Abstract
This study examines all patents associated with biologic litigation to understand how manufacturers use ancillary product patents to delay biosimilar market entry.
In 2021, 46% ($260 billion) of all gross prescription drug spending in the US was on biologic products.1 Patents are government-granted monopolies that last 20 years; by obtaining multiple patents for different aspects of the same product, biologic manufacturers create “patent thickets” that can block or delay biosimilar competition to protect market share.2,3
Although patent gamesmanship by biologic manufacturers has been well documented, a key strategy that has not received sufficient attention is use of “ancillary product patents,” which cover critical features of the biologic’s active ingredient that enable it to act on the molecular target and achieve the desired therapeutic effect, such as glycan profiles, oxidation levels, or other physiochemical properties.
Rather than filing ancillary product patents as part of their initial primary patent filing, manufacturers often keep ancillary product features confidential as trade secrets and wait years before obtaining ancillary product patents.3 The US Food and Drug Administration (FDA) possesses ancillary product information but also maintains it as a trade secret.4 By keeping this information confidential, biologic manufacturers make it more difficult for competitors to access information needed to develop biosimilars.5 In addition, this strategy may allow biologic manufacturers to extend periods of market exclusivity because later-filed ancillary patents typically expire after the primary patents.
We reviewed all patents associated with biologic litigation to understand how manufacturers use ancillary product patents in the US to delay biosimilar market entry.
Methods
We identified all patents involved in litigation against biosimilar firms in the US from January 2010, when the biosimilar approval pathway was first established, to April 2023. Patents involved in litigation were identified using Lex Machina, a commercial patent litigation database listing all patents mentioned in litigation complaints. We specifically focused on patents involved in litigation because manufacturers do not have to reveal their biologic patents until litigation is started.
We categorized all patents as primary (on the active ingredient) or secondary (on other features of the product, such as the formulation, method of use, device, or method of manufacture). We then coded all secondary patents as ancillary (claiming a drug’s physiochemical properties) or nonancillary.
We determined the duration of added protection afforded by ancillary product patents by subtracting the ancillary product patent expiration date from the expiration date of the primary patent. We focused on extension relative to primary patent expiration rather than other secondary patent expiration because ancillary patents are the strongest type of secondary patent, and understanding how these patents function alongside similarly strong primary patents is important.
Results
Manufacturers of 12 biologics brought litigation against 48 biosimilar manufacturers from 2010 to 2023. There were 271 total litigated patents, of which 12 (4%) were primary, 22 (8%) ancillary secondary, and 237 (87%) nonancillary secondary patents. Four biologics (33%) were protected by ancillary product patents (Table), whereas 8 (67%) were not. Ancillary product patents were filed a median of 18.3 years (IQR, 17.4-19.6 years) after the first primary patent was filed and extended the expected duration of protection by a median of 10.4 years (range, 2.4-17.9 years) beyond the primary patents (Table).
Table. Biosimilars With Litigated Ancillary Product Patentsa.
