Biologics and Bio-Betters: What 89 Biosimilars Did to the Patent Clock

Humira earned AbbVie $4.54 billion worldwide in 2025. [1] Its peak was about $22 billion in 2021. [2] The 2025 figure is about 79% below that peak (analysis: 1 minus 4.54 divided by 22). Biosimilar competition did most of that work.

FDA’s biosimilar table had 89 rows on October 5, 2026. [3] Brand makers have responded with bio-betters: changed versions of their own biologics that are easier to give, dosed less often, or built with a longer half-life. This article tests that response against public records. It covers FDA lists, company filings, court decisions, and statute. Where we calculate a number, we label it as analysis.

The Short Answer

A biosimilar copies an existing biologic. A bio-better changes it. A biosimilar is “highly similar to the reference product notwithstanding minor differences in clinically inactive components.” [4] A bio-better is a biologic built on an innovative biologic and altered to improve its properties. [5]

Biosimilar makers compete on price after patents and exclusivity end. Brand makers use bio-betters to move patients to a protected version before that happens. Four facts show how this works in practice:

FDA’s list added 44 of its 89 rows between January 2024 and July 2026 (analysis of FDA data). [3]
Humira global revenue fell 49.5% in 2025. Stelara fell 41.3%. [1][6]
Regeneron’s higher-dose Eylea HD rose from 20.1% to 37.3% of its US Eylea franchise sales between 2024 and 2025 (analysis of Regeneron data). [7]
Merck lists a 2028 US patent expiry for Keytruda and 2043 for the subcutaneous Keytruda Qlex. [8]

The Five Findings That Matter (Plus Three More)

Each finding below stands alone. Calculated figures are marked as analysis.

FDA’s biosimilar table lists 89 rows as of its October 5, 2026 update. FDA listed 18 rows each in 2024 and 2025. No earlier year has more than 10 (analysis). [3]
Four reference molecules account for 34 of the 89 rows, or 38%: adalimumab (10), denosumab (10), ustekinumab (8), and aflibercept (6) (analysis). [3]
In 2025, FDA’s biosimilar table added 18 rows. FDA’s novel approvals report lists 12 biologics among 46 novel approvals. Biosimilar rows outnumbered novel biologics 18 to 12 (analysis comparing two FDA documents). [3][9]
Humira US revenue fell 57.1% in 2025, in the third calendar year of US biosimilar competition. [1][10]
Stelara sales fell 41.3% to $6.08 billion in 2025, the year US biosimilars launched. [6]
Eylea HD supplied 46.7% of Regeneron’s US Eylea-franchise sales in the fourth quarter of 2025, up from 20.4% a year earlier (analysis). [7]
Four of six FDA-approved aflibercept biosimilars had not launched in the US as of August 3, 2026 (analysis). Approval-to-launch gaps run from about 2 months to about 30 months. [11][3]
Merck reports Keytruda sales of $31.68 billion for 2025. A final PTAB decision on May 12, 2026 invalidated claims of one Halozyme patent asserted against Keytruda Qlex. [8][12]

How We Built the Numbers: Methodology

What Data We Analyzed and for Which Period

The approval counts come from FDA’s Biosimilar Product Information page. The page was current as of October 5, 2026. [3] It runs from the March 2015 approval of Zarxio through the July 2026 approvals of Zimrixby and Garzulys. [3]

Revenue figures come from company releases and filings where we could retrieve them. These are AbbVie’s February 4, 2026 release, Regeneron’s January 30, 2026 release, and Merck’s FY2025 Form 10-K. [1][7][8] The Stelara figure comes from a secondary report of Johnson & Johnson’s results. [6]

How We Counted Records

One record is one row in the FDA table. Eleven rows name two products each, so the table names 100 products. We counted rows, not products.
FDA gives approval dates by month. We assigned each row to its calendar year. Data for 2026 cover January to July only.
We grouped rows by the active ingredient in each nonproprietary name, for example “denosumab-bbdz.”
We found no duplicate rows. A row with two brand names counted once.

Definitions Used in This Article

Reference product: the licensed biologic that a biosimilar copies. The statute gives it 12 years of exclusivity from first licensure. [4]

Biosimilar: a biological product that is “highly similar to the reference product notwithstanding minor differences in clinically inactive components.” [4]

Interchangeable biosimilar: a biosimilar that “can be expected to produce the same clinical result as the reference product in any given patient.” [4] Pharmacies may substitute an interchangeable product in most states. [13]

Bio-better: a biologic based on an innovative biologic that has been altered to improve its properties. The innovative drug must have at least clinical proof of concept. [5] This is a literature definition. It is not a legal category in the statute we cite.

