Blockbuster Patent Expirations 2025 and Beyond: Timeline, Drugs, and Market Impact

By mid-2025, the pharmaceutical world will face its biggest shift in decades. Dozens of top-selling drugs, each bringing in billions annually, will lose patent protection. This isn’t just a legal footnote-it’s a financial earthquake that will change how patients pay for medicine, how pharmacies stock shelves, and how drug companies plan their futures. The blockbuster patent expirations starting in 2025 aren’t scattered events. They’re a synchronized wave, hitting hard and fast.

What’s Expanding in 2025? Entresto Leads the Way

The first major hit comes in July 2025: Novartis’ Entresto (sacubitril/valsartan). This heart failure drug brought in $7.8 billion globally in 2024. It’s not a simple pill-it’s a combination drug that works differently than older treatments. But its core patent (US8329752) expires that month, and the FDA has already approved the first generic version of sacubitril ahead of schedule. That’s unusual. It means generic manufacturers are ready to flood the market the moment the patent falls.

Patients currently paying $150 to $300 a month for Entresto could see prices drop to $20-$40 within weeks. Hospitals and pharmacy benefit managers are already negotiating discounts. One hospital system in Ohio locked in 60% price cuts with insurers before the generic even hit shelves. This isn’t speculation-it’s happening now.

2026: Eliquis Goes Generic, and the Anticoagulant Market Shifts

November 2026 is when Bristol Myers Squibb and Pfizer’s Eliquis (apixaban) loses its key patent protection. Eliquis raked in $13.2 billion in 2024 alone. It’s one of the most prescribed blood thinners in the U.S., used by millions to prevent strokes and blood clots.

Unlike Entresto, Eliquis doesn’t have a unique mechanism. It competes in a crowded space with other anticoagulants like Xarelto and Pradaxa. That means once generics arrive, prices will crash fast. Historically, when a drug like this loses exclusivity, 90% of prescriptions switch to generics within two years. The FTC’s 2023 data shows small-molecule generics typically cause 80-90% price drops within 12 months. For Eliquis, that could mean $10 billion in lost revenue for the makers in just 18 months.

Pharmacists are already preparing. Many are training staff on substitution rules, since not all states allow automatic switching for complex generics like Eliquis. Some patients may need a new prescription just to get the cheaper version.

2028: The $30 Billion Giant-Keytruda’s Fall

If Entresto and Eliquis are major blows, Merck’s Keytruda (pembrolizumab) is a Category 5 hurricane. In 2024, it generated $29.3 billion in sales. That’s more than the entire annual budget of many U.S. states. Keytruda revolutionized cancer treatment as the first widely used PD-1 inhibitor, helping patients with melanoma, lung cancer, and more.

Its core patent expires in 2028. But here’s the twist: there’s no simple generic version. Keytruda is a biologic-a complex protein made from living cells. That means instead of generics, we’ll get biosimilars. These are close copies, but harder and slower to make. The FDA has approved only a handful so far, and they’ll likely enter the market 18-24 months after the patent expires.

Merck knows this is coming. In November 2024, it announced a $12 billion investment in next-gen cancer drugs to replace Keytruda’s revenue. But even with new products, analysts predict Merck could lose up to $15 billion in annual sales within 18 months of biosimilar entry. That’s the largest single-year revenue drop in pharmaceutical history.

Doctors aren’t waiting. Oncology clinics are starting conversations with patients about future cost changes. Many are already tracking which insurance plans will cover biosimilars and which will require prior authorizations.

Why This Wave Is Different

Past patent cliffs-like when Lipitor went generic in 2011-were big. But this one is unprecedented in scale and timing. Between 2025 and 2030, 65 drugs with over $100 million in annual sales each will lose protection. That’s $187 billion in global revenue at risk.

What makes this unique is the concentration. Three drugs-Keytruda, Eliquis, and Entresto-account for nearly $50 billion of that total. And they’re not spread out. They’re clustered in just four years.

