Patent Portfolios Protecting 10 Top-Selling Prescription Drugs

This cross-sectional study examines the composition of the patents protecting the 10 top-selling prescription drugs in the US.

Key Points

Question

What is the makeup of multiple overlapping patents (ie, patent thickets) for top-selling prescription drugs?

Findings

In this cross-sectional study of 1429 patents and patent applications protecting the 10 highest-revenue brand-name drugs in the US in 2021, almost three-quarters were filed after US Food and Drug (FDA) approval. Patents filed after FDA approval and those protecting parts of the drug other than the active ingredient contributed to dense patent thickets.

Meaning

Findings of this study suggest that since patent thickets for top-selling drugs consist of many patents initially sought after FDA approval, careful scrutiny of patent applications and of patents filed after FDA approval is needed to facilitate timely generic and biosimilar competion.

Abstract

Importance

Brand-name drugs are sold at high prices in the US during market exclusivity periods protected by patents. Multiple overlapping patents protecting a drug are known as patent thickets and can effectively delay the emergence of price-lowering generic competition for many years.

Objective

To evaluate the composition of patent thickets of 10 top-selling prescription drugs in the US and compare the characteristics of drug patents filed during development with those filed on these products after US Food and Drug Administration (FDA) approval.

Design and Setting

This cross-sectional study examined US patent thickets of the 10 prescription drugs with the highest US net sales revenue in 2021 using information on issued patents and patent applications as of June 30, 2022, obtained from a public database by the Initiative for Medicines, Access, and Knowledge. Data were analyzed from September 2022 to June 2023.

Main Outcomes and Measures

Prevalence of patents filed before and after FDA approval; types of claims present in issued patents (ie, chemical composition, method of use, process or synthesis, formulation, and delivery device); and patent thicket density (number of active patents at a given time).

Results

The 10 top-selling prescription drugs in the US for 2021 included 4 small-molecule drugs and 6 biologics. These 10 drugs were linked to 1429 patents and patent applications: 742 (52%) issued patents, 218 (15%) pending applications, and 469 (33%) abandoned applications. Almost three-quarters of patent applications (1028 [72%]) were filed after FDA approval. The postapproval proportion was higher for biologics (80%) than for small-molecule drugs (58%). Postapproval filing of patent applications peaked in the first 5 years after FDA approval for small-molecule drugs and 12 years after FDA approval for biologics. Of 465 patents issued for applications filed after FDA approval, 189 (41%) had method of use claims, 127 (27%) had formulation claims, and 103 (22%) had process or synthesis claims, while 86 (19%) had chemical composition claims and 46 (10%) had device claims. Patent thicket density peaked 13 years after FDA approval, at which time these 10 drugs were protected by a median (IQR) of 42 (18-83) active patents, 66% of which were filed after FDA approval.

Conclusions and Relevance

This study found that among the 10 top-selling prescription drugs in the US in 2021, patents filed after FDA approval and containing claims covering aspects other than the active ingredient of the drug contributed to patent thickets. Scrutiny of patent applications and of patents filed after FDA approval is needed to facilitate timely generic or biosimilar competition.

Introduction

The high costs of brand-name prescription drugs that individuals in the US face have been a pressing concern for policymakers and patients.^1,2 In the US, manufacturers of brand-name drugs set high prices during periods of market exclusivity that can last 12 to 14 years or longer based on the patents covering the drug.³ After exclusivity periods expire, the availability of generic and biosimilar drugs can contribute to substantially lower prices and reduced spending for patients and payers.⁴

Each drug patent typically provides 20 years of market exclusivity. Patents are routinely obtained for a drug’s active ingredient; however, for successful drug products, manufacturers of brand-name pharmaceuticals obtain additional patents on other aspects of the drug, such as its formulation, methods of use, and manufacturing processes.^5,6 Multiple patents protecting a successful brand-name drug are known as patent thickets, and they can delay and deter generic and biosimilar drug availability because competing manufacturers often must either wait until the patents expire or file a lawsuit to have certain patents invalidated (or settle with the brand-name manufacturer) before they can market their product.⁷

Lack of timely generic and biosimilar competition in the US drug market caused by patent thickets keeps drug costs high for patients and payers. To address this problem, the Biden administration issued an Executive Order in July 2021 directing the US Food and Drug Administration (FDA) and the US Patent and Trademark Office (USPTO) to cooperate “to help ensure that the patent system, while incentivizing innovation, does not also unjustifiably delay generic drug and biosimilar competition beyond that reasonably contemplated by applicable law.”⁸ Both agencies have agreed to collaborate on policy solutions to “protect against the patenting of incremental, obvious changes to existing drugs that do not qualify for patents.”⁹ The FDA and USPTO exchanged letters outlining potential initiatives, such as giving patent examiners access to more FDA resources to investigate the approvability of applications and avoid granting patents that do not meet the basic statutory criteria.^10,11 So far, the agencies have begun collaborating through a joint public listening session and staff cross-training events, but have not made major policy changes.¹²