Limits of This Analysis

FDA row counts differ from other published counts. Settlement terms are often confidential. Launch dates come from company statements and law-firm reports, not from FDA. Revenue changes mix global and US figures, and we label each one. We did not retrieve patent-level data from the USPTO for this article.

What Is the Difference Between a Biosimilar and a Bio-Better?

A biosimilar must match its reference product. A bio-better must differ from it in a useful way. The two products follow different commercial logic, and they often compete in the same market.

Biosimilar: The Legal Standard

Section 351(k) of the Public Health Service Act sets the biosimilar standard. An applicant must show the product is biosimilar to a reference product, based on analytical, animal, and clinical data. [4] The statute allows FDA to set a higher bar for interchangeability. The applicant must show the product can be expected to produce the same clinical result in any given patient. [4]

Bio-Better: The Literature Definition

William Strohl, then at Janssen BioTherapeutics, reviewed biobetter design in BioDrugs in 2015. He separates three groups. Biosimilars are close copies. Biobetters are altered versions of an innovative biologic. Next-generation biologics bind targets in a different way. [5]

A Four-Type Taxonomy of Bio-Betters (Original Framework)

The taxonomy below is our own framework for sorting current products. It is not an established industry classification. Strohl classifies half-life extension strategies into six groups, and our scheme is broader. [5]

Type 1: Delivery Bio-Betters

These products keep the molecule and change how a patient receives it. Keytruda Qlex is a subcutaneous injection with a hyaluronidase component. It takes a couple of minutes, against a 30-minute IV infusion. [14] Opdivo Qvantig is the subcutaneous form of Opdivo. FDA approved it on December 27, 2024. [15]

Type 2: Dosing-Interval Bio-Betters

These products reduce the number of doses. Ultomiris is dosed every eight weeks. Soliris is dosed every two weeks. [16] Eylea HD is the 8 mg version of Eylea. Regeneron reports it as a separate product line. [7]

Type 3: Molecule-Engineered Bio-Betters

These products change the protein. Neulasta (PEGylated filgrastim) was approved in January 2002. The review lists Neupogen as its reference, approved in February 1991. The gap is 10 years and 11 months (analysis). [5] Aranesp, a darbepoetin with modified glycosylation, was approved in September 2001. Epogen was approved in June 1989. The gap is 12 years and 3 months (analysis). [5]

Trulicity (dulaglutide), a GLP-1 fused to an Fc domain, was approved on September 18, 2014. [5] It is also on CMS’s list of 15 drugs selected for Medicare price negotiation in 2028. [17]

Type 4: Targeting Bio-Betters

These products improve where the drug acts, not how long it lasts. Strohl cites IL-2 fused to a tumor-targeting antibody as one example. He lists MM-111, an albumin-based bispecific, in phase 2 for the same reason. [5]

Why Some Bio-Betters Fail: Egranli and Albuferon

A new design does not guarantee approval. Balugrastim (Egranli), a G-CSF fused to albumin, had FDA and EMA applications withdrawn after phase 3. [5] Albuferon, an interferon alfa-2b fused to albumin, had applications withdrawn after phase 2b. It was discontinued in 2010 over safety concerns. [5] Elonva was approved by the EMA in February 2010 but not by FDA. [5]

Analysis: a bio-better has to show a clinical or practical gain, not only a design change. Opdivo Qvantig needed its own randomized trial, CheckMate-67T, with 495 patients. [15]

FDA Biosimilar Approvals Timeline: What the List Shows

Biosimilar Approvals per Year, 2015 to July 2026

The table counts FDA rows by calendar year of approval (analysis of FDA data).

Year	Rows added	Source
2015	1	FDA list
2016	3	FDA list
2017	5	FDA list
2018	7	FDA list
2019	10	FDA list
2020	3	FDA list
2021	4	FDA list
2022	7	FDA list
2023	5	FDA list
2024	18	FDA list
2025	18	FDA list
2026 (January to July)	8	FDA list
Total	89	FDA list

Source for all rows: FDA Biosimilar Product Information. [3]

The table shows 44 rows from January 2024 to July 2026. That is 49% of all rows in 31 months (analysis). [3]

Four Reference Molecules Account for 38% of Rows

Reference molecule	Rows	Earliest approval on list	Latest approval on list
Adalimumab (Humira)	10	September 2016 (Amjevita)	February 2024 (Simlandi)
Denosumab (Prolia, Xgeva)	10	March 2024 (Jubbonti and Wyost)	March 2026 (Ponlimsi and Degevma)
Ustekinumab (Stelara)	8	October 2023 (Wezlana)	May 2025 (Starjemza)
Aflibercept (Eylea)	6	May 2024 (Yesafili, Opuviz)	October 2025 (Eydenzelt)
All other molecules	55	March 2015 (Zarxio)	July 2026

Source: analysis of FDA Biosimilar Product Information. [3]

Three of these molecules (denosumab, ustekinumab, aflibercept) account for 23 of the 44 rows since January 2024. That is 52% (analysis). [3]

FDA Count vs. Samsung Bioepis Count

Published counts differ. Morgan Lewis reports 89 approved US biosimilars in its August 2026 review. [18] Samsung Bioepis reported 92 approvals as of March 2026, covering 20 molecules. It counted 67 launched products, or 73% of approvals. [19] The sources do not explain the three-product difference. We use the FDA row count for all calculations.