Also, this isn’t just about small molecules. Biologics like Keytruda and Humira (which lost protection in 2023) have longer development timelines for biosimilars, more complex patents, and more legal battles. Biologics average 132 patents per product. Small molecules? Around 14. That’s why biosimilar entry is slower-and why companies are still fighting in court even after patents expire.

Who Wins? Who Loses?

Patients win. Savings will be massive. The Congressional Budget Office estimates $312 billion in U.S. healthcare savings between 2025 and 2035. A heart failure patient switching from Entresto to generic could save $3,000 a year. A lung cancer patient on Keytruda could see out-of-pocket costs drop from $10,000 to $2,000 per year.

Generic manufacturers win. Teva, Mylan, and Sandoz are pouring billions into developing these copies. Teva alone has 37 products in the pipeline targeting expirations through 2030.

Big pharma loses. Merck, Bristol Myers Squibb, Novartis, and Amgen will collectively lose over $100 billion in revenue. Amgen could lose 52% of its current income. That’s why companies are buying smaller biotechs-Bristol Myers Squibb spent $4.1 billion on Karuna Therapeutics to build a new pipeline.

Insurance companies and PBMs (pharmacy benefit managers) win too. Lower drug costs mean lower premiums and better margins. But they’re also facing chaos: managing formulary changes, negotiating with multiple generic suppliers, and training staff on new substitution rules.

How Are Providers Getting Ready?

Hospitals and pharmacies aren’t sitting idle. The American Society of Health-System Pharmacists found that 87% of hospital pharmacy directors are actively preparing for the 2025-2030 wave. That means:

• Updating electronic health records to flag generic switches
• Training pharmacists on biosimilar substitution rules
• Building inventory buffers to avoid shortages (like the ones seen with Humira biosimilars)
• Creating patient education materials explaining why a cheaper version is just as safe

Some states still don’t have laws allowing pharmacists to automatically substitute complex generics. That means even if a cheaper version is available, a doctor may need to rewrite the prescription. Patients are being told to check with their pharmacy before refilling.

What Comes Next? The Aftermath

After the initial wave, the industry won’t go back to how it was. The days of relying on one blockbuster drug for 15 years are over. Companies are shifting to:

• Gene therapies and personalized medicine (expensive, but harder to copy)
• Oral biologics (pills instead of injections)
• Drugs targeting rare diseases (smaller markets, but less competition)

The FDA is also under pressure to speed up approvals. In 2024, it received 127 new generic applications targeting 2025 expirations-up 27% from the year before. That’s a sign the system is trying to keep up.

But challenges remain. Will there be enough manufacturing capacity? Will patients trust biosimilars? Will insurers make the switch easy-or create new barriers?

Where to Track the Timeline

If you’re a patient, pharmacist, or provider, you don’t need to guess when the next drug goes generic. The FDA maintains two public databases:

• Orange Book: Lists small-molecule drugs and their patents
• Purple Book: Lists biologics and biosimilar status

Industry groups like the Association for Accessible Medicines also offer free tools like the “Patent Cliff Navigator,” used by 82% of pharmacy benefit managers. You can search by drug name or expiration date and get real-time updates.

Bottom Line: A New Era for Medicine

The patent expirations from 2025 to 2030 aren’t just about money. They’re about access. For the first time, millions of patients who couldn’t afford drugs like Keytruda or Entresto will be able to get them at a fraction of the cost. But it’s not automatic. It requires coordination between regulators, manufacturers, pharmacies, and doctors.

The biggest risk? Supply shortages. If too many companies rush to produce generics at once, we could see shortages like those with Humira biosimilars. That’s why hospitals are already stockpiling. That’s why pharmacists are training.

This isn’t the end of innovation. It’s the beginning of a more affordable, more competitive system. The question isn’t whether this will happen. It’s whether we’re ready for it.