麻豆传媒

An analysis of patent applications for 10 top-selling prescription drugs found that nearly three-quarters of them were filed after FDA approval, a cross-sectional study of U.S. patent thickets found.

The 10 brand-name drugs with the highest U.S. sales in 2021 were tied to 1,429 patents and patent applications, of which 72% were filed after the drugs gained approval, according to Aaron Kesselheim, MD, JD, MPH, of Brigham and Women's Hospital and Harvard Medical School in Boston, and colleagues.

The share of patents filed post-approval was higher for the four biologics than for the six small molecule drugs among those 10 blockbusters (80% vs 58%), according to the study published in .

Overall, drug companies filed a median of 37 applications per drug prior to FDA approval and 99 after approval, the authors noted.

A key finding of the study is the sheer breadth of the patent thickets -- overlapping patents -- uncovered and the high numbers filed after the drug had already received FDA approval, Kesselheim told 麻豆传媒.

"There aren't a lot of major changes that drugs undergo once they've been approved by the FDA, because then they would ... suddenly become a different product," he said. So, the volume of patents filed post-approval begs the question of whether manufacturers are trying to protect an "important new innovation" or simply delay competition and maintain their revenue stream, he added.

For every patent, a drug typically receives 20 years of market exclusivity, which is "one more hurdle that a generic or biosimilar manufacturer has to navigate its way around, in trying to get on the market," Kesselheim said. The delayed competition keeps drug costs high for patients and payers, he and his team noted.

As one example, etanercept (Enbrel), a biologic used to treat plaque psoriasis and rheumatoid arthritis, received FDA approval in 1998 and has patent protection for 41 years, until 2039.

This analysis did not drill down to the level of individual patents to assess their legitimacy, Kesselheim stressed. However, past dubious patents include one filed on the stopper of a vial containing a drug (rather than the drug itself) and another filed on the flavoring added to a drug to make it more kid-friendly, he told 麻豆传媒.

Patent thickets peaked near the 5-year mark for small molecule drugs and around 12 years for biosimilars, the study found. These "differential peaks" coincide with the ending of market exclusivity periods under the Hatch-Waxman Act for the two types of drugs and thus represent one more signal of "strategic behavior" by drug companies pursuing the patents, Kesselheim suggested.

In recent years, the Biden administration, via the FDA and the the U.S. Patent and Trademark Office, has begun to close in on strategies to "protect against the patenting of incremental, obvious changes to existing drugs that do not qualify for patents," Kesselheim and team noted.

And just in the last few weeks, the Federal Trade Commission has issued warnings to drug manufacturers for improperly listing patents in the FDA's for small molecule drugs.

Kesselheim said he believes the findings from this study could help support policymaking that targets "low-quality patents" and ensures timely competition from generic and biosimilar drugs.

One policy change could be to "draw a line" and prohibit any patent filed after FDA approval from being listed in the FDA's Orange Book, said Kesselheim.

Along with that book and the similar for biologics, Kesselheim also suggested the creation of a third book he's dubbed the "Green Book" that would list every drug patent, providing greater transparency for competitors and saving researchers time.

Study Design

The study sample consisted of the 10 prescription drugs with the highest U.S. net sales revenue in 2021 based on patent data as of June 30, 2022, from the Drug Patent Book -- a public database of these 10 drugs constructed by the nonprofit .

These drugs were bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy) for HIV; the anticoagulant apixaban (Eliquis); cancer drugs ibrutinib (Imbruvica), pembrolizumab (Keytruda), and lenalidomide (Revlimid); arthritis drugs etanercept (Enbrel) and adalimumab (Humira); aflibercept (Eylea) for macular degeneration; psoriasis and Crohn's disease drug ustekinumab (Stelara); and the diabetes drug dulaglutide (Trulicity). As of June 30, 2022, the drugs in the sample had been approved for 4.4 to 23.7 years (median 10.1 years).

In assessing patent characteristics, the authors independently coded a sample of the patents to reach consensus around definitions.

Of the 1,429 patent and patent applications in the analysis, 742 represented issued patents, 218 were for pending applications, and 469 were abandoned applications. As of June 30, 2022, 571 of the 742 issued patents (77%) were still active, while 171 (23%) had expired.

For biologics, 729 of 912 were for applications filed after FDA approval; for small molecule drugs, 299 of 517 applications were filed following approval.

Among the patents filed after FDA approval:

• 41% were for method of use claims (reflecting the disease process the drug treats)
• 27% had formulation claims
• 22% had process or synthesis claims
• 19% had chemical composition claims
• 10% had device claims

Notably, the majority of post-approval drug patents were "peripheral to their active ingredients," including patents related to methods of use claims, formulations, and manufacturing processes.

Device claims, in particular, accounted for only 10% of patents in the study, but all were filed post-approval, the authors noted. (Given that most patents detail multiple claims, each could be assigned to more than one category.)

The study excluded drugs for rare diseases or any low-revenue drugs, which limits its generalizability, Kesselheim said. The study was also not designed to make claims about specific patents being granted properly or improperly, he added.

"I don't think that all of these patents are illegitimate," Kesselheim said, "but we need to make sure that if we're going to give companies 20 years of market exclusivity ... that they actually deserve it and that the patent truly covers something that is innovative and useful to patients."

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