How the BPCIA Patent Dance Delays Biosimilar Launch

Twelve Years of Exclusivity and a Four-Year Filing Bar

The Biologics Price Competition and Innovation Act sets two clocks. FDA cannot approve a biosimilar until 12 years after the reference product was first licensed. [4] An applicant cannot file until 4 years after first licensure. [4]

The first interchangeable biosimilar can also receive exclusivity. The statute ends that period at the earliest of several dates, including one year after the first commercial marketing of the first interchangeable product. [4]

The Patent Dance Timeline

Section 262(l) sets the exchange of patent information between a biosimilar applicant and the reference sponsor. The table lists each statutory step. [4]

Step	Statute	Time limit
Applicant gives its application and manufacturing information to the sponsor	262(l)(2)	20 days after FDA accepts the application for review
Sponsor lists patents it believes the product infringes	262(l)(3)(A)	60 days
Applicant lists its own patents and gives detailed statements	262(l)(3)(B)	60 days
Sponsor responds on infringement	262(l)(3)(C)	60 days
Parties negotiate which patents to litigate	262(l)(4)(B)	15 days, then the exchange route applies
Parties exchange lists of patents to litigate	262(l)(5)(B)(i)	No later than 5 days after applicant notice
Sponsor files suit	262(l)(6)	30 days
Applicant gives notice of commercial marketing	262(l)(8)(A)	At least 180 days before first commercial marketing

Source: 42 U.S.C. § 262. [4]

Analysis: the maximum periods in steps (l)(2) through (l)(6) add up to about 250 days (20 + 60 + 60 + 60 + 15 + 5 + 30). The 180-day marketing notice comes after that. A sponsor may also seek a preliminary injunction after the notice and before marketing starts. [4]

Sandoz v. Amgen (2017): What the Supreme Court Decided

The Holdings

The Supreme Court decided Sandoz Inc. v. Amgen Inc. on June 12, 2017. Justice Thomas wrote for a unanimous Court. [20]

The Court held that an applicant may give the 180-day notice before FDA licenses the biosimilar. [20] It also held that the duty to share application and manufacturing information is not enforceable by a federal injunction. [20] The sponsor’s remedy is an immediate declaratory-judgment action under § 262(l)(9)(C). [20]

What This Means for Launch Timing

Analysis: the decision lets a biosimilar maker start the 180-day clock during FDA review. A maker can therefore plan a launch for the day after approval. In practice, the aflibercept record below shows that launches often wait for settlements instead.

Humira Case Study: 132 Patents and One 2023 Entry Date

The Humira Patent Thicket in Numbers

AbbVie’s original Humira patent expired in 2016. [10] The Seventh Circuit counted 132 additional patents that AbbVie obtained. [21] At a 2019 Senate Finance Committee hearing, AbbVie CEO Richard Gonzalez said the company held 136 patents. [10] The two numbers come from different sources and dates.

Gonzalez told Senator John Cornyn: “Humira is like nine different drugs, or 10 different drugs.” [10]

Additional patents extended protection to 2034. Under the settlements, the first competitor could enter in 2023. [10] FDA had approved Amjevita in September 2016. [3] Analysis: more than six years passed between that approval and the 2023 entry date.

I-MAK data on the ten top-selling US drugs in 2021, as reported by STAT authors Tahir Amin and Rohit Malpani, show an average of 74 granted patents per drug. They also show more than 140 patent applications per drug, and 66% of those filings came after FDA approval. [10]

Seventh Circuit 2022: Is a Patent Thicket an Antitrust Violation?

No, not by itself, according to the Seventh Circuit. On August 1, 2022, the court affirmed dismissal of Sherman Act claims in Mayor and City Council of Baltimore v. AbbVie, No. 20-2402. [21] The panel was Judges Easterbrook, Wood, and Kirsch. [21]

The court wrote that “amassing patents by itself is not enough to give rise to an antitrust claim.” [21] It noted that the patent laws set no cap on the number of patents a company can hold. [21] The payors had not tried to show that each Humira patent was invalid. [21]

What Did Biosimilar Entry Do to Humira Revenue?