To help better understand pathways to improve timely generic and biosimilar competition, we evaluated the characteristics of patent thickets for the 10 top-selling prescription drugs in the US for 2021. We compared the characteristics of patents filed during the product’s development with patents filed on these products after FDA approval.

Methods

Data Sources, Extraction, and Coding

We started with patent data drawn from the publicly available Drug Patent Book compiled by the Initiative for Medicines, Access, and Knowledge, a nonprofit legal organization.¹³ The Drug Patent Book was developed through systematic characterization of the patent landscapes of the 10 drugs with the highest US net sales revenue in 2021 (in this case, the drugs included both small-molecule drugs and biologics). The database includes information on granted patents and patent applications published as of June 2022.¹⁴ The database was constructed by including patents from the FDA’s Approved Drug Products With Therapeutic Equivalence Evaluations (Orange Book) and Database of Licensed Biological Products (Purple Book) (publicly available compilations of certain kinds of patents that manufacturers submit to the FDA at the time of approval for all small-molecule drugs and at later times for certain biologics, respectively) listed as of June 2022 and supplemented with patents asserted in litigation and identified through searches of the intellectual property databases Orbit Intelligence (Questel), CAS SciFinder (American Chemical Society), Lens.org, and Espacenet. In accordance with the Common Rule, this cross-sectional study was exempt from review, as it was based on publicly available data and involved no personal health information.

To confirm the relevance of patents in the Drug Patent Book to a particular drug, we cross-checked against historical Orange Book listings from 1985 to 2022, the Unified Patents database of US litigation from 2000 to 2020, and the Lex Machina database of US litigation from 2000 to June 2023. We used the patent expiration dates listed in the Drug Patent Book. For any patent listed as expiring more than 20 years after its filing date, we cross-checked with the USPTO public list of Patent Term Extensions and USPTO Patent Center to confirm whether the patent had received an adjustment in its expiration date.

The dates of each drug’s FDA approval and authorization of therapeutic equivalents were identified from Drugs@FDA.¹⁵ To facilitate comparison across drugs, we converted each patent’s filing, granting, and expiration dates into the number of years before or after FDA approval. To assess trends in manufacturer filing practices, we analyzed the actual filing dates (the dates on which applications were submitted to the USPTO) of all patent applications, including those that resulted in issued patents and those that are pending or have been abandoned. The status of each patent or application (active, expired, pending, or abandoned) was determined as of June 30, 2022, the end of data collection. For each drug, we calculated the number and percentage of patent applications and issued patents filed by year before and after FDA approval.

Patent Characteristics

For our analysis of patent characteristics, only issued patents were included, since those contained claims that the USPTO had deemed to be patentable. Based on the claims present, patents were assigned to 1 or more categories: (1) chemical composition claims, which describe the molecular entity; (2) method of use claims, which describe the treatment or prevention of a disease, assessment of a diagnosis, or alteration of a biomarker associated with disease; (3) process or synthesis claims related to manufacturing; (4) formulation claims, which describe a novel dosage form, route of administration, strength, or combination of drugs; and (5) device claims, which describe a mechanism for delivering a product into the body (eMethods in Supplement 1). Since most patents contain multiple claims, each patent could be assigned to multiple categories. Two authors (C.H. and S.M.E.G.) independently coded samples of 25 patents and discussed each patent to reach consensus on category definitions. After full review, unclear claims were reviewed jointly by the 2 coders and in discussion with other authors as needed to reach consensus. We compared the number and percentage of patents in each claim category filed before and after FDA approval.

Statistical Analysis

To analyze patent thickets, we used grant and expiration dates to calculate the number of patents active at each 1-year interval before or after FDA approval. The patent thicket density was defined as the number of active patents on a drug at a given time. Data were analyzed from September 2022 to June 2023 using Excel, version 16 (Microsoft Corp).

Results

The sample included patents for 4 small-molecule drugs and 6 biologics (Table). As of June 30, 2022, the drugs had been approved for 4.4 to 23.7 years (median [IQR], 10.1 [8.0-15.6] years). To these 10 drugs, we linked 1429 patents and patent applications: 742 (52%) issued patents, 218 (15%) pending applications, and 469 (33%) abandoned applications. As of June 30, 2022, 571 (77%) of the issued patents were active and 171 (23%) had expired.

