there is now competition with some insulin products, that process has been slowed because of the patents. He noting that when a patent is listed in the Orange Book, the FDA can’t approve a generic version for marketing until the patent expires or is successfully challenged, which then triggers a 30-month stay from the FDA, whether the patient is on the delivery device or the active ingredient (ie, the insulin).

He pointed to a 2020 lawsuit in which the US Court of Appeals for the First Circuit held that Sanofi’s patent on the drive mechanism of the SoloStar pen had been improperly listed in the Orange Book because it made no mention of insulin glargine.

“Even when the patents are not on the active ingredients, they can still delay competition. This is, in part, why the [Federal Trade Commission] is now paying such close attention to patents on delivery devices of drug-device combinations,” Feldman said.

In a statement to Medscape Medical News, Sanofi said, “Our patents only protect our proprietary discoveries. They do not prevent competition in the marketplace. In fact, there is robust competition among treatments for diabetes, with multiple approved follow-on biologics and biosimilars, and more in development. That competition, along with newer therapies that may delay or disrupt the onset of insulin dependent diabetes altogether, has resulted in significant erosion of the net price. In fact, the average net price of Lantus, our most prescribed insulin, is below 2004 levels. Unfortunately, patients with diabetes have not been the primary beneficiary of the significant net price decline.”

And according to Lilly, “The patent for Lilly’s most prescribed insulin expired in 2014, and none of Lilly’s other most commonly used insulins are patent protected. Lilly supports generic and biosimilar competition when patents expire to drive affordable options for patients. The barriers to entry for the insulin market are much higher than for traditional small molecule pills because insulin is more difficult and expensive to manufacture. Generic manufacturers may have chosen not to enter the insulin market as a result.”

Novo Nordisk declined to comment.

One barrier for biosimilars, the authors note, is that the threshold for issuing new drug-related patents at the US Patent and Trademark Office (USPTO) may be too low, particularly for the device patents that often predominate on drug-device combinations.

“In conjunction with recently passed legislation to help rein in prices on insulin, Congress, the FDA, and the USPTO should continue to work on reforming the patent and regulatory system to prevent such thickets from continuing to interfere with a healthy pipeline of cheaper — and even interchangeable — insulin products for the benefit of patients,” Olsen and colleagues conclude.

At the same time, Feldman agrees that PBMs have also contributed to high out-of-pocket costs by pushing for higher rebates. “Ultimately, we need patent and regulatory reform to ensure more timely generic and biosimilar competition across the pharmaceutical market, and we need PBM and payer reform to ensure that formularies favor low-cost products and that out-of-pocket costs are kept down.”

Olsen serves as a fellow in the Office of the Assistant Secretary for Planning and Evaluation. Feldman serves as a consultant for the nonprofit Alosa Health and to Aetion and as an expert witness in litigation against inhaler manufacturers. Taylor serves as a consultant for Ionis Pharmaceuticals and receives an inventor’s share of royalties from the National Institute of Diabetes, Digestive, and Kidney Diseases for metreleptin as a treatment for generalized lipodystrophy.

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter @MiriamETucker.