Humira global revenue fell about 79% from its peak by 2025 (analysis). The table shows the reported figures.

Metric	Value	Basis	Source
Global revenue, 2021 peak	About $22 billion	Reported	BioSpace
Global revenue, 2025	$4,540 million	Reported	AbbVie
US revenue, 2025	$3,062 million	Reported	AbbVie
Change in 2025, global	Down 49.5%	Reported	AbbVie
Change in 2025, US	Down 57.1%	Reported	AbbVie
Implied 2024 global revenue	About $8.99 billion	Analysis	Calculated from AbbVie
Implied 2024 US revenue	About $7.14 billion	Analysis	Calculated from AbbVie

Sources: [1][2]. The AbbVie release does not give 2024 Humira figures. We back-calculated them from the reported declines.

How PBM Private Labels Moved the Market

CVS Cordavis launched a private-label adalimumab in April 2023, initially using Sandoz’s Hyrimoz. The list price was about 80% below Humira’s at launch. [2] CVS Caremark removed branded Humira from its formularies in April 2024. Hyrimoz prescriptions rose sharply afterward. [2]

Spherix Global Insights survey data show Humira’s share of advanced rheumatoid arthritis use fell from 22% in Q4 2023 to 16% in Q4 2024. Biosimilar share rose from 3% to 10% in the same survey. [2] Samsung Bioepis reports adalimumab biosimilar adoption of 60% as of February 2026. The report says the rise partly reflects the addition of Quallent private-label sales to its share calculation. [19]

Amgen’s Amjevita earned $761 million in 2024, up 22% in its first full US year. [2]

Humira vs. Stelara vs. Eylea: Comparing Reported Revenue Erosion

Product	Metric	2025 change	Source
Humira	Global revenue	Down 49.5%	AbbVie
Humira	US revenue	Down 57.1%	AbbVie
Stelara	Global sales	Down 41.3%	Zacks report of J&J results
Eylea (2 mg)	US net sales	Down 42%	Regeneron
Eylea plus Eylea HD	US net sales	Down 27%	Regeneron

Sources: [1][6][7]. The rows are not like for like. They differ by geography and by years of biosimilar competition. Humira’s 2025 figures come from the third calendar year of US biosimilar competition, following the 2023 entry date. [10] Stelara’s come from the first year. [6]

Stelara Biosimilar Launch Timeline and Settlement Terms

Ustekinumab Timeline, 2009 to 2025

Date	Event	Status	Source
2009	Stelara launches. Sales exceed $9.7 billion in 2022.	Confirmed	AJMC
October 2023	FDA approves Wezlana (ustekinumab-auub) with an interchangeability designation	Confirmed	FDA list; AJMC
Late 2023	J&J settles with Samsung Bioepis and Sandoz	Confirmed	Fierce Pharma
By January 1, 2025	Amgen may sell Wezlana “no later than January 1, 2025”	Settlement term	AJMC
February 22, 2025	Settlement allows Pyzchiva launch	Settlement term	Fierce Pharma
Q4 2025	Ustekinumab biosimilar share reaches 27%	Reported	Samsung Bioepis
Full-year 2025	Stelara sales fall 41.3% to $6.08 billion	Reported	Zacks

Sources: [13][3][22][19][6].

Analysis: Stelara sales were about $10.4 billion in 2024, implied by the 41.3% decline to $6.08 billion. Wezlana was approved about 15 months before its permitted sale date. Pyzchiva was approved in June 2024, about 8 months before its February 2025 date.

J&J v. Samsung Bioepis (2025): A Settlement Dispute Over Private Labels

J&J sued Samsung Bioepis in a federal court in New Jersey for breach of contract. Fierce Pharma reported the filing in its February 25, 2025 article. [22] J&J said Samsung Bioepis tried to sublicense a second biosimilar to a PBM’s private-label distributor. [22] J&J did not seek to stop Samsung Bioepis from marketing Pyzchiva. [22]

Jennifer Taubert, J&J’s worldwide chairman of innovative medicines, said: “we’ve talked about the Humira erosion curve being probably the best thing to model.” [22] The 2025 revenue data above fit that comparison at the global level. Stelara fell 41.3% in its first year, and Humira fell 49.5% in its third (analysis).

