The Ambrisentan Patent: Legal Issues Surrounding PAH Treatment

Daniel Whittaker

Ambrisentan is a medication used to treat pulmonary arterial hypertension (PAH), a rare but serious condition that raises blood pressure in the lungs. It works by relaxing blood vessels to improve blood flow and reduce strain on the heart. But behind its clinical success lies a complex legal battle that shaped access, pricing, and competition in the PAH treatment market. The patent history of ambrisentan isn’t just a footnote in pharmaceutical history-it’s a case study in how patent extensions, litigation, and regulatory loopholes can delay generic alternatives and impact patient care.

What Is Ambrisentan and How Does It Work?

Ambrisentan, sold under the brand name Letairis, is an endothelin receptor antagonist. It blocks endothelin-1, a substance in the body that causes blood vessels to narrow. In PAH patients, this narrowing makes it harder for the heart to pump blood through the lungs, leading to fatigue, shortness of breath, and eventually heart failure.

Ambrisentan was developed by Gilead Sciences and approved by the U.S. Food and Drug Administration (FDA) in 2007. Unlike older PAH drugs that required multiple daily doses, ambrisentan offered once-daily dosing, which improved adherence and quality of life. It quickly became a first-line treatment, especially for patients with Class II and III PAH according to the World Health Organization functional classification.

By 2015, over 20,000 patients in the U.S. alone were using ambrisentan. Its effectiveness, combined with a favorable safety profile compared to alternatives like bosentan, made it a cornerstone of PAH therapy.

The Original Patent and Its Expiration

Gilead’s original patent for ambrisentan, U.S. Patent No. 5,688,798, was filed in 1995 and issued in 1997. This patent covered the chemical structure of ambrisentan and its use in treating PAH. Under normal circumstances, this patent would have expired in 2012-20 years after filing.

But in pharmaceuticals, patent expiration doesn’t always mean generic entry. Gilead secured a pediatric exclusivity extension in 2008 after completing required clinical trials in children with PAH. This added six months to the exclusivity period, pushing the earliest possible generic entry to mid-2012.

Then came the next hurdle: a second patent, U.S. Patent No. 6,518,293, filed in 2001 and issued in 2003. This one covered a specific crystalline form of ambrisentan-the form used in the commercial tablet. This patent was designed to protect the manufacturing process, not the drug itself. But under U.S. patent law, even secondary patents can block generics if they’re deemed valid.

Patent Evergreening and the Legal Battle

The second patent became the center of a major legal dispute. Generic drug manufacturers like Teva and Actavis filed Abbreviated New Drug Applications (ANDAs) in 2010, challenging the validity of the crystalline form patent. They argued that the form was obvious and not novel-essentially, that it was just a minor variation of the original compound.

Gilead fought back. In 2011, they sued Teva for patent infringement. The case went to the U.S. District Court for the District of Delaware. In 2013, the court ruled in favor of Gilead, upholding the patent. The judge found that the crystalline form had unexpected stability and solubility properties that weren’t predictable from the original compound.

This decision was a win for Gilead but a blow to patients and insurers. It meant generic ambrisentan couldn’t enter the market until 2019, when the second patent finally expired. Critics called this patent evergreening-using minor modifications to extend market exclusivity without meaningful innovation.

By 2018, the cost of Letairis had climbed to over $10,000 per month in the U.S. For many patients, even with insurance, out-of-pocket costs exceeded $1,000 per month. In contrast, when generics finally arrived in late 2019, the price dropped by 80% within six months.

How Generic Entry Changed the Market

On November 1, 2019, the first generic versions of ambrisentan hit the U.S. market, approved by the FDA and manufactured by Teva, Actavis, and Mylan. Within a year, generic ambrisentan captured over 70% of the U.S. market share.

Insurance companies quickly shifted formularies to favor generics. Medicare Part D plans reduced copays for generic ambrisentan to $10-$20 per month, compared to $300-$500 for the brand. Hospitals and specialty pharmacies began switching patients to generics as a standard practice.

The price drop didn’t just help patients-it freed up billions in healthcare spending. A 2021 study in the Journal of the American College of Cardiology estimated that the introduction of generic ambrisentan saved the U.S. healthcare system over $1.2 billion in the first two years alone.

Global Patent Differences and Access Issues

The U.S. patent landscape isn’t the same everywhere. In the European Union, the European Medicines Agency (EMA) approved ambrisentan in 2008. But the patent protections were weaker. The European patent covering the crystalline form was invalidated in 2014 after opposition from generic companies. As a result, generics entered the EU market in 2015-four years before the U.S.

In Canada, Health Canada approved ambrisentan in 2009. The patent for the crystalline form was challenged in 2017 and revoked in 2018. Generic versions became available in 2018, making Canada one of the first countries to offer affordable ambrisentan.

In contrast, in countries like India and Brazil, where patent enforcement is less strict, generic manufacturers began producing ambrisentan as early as 2013. These generics were exported to low-income nations, helping patients who otherwise couldn’t afford treatment. But in the U.S., where patent law is aggressively defended, access was delayed.

What This Means for Future PAH Treatments

The ambrisentan patent saga set a precedent. It showed how pharmaceutical companies can use secondary patents to extend monopolies, even when the core innovation is decades old. This strategy isn’t unique to ambrisentan-it’s been used with drugs like Humira, Nexium, and many others.

But the public backlash has grown. In 2022, the U.S. Congress passed the CREATES Act, which makes it harder for brand-name companies to block generic manufacturers from obtaining samples of their drugs for testing. In 2024, the FDA updated its guidelines to require more transparency in patent listings.

For PAH patients, the lesson is clear: access to life-saving drugs shouldn’t depend on legal technicalities. The delay in generic ambrisentan cost lives-some patients skipped doses, others switched to less effective treatments, and some simply couldn’t afford care.

Now, with generics widely available, the focus has shifted to ensuring long-term supply, monitoring for quality, and expanding access in underserved areas. Ambrisentan is no longer a luxury. It’s a basic treatment-and the law should reflect that.

How Patients Can Check for Generic Ambrisentan

If you’re taking ambrisentan, ask your pharmacist or doctor if you’re on the brand or generic version. Generic ambrisentan is chemically identical and FDA-approved. It’s safe, effective, and costs a fraction of the brand.

Look for the drug name on the label: it should say "ambrisentan" without the brand name Letairis. Common generic manufacturers include Teva, Mylan, and Actavis. If your insurance denies coverage for the generic, appeal the decision-many insurers now cover it at the lowest tier.

For patients without insurance, patient assistance programs through the American Heart Association and the Pulmonary Hypertension Association offer free or low-cost ambrisentan to qualifying individuals.

Next Steps for Patients and Providers

If you’re on ambrisentan, confirm you’re on the generic version. If you’re not, ask why. If you’re a provider, make generic ambrisentan the default choice unless there’s a documented medical reason not to. If you’re a policymaker, push for reforms that prevent secondary patents from blocking affordable drugs.

The story of ambrisentan isn’t just about one drug. It’s about how the system works-and how it can be fixed. Patients shouldn’t have to wait years for life-saving medications because of legal loopholes. The science is ready. The generics are here. The only thing left to change is the policy.