| Branded drug name (generic name) | Primary patent (expiration date)b | FDA approval date | Litigated ancillary product patent (expiration date)c | Extension of time, dd | Ancillary product claim subject matter |
|---|---|---|---|---|---|
| Epogen/Procrit (epoetin alfa) | US 5 547 933 (Aug 20, 2013) | Jun 1, 1989 | US 5 856 298 (Jan 5, 2016) | 868 | Silylation profile |
| Eylea (aflibercept) | US 7 070 959 (Jun 16, 2023) | Nov 18, 2011 | US 11 186 625 (Aug 18, 2040) US 11 306 135 (Aug 18, 2040) US 11 066 458 (Jun 14, 2027) US 10 464 992 (Jun 14, 2027) |
6273 | Oxidation profile Oxidation profile Glycosylation profile Aggregation profile |
| Herceptin (trastuzumab) | US 5 821 337 (Oct 13, 2015) | Sep 25, 1998 | US 6 339 142 (May 3, 2019) US 9 249 218 (May 3, 2019) |
1298 | Acidic profile Acidic profile |
| Humira (adalimumab) | US 6 090 382 (Dec 31, 2016) | Dec 31, 2002 | US 8 916 153 (Nov 14, 2034) US 9 550 826 (Nov 14, 2034) US 9 181 337 (Nov 12, 2033) US 9 200 070 (Nov 12, 2033) US 9 505 833 (Nov 12, 2033) US 9 085 618 (Nov 12, 2033) US 9 522 953 (Nov 12, 2033) US 9 334 319 (Mar 14, 2033) US 9 683 033 (Mar 14, 2033) US 9 708 400 (Mar 14, 2033) US 9 365 645 (Apr 26, 2032) US 9 255 143 (Apr 26, 2032) US 8 231 876 (Apr 4, 2027) US 8 895 009 (Apr 4, 2027) US 9 096 666 (Apr 4, 2027) |
6527 | Purity level Glycosylation profile Lysine species Acidic profile Methylglyoxal species Acidic profile Acidic profile Acidic profile Acidic profile Lysine species Fucosylation profile Fucosylation profile Purity level Purity level Purity level |
| Avastin (bevacizumab) | US 6 407 213 (Jun 20, 2020) US 6 054 297 (Feb 26, 2018)e |
Feb 26, 2004 | |||
| Enbrel (etanercept) | US 8 163 522 (Apr 24, 2029) RE 36 755 (Oct 23, 2012)e |
Nov 2, 1998 | |||
| Neulasta (pegfilgrastim) | US 5 824 784 (Oct 20, 2015) | Jan 31, 2002 | |||
| Neupogen (filgrastim) | US 5 580 755 (Dec 3, 2013) | Feb 20, 1991 | |||
| Remicade (infliximab) | US 6 284 471 (Sep 4, 2018) | Aug 24, 1998 | |||
| Rituxan (rituximab) | US 5 736 137 (Apr 7, 2015) US 5 677 180 (Oct 14, 2014) |
Nov 26, 1997 | |||
| Stelara (ustekinumab) | US 6 902 734 (Sep 25, 2023)e | Sep 25, 2009 | |||
| Tysabri (natalizumab) | US 5 840 299 (Apr 27, 2017)e US 6 602 503 (Aug 5, 2020) |
Nov 23, 2004 |
Abbreviation: FDA, Food and Drug Administration.
We identified all patents litigated against biosimilars identified by reviewing all complaints filed in federal court by branded drug companies alleging patent infringement against biosimilar manufacturers. The independent claims of all litigated patents were reviewed.
Primary product patents were identified as the first product patent to disclose the active ingredient of the biologic drug.
Ancillary product patents were identified as having a later effective filing date and expiry date than the primary product patent and including at least 1 physiochemical property of the drug.
Extension of time was determined by subtracting the last-to-expire ancillary product patent’s expiration date from the primary patent’s expiration date.
Patent is associated with patent term extension.
Discussion
Although a small proportion of litigated patents were ancillary product patents, they extended the length of market exclusivity on several products. Ancillary product patents pose obstacles for biosimilar entry because, unlike manufacturing and formulation patents, they cannot be designed around, and unlike method-of-treatment patents, they cannot be carved out of the label. This analysis is limited by focusing exclusively on litigated patents and it is unknown how many ancillary product patents are filed but not litigated; however, these are key patents that limit biosimilar entry and are the only way biologic patents are publicly revealed.
The FDA and the patent office should work together to ensure that key information on biologics is timely disclosed, either through direct release by the FDA or transmission from the FDA to the patent office during the patent examination process. Agency coordination could facilitate biosimilar development, reduce market exclusivity periods by promoting earlier patent filings, and ensure that patients have earlier access to lower-cost therapies.
Section Editors: Jody W. Zylke, MD, Deputy Editor; Karen Lasser, MD, and Kristin Walter, MD, Senior Editors.
Data Sharing Statement
References
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Supplementary Materials
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