Eylea vs. Eylea HD: A Bio-Better Cushion During Biosimilar Entry

Regeneron Eylea Sales, 2024 and 2025

US net sales ($ millions)	FY 2024	FY 2025	Change
Eylea (2 mg)	4,767.1	2,747.8	Down 42%
Eylea HD (8 mg)	1,201.1	1,636.9	Up 36%
Total	5,968.2	4,384.7	Down 27%
Eylea HD share of total (analysis)	20.1%	37.3%	Up 17.2 points

Source: Regeneron fourth-quarter and full-year 2025 release, January 30, 2026. Share row is analysis. [7]

In the fourth quarter of 2025, Eylea HD reached $506.3 million of $1,083.2 million, or 46.7% (analysis). The year-earlier share was 20.4%. [7]

Regeneron did not blame biosimilars alone for the decline. The release cites “continued competitive pressures,” “loss in market share to compounded bevacizumab due to patient affordability constraints,” “the continued transition of patients to EYLEA HD,” and a lower net selling price. [7] The release does not discuss biosimilars for Eylea in its results text. [7]

Analysis: the data show a franchise shifting patients to a higher-dose version while the lower-dose version loses sales. The total fell 27%, and Eylea 2 mg fell 42%. Regeneron’s own sales data do not show how much of that gap came from patient transition and how much from competitors.

Aflibercept Biosimilar Launch Queue

FDA’s list shows six approved aflibercept biosimilars. [3] The table compares each approval month with its launch date.

Product (company)	FDA approval	US launch	Approval-to-launch gap (analysis)	Status
Pavblu (Amgen)	August 2024	October 2024	About 2 months	Launched
Yesafili (Biocon)	May 2024	August 3, 2026	About 27 months	Launched
Enzeevu (Sandoz)	August 2024	Q4 2026	About 26 to 28 months	Expected
Ahzantive (Formycon, Klinge)	June 2024	Q4 2026	About 28 to 30 months	Expected
Eydenzelt (Celltrion)	October 2025	December 31, 2026	About 14 months	Settlement date
Opuviz (Samsung Bioepis)	May 2024	Not stated	Not stated	Injunction granted June 14, 2024; upheld January 29, 2025

Sources: FDA list for approval months. [3] Launch and status data from [23][24][11]. Gaps are analysis based on month-level approval data.

Analysis: as of the August 3, 2026 report, two of six approved products were on the US market. [11] Four waited, including one with a court injunction in place.

Why Do Approval-to-Launch Gaps Run From 2 to 30 Months?

Court orders and settlements explain most of the gap. On June 11, 2024, the Northern District of West Virginia issued a permanent injunction that blocked Biocon’s Yesafili until at least the expected June 14, 2027 expiry of US Patent No. 11,084,865. [23] Biocon and Regeneron settled in April 2025, and the court vacated the injunction on April 22, 2025. [23] Biocon launched on August 3, 2026. [23]

Amgen’s Pavblu followed a different path. Amgen launched in October 2024 after the Federal Circuit denied Regeneron’s application for an injunction. [11] Regeneron filed new BPCIA litigation against Amgen in June 2025. [24] The sources do not say whether the same patents were at issue in each case.

Why FDA’s Comparative Efficacy Draft Matters for Intravitreal Products

Aflibercept and ranibizumab are given by intravitreal injection. Jones Day reports that FDA’s October 2025 draft lists intravitreally administered products among the exceptions where a comparative efficacy study may still apply. [25] The FDA list includes two ranibizumab biosimilars approved in December 2025 and June 2026, Nufymco and Ranluspec. [3]

Keytruda LOE in 2028: Can Subcutaneous Keytruda Qlex Move the Patent Clock?

Keytruda Patent Expiration Dates and Sales

Item	Value	Source
Keytruda US patent expiry	2028 (two additional compound-family patents expire in 2029 through patent term adjustment)	Merck FY2025 10-K
Keytruda EU patent expiry (France, Germany, Italy, Spain)	2031	Merck FY2025 10-K
Keytruda Qlex US patent expiry	2043	Merck FY2025 10-K
Keytruda Qlex EU patent expiry	2031 (a pending application, if granted, would expire in 2040)	Merck FY2025 10-K
Keytruda and Keytruda Qlex sales, 2024	$29,482 million	Merck FY2025 10-K
Keytruda and Keytruda Qlex sales, 2025	$31,680 million	Merck FY2025 10-K
Sales growth, 2025 (analysis)	About 7.5%	Calculated from Merck

Source: [8]. Merck says the 2029 patents “will be the subject of litigation in the future.” [8] The 10-K sales line combines Keytruda and Keytruda Qlex. [8]

Keytruda accounts for nearly 60% of Merck’s turnover, according to pharmaphorum. [14]

Keytruda Qlex vs. IV Keytruda: Dosing and Clinical Data

FDA approved Keytruda Qlex in September 2025. Merck announced it with a news release. [26] It is a subcutaneous injection approved for most solid tumor indications of the IV version. [26] Doses are every three weeks or every six weeks. [26]

In the non-small cell lung cancer study reported with the approval, the overall response rate was 45% for Keytruda Qlex and 42% for IV Keytruda. [26] Progression-free survival and overall survival were similar. [26] A Merck spokesperson told Endpoints News that pricing is at parity with the IV version. [26]

Merck expects Keytruda Qlex could eventually account for 30% to 40% of patients taking pembrolizumab. pharmaphorum attributes this to the company. [14]

Halozyme v. Merck: The Patent Fight Over the Subcutaneous Component

Keytruda Qlex uses berahyaluronidase alfa, a component owned by Alteogen. Halozyme claims the component infringes its patents. [14] Halozyme’s April 2025 New Jersey complaint alleges infringement of 15 patents. [12]

PTAB Final Written Decision, May 12, 2026

On May 12, 2026, the Patent Trial and Appeal Board issued a final written decision in post-grant review PGR2025-00003. It found claims 1 to 4 and 8 to 21 of US Patent No. 11,952,600 invalid for lack of enablement and failure to meet the written description requirement. Halozyme had disclaimed claims 5 to 7. [12]

Merck challenged 14 other Halozyme patents in post-grant reviews between November 2024 and November 2025. The PTAB instituted 13 of them. [12] On March 23, 2026, Merck filed three inter partes review petitions. They target US 11,066,656, US 11,041,149, and US 10,865,400. They were pending when Pearce IP reported. [12] The source does not report an appeal of the May 12 decision.

Munich Regional Court Injunction, December 2025

In December 2025, the Munich Regional Court granted Halozyme a preliminary injunction that prevents Merck from distributing and offering Keytruda SC in Germany. The court found imminent infringement of EP 2797622. [12] Merck filed invalidation suits against that patent in Germany, the UK, the Netherlands, and France. [12]

Scenario Analysis: How Much Keytruda Revenue Sits in the Subcutaneous Form?

This scenario applies Merck’s stated 30% to 40% conversion range to Merck’s 2025 sales. It is an illustration, not a forecast. The assumptions are flat 2025 sales of $31.68 billion, price parity, and no change in patient volume. [8][14][26]

Qlex share of pembrolizumab patients	Qlex revenue (analysis)	IV revenue (analysis)
30%	$9.5 billion	$22.2 billion
35%	$11.1 billion	$20.6 billion
40%	$12.7 billion	$19.0 billion

Analysis: under these assumptions, between $9.5 billion and $12.7 billion of annual sales would sit in a product with a listed US patent expiry of 2043. The remainder would sit in the IV product, which Merck lists at 2028. [8] The outcome depends on the Halozyme cases, on payer rules, and on whether biosimilar makers can reach the subcutaneous formulation.

Opdivo Qvantig and the Subcutaneous Conversion Pattern

What FDA Approved on December 27, 2024

FDA approved Opdivo Qvantig (nivolumab and hyaluronidase-nvhy) on December 27, 2024. It covers adult solid tumor indications of IV Opdivo, with several combinations. It is not indicated with IV ipilimumab. [15] Dosing options are 600 mg every 2 weeks, 900 mg every 3 weeks, or 1,200 mg every 4 weeks. [15]

CheckMate-67T Data

CheckMate-67T randomized 495 patients with advanced clear cell renal cell carcinoma to subcutaneous or IV nivolumab. [15] The trial met its pharmacokinetic margin, with the lower boundary of the 90% confidence interval at 0.8 or higher for Cavg over 28 days and for Cmin at steady state. [15] Response rates by blinded independent central review were 24% for subcutaneous and 18% for IV. [15]

Analysis: the primary objective was exposure, not efficacy. The response-rate difference is descriptive. The trial design shows what a delivery bio-better must prove: matching drug levels with a different route.

Soliris to Ultomiris: Interval Extension as a Biosimilar Defense

Eculizumab Biosimilars Reach the US Market

Amgen’s Bkemv and Teva and Samsung Bioepis’s Epysqli were available in the US by April 2025, after patent settlements delayed launch from their 2024 FDA approval dates. [16] FDA lists Bkemv in May 2024 and Epysqli in July 2024. [3] Bkemv is interchangeable with Soliris. [16]

pharmaphorum reports Soliris’s US list price at $6,523 per vial. Bkemv launched at roughly a 10% WAC discount and Epysqli at 30%. [16] Samsung Bioepis reports discounts against reference ASP of 9% for Bkemv and 32% for Epysqli. [19]

What the Ultomiris Dosing Interval Changes

Ultomiris (ravulizumab) is dosed every eight weeks. Soliris (eculizumab) is dosed every two weeks. [16] Both drugs came to AstraZeneca through its $39 billion acquisition of Alexion in 2021. [16] Analysis: this is a Type 2 bio-better. The same company owns the product losing exclusivity and the longer-interval product that patients can move to.

FDA Biosimilar Reform, 2025 to 2026: What Changes If the Drafts Become Final

The October 29, 2025 Draft on Comparative Efficacy Studies

FDA issued a draft guidance on October 29, 2025. Its title is “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies.” [27] FDA calls comparative efficacy studies “resource-intensive” and “unnecessary” for most biosimilars. [27]

For a product found highly similar in a comparative analytical assessment, FDA would require only a pharmacokinetic similarity study and an immunogenicity assessment. [27] FDA keeps the option to require a study in some cases. [27] Jones Day reports that a 2025 HHS-commissioned study found current requirements had increased development time and costs. [25]

FDA Commissioner Makary said: “we can achieve massive cost reductions for advanced treatments for cancer, autoimmune diseases, and rare disorders.” [27]

Interchangeability and Switching Studies

Jones Day reports that the interchangeability draft guidance says clinical switching studies are “generally no longer needed to demonstrate interchangeability.” [25] Arnold & Porter reports that FDA intends to treat all approved biosimilars as interchangeable. [27]

The drafts are not final. Jones Day wrote in December 2025 that FDA planned to finalize both documents in the first half of 2026. [25] A BioPharm International FAQ dated August 26, 2026 still described the recommendations as draft. [28]

What This Means for Biosimilar Developers

Lower Clinical Cost

Analysis: a developer that skips a comparative efficacy study saves the cost of a large clinical trial. The savings apply mainly to products that meet FDA’s analytical and pharmacokinetic criteria. [27]

No Change to Patent Barriers

Faster approval does not remove patent barriers. The aflibercept table shows approval-to-launch gaps of 14 to 30 months for four products. Those gaps came from litigation and settlements, not from FDA review. [11][23]

What This Means for Brand Manufacturers

More Pressure on Lifecycle Strategy

Analysis: if approval costs fall, more biosimilar applicants can afford to enter. Brand makers then have more reason to protect franchises with bio-betters, as Regeneron did with Eylea HD and Merck did with Keytruda Qlex. [7][8]

More Importance for Formulation Patents

Keytruda Qlex carries a listed US patent expiry 15 years after the IV product. [8] Halozyme’s dispute shows that formulation components carry their own patent risk. [12]

Medicare Price Negotiation and Biologics: The 2028 Selected Drug List

Which Biologics Did CMS Select for 2028?

CMS released the initial price applicability year 2028 selected drug list on January 27, 2026. It names 15 drugs: 10 from Medicare Part D and 5 from Part B. [17] The list includes Orencia, Cosentyx, Entyvio, Xolair, Cimzia, Botox, and Trulicity. [17]

Milliman notes that a drug leaves the selection pool once a generic or biosimilar is approved and marketed. It cites Humira, Prolia, and Eylea as examples. [17]

Does Biosimilar Approval Remove a Drug From Negotiation?

Approval alone does not. Marketing also matters. FDA’s list shows Omlyclo (omalizumab-igec) approved in March 2025. [3] Xolair is on the 2028 selected list. [17] The sources do not say whether Omlyclo is marketed in the US. Analysis: this is a case to watch, because launch timing can change a product’s negotiation status.

How Much Have Biosimilars Saved the US Healthcare System?

The Biosimilars Council and the Association for Accessible Medicines estimate savings of $20.2 billion in 2024 and $56.2 billion since 2015.

Biosimilar savings “nearly doubled from the previous year, to $20.2 billion” in 2024, and biosimilars “generated $56.2 billion in savings” since entering the market in 2015. (Biosimilars Council and Association for Accessible Medicines, September 3, 2025) [29]

Analysis: 2024 alone accounts for about 36% of the cumulative total (20.2 divided by 56.2). [29] This is an industry-group estimate. It does not come from a government source.

Price gaps vary by product. Samsung Bioepis reports denosumab biosimilar WAC discounts of 6% to 79% against Prolia, and 6% to 86% against Xgeva. [19] Biosimilar makers also post inter partes review petitions as a lever. Morgan Lewis reports a 57% institution rate for IPRs challenging patents that claim biologics, excluding IPRs that settled or ended. [18]

Where DrugPatentWatch Fits in Biologics IP Research

DrugPatentWatch is a subscription platform that covers patents, pipelines, litigation, pricing, and global market opportunities, according to its homepage. [30] Its site lists Keytruda and Humira among its examples of patent expiry opportunities. [30]

The site says it draws on sources such as the USPTO, the FDA Orange Book, ANDA filings, and litigation records. [30] Analysts can use a platform like this to track expiry dates and litigation events, then confirm each date against USPTO records, FDA’s Purple Book, and court dockets. We built this article’s tallies from FDA’s published table, company filings, and court-related reports. We did not use DrugPatentWatch data as evidence for any claim above.

What Happens Next: A Watch List for 2026 to 2028

Date	Event	Status	Source
Q4 2026	Enzeevu and Ahzantive US launches	Expected under settlements	Pearce IP
December 31, 2026	Eydenzelt US launch	Settlement date	Pearce IP
Q4 2026	Alvotech and Teva AVT06 launch	Expected, subject to FDA approval (BLA resubmitted June 2026)	Pearce IP
June 14, 2027	Expected expiry of US Patent No. 11,084,865	Expected	Goodwin
2028	Keytruda US patent expiry	Listed by Merck	Merck 10-K
2028	First year of negotiated prices for the 15 selected drugs	Scheduled	Milliman
Pending	FDA final guidance on comparative efficacy studies and interchangeability	Draft as of August 2026	BioPharm International
Pending	Merck IPR petitions against three Halozyme patents	Not yet instituted when reported	Pearce IP
Pending	Regeneron v. Amgen over Pavblu	Pending when reported	Pearce IP

Sources: [11][24][23][8][17][28][12]. Expected dates are not confirmed events.

Key Takeaways

FDA’s biosimilar table has 89 rows as of October 5, 2026. Forty-four were added from January 2024 to July 2026. [3]
Adalimumab, denosumab, ustekinumab, and aflibercept account for 34 of the 89 rows. [3]
Humira global revenue fell 49.5% in 2025. Stelara fell 41.3%. [1][6]
Eylea HD supplied 37.3% of Regeneron’s 2025 US Eylea-franchise sales, up from 20.1% (analysis). [7]
Merck lists a 2028 US patent expiry for Keytruda and 2043 for Keytruda Qlex. [8]
A May 12, 2026 PTAB decision invalidated claims of one Halozyme patent asserted against Keytruda Qlex. Other challenges are pending. [12]
FDA’s October 2025 drafts would remove most comparative efficacy studies. They were still draft in August 2026. [27][28]
Patent settlements, not FDA review, set most US launch dates for aflibercept biosimilars. [23][11]

FAQ

Can a pharmacist substitute a biosimilar without calling the prescriber?

Only if FDA has designated the biosimilar as interchangeable, and state law allows substitution. Bkemv is interchangeable with Soliris. [16] FDA has not designated Pavblu as interchangeable with Eylea. [11] Yesafili was approved as interchangeable in May 2024. [23]

Does a bio-better need its own clinical trial?

The Opdivo Qvantig record suggests yes for a change in route. FDA’s approval rests on CheckMate-67T, a randomized trial of 495 patients that compared subcutaneous and IV nivolumab. [15] The Strohl review does not describe regulatory pathways in detail. [5]

Why do biosimilars launch years after approval?

Patents and settlements delay launch. Biocon’s Yesafili launched about 27 months after its May 2024 approval (analysis). A court had enjoined launch until at least the expected June 14, 2027 expiry of US Patent No. 11,084,865, and the parties settled in April 2025. [23]

How big are biosimilar discounts?

They vary widely. Denosumab biosimilars list at 6% to 79% below Prolia. [19] Epysqli launched at a 30% WAC discount to Soliris, and Bkemv at roughly 10%. [16] Hyrimoz through Cordavis listed about 80% below Humira at its April 2023 launch. [2]

How often do IPR petitions succeed against biologics patents?

The institution rate is 57% for IPRs challenging patents that claim biologics, excluding IPRs that settled or ended. [18] Institution is not a final invalidity ruling.

Which biologics are on the Medicare negotiation list for 2028?

CMS selected 15 drugs on January 27, 2026. Biologics on the list include Orencia, Cosentyx, Entyvio, Xolair, Cimzia, Botox, and Trulicity. [17]

How much do originator biologics lose after biosimilar entry?

Reported 2025 declines were 49.5% for Humira globally, 41.3% for Stelara globally, and 42% for US Eylea 2 mg. [1][6][7] The figures cover different years of competition and different geographies.

When do Keytruda’s patents expire?

Merck lists 2028 in the US and 2031 in France, Germany, Italy, and Spain. Two additional US patents in the compound family expire in 2029 through patent term adjustment. [8]

Is a patent thicket illegal under US antitrust law?

Not by itself, according to the Seventh Circuit in its August 1, 2022 Humira decision. The court said “amassing patents by itself is not enough to give rise to an antitrust claim.” [21] Settlement terms can still support a Section 1 claim if the plaintiff proves injury from them. [21]

Why did FDA propose dropping comparative efficacy studies?

FDA calls the studies resource-intensive and unnecessary for most biosimilars. Jones Day reports that FDA cites more sensitive analytical tools and accumulated experience with biosimilars. [27][25]