Table. Ten Top-Selling Brand-Name Drugs in US in 2021 Subject to Patent Thicket Review.

Type of drug	Primary clinical use	FDA approval date	Years of postapproval dataa
Small-molecule drugs
Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide)	HIV	02/07/18	4.4
Eliquis (apixaban)	Stroke or embolism	12/28/12	9.5
Imbruvica (ibrutinib)	Cancer	11/13/13	8.6
Revlimid (lenalidomide)	Multiple myeloma	12/27/05	16.5
Biologics
Enbrel (etanercept)	Arthritis	11/02/98	23.7
Eylea (aflibercept)	Macular degeneration	11/18/11	10.6
Humira (adalimumab)	Arthritis	12/31/02	19.5
Keytruda (pembrolizumab)	Cancer	09/04/14	7.8
Stelara (ustekinumab)	Psoriasis	09/25/09	12.8
Trulicity (dulaglutide)	Diabetes	09/18/14	7.8

Abbreviation: FDA, Food and Drug Administration.

^a Time from the date of original FDA approval to the end of data collection (June 30, 2022).

For small-molecule drugs, the sample contained 279 issued patents, of which 102 (37%) had been listed in the Orange Book between 1985 and 2022. For biologics, the sample contained 463 issued patents, of which 88 (19%) had been listed in the Purple Book version dated June 2022. Of all issued patents, 242 (33%) have been litigated since 2000. The dataset included 12 small-molecule drug patents that were litigated but were not listed in the Orange Book and 56 biologics patents that were litigated but not listed in the Purple Book.

Preapproval and Postapproval Patent Filing

Almost three-quarters (1028 [72%]) of the 1429 patents and patent applications were filed after FDA approval. For small-molecule drugs, 299 (58%) of 517 applications were filed after FDA approval. For biologics, 729 (80%) of 912 applications were filed after FDA approval. For 8 drugs, the majority of patent applications were filed after approval (Figure 1). Manufacturers filed a median (IQR) of 37 (10-61) applications before FDA approval and 99 (51-134) applications after approval.

Figure 1. Patents and Applications Filed Before and After US Food and Drug Administration (FDA) Approval for 4 Small-Molecule Drugs and 6 Biologics.

For small-molecule drugs, the number of postapproval applications filed per year remained high for 5 years after FDA approval, then gradually decreased (Figure 2A). The median (IQR) application filing date for small-molecule drugs was 1.2 years after FDA approval (1.9 years before approval to 5.0 years after approval). For biologics, the number of postapproval filings of patents and applications peaked in year 12 after approval (Figure 2B). The median (IQR) application filing date for biologics was 5.9 years after FDA approval (0.8 years before approval to 11.9 years after approval). Filing practices varied by drug (eFigure 1 in Supplement 1).

Figure 2. Average Number of Patents and Applications Filed per Year for 4 Small-Molecule Drugs and 6 Biologics and Their Status as of June 30, 2022.

The vertical line represents the date of US Food and Drug Administration (FDA) approval.

Of 742 issued patents, 466 (63%) were filed after FDA approval: 48% (133 of 279) for small-molecule drugs and 72% (333 of 463) for biologics. Manufacturers were issued a median (IQR) of 28 (15-39) patents that were filed before FDA approval and 39 (15-58) patents filed after approval, or an overall median (IQR) of 77 (40-95) total patents per drug. Postapproval patent portfolios added a median (IQR) of 7.9 (3.2-11.1) years of patent protection after the expiration of preapproval patents.

Density of Patent Thickets

At FDA approval, drugs were protected by a median (IQR) of 16 (8-22) active patents. Patent thickets peaked in density 13 years after FDA approval. At that time, drugs were protected by a median (IQR) of 42 (18-83) active patents, 66% (317 of 483) of which were filed after FDA approval. Protection from patents filed before FDA approval peaked at 5 years after FDA approval, when drugs were protected by a median (IQR) of 23 (14-32) patents filed before FDA approval. Protection from patents filed after FDA approval peaked 15 years after approval, when drugs were protected by a median (IQR) of 21 (11-40) patents filed after approval. By this time, postapproval patents comprised 79% (347 of 438) of active patents.

Small-molecule drugs were protected by a median (IQR) of 17 (16-19) patents at the time of FDA approval. The median (IQR) small-molecule drug patent thicket grew to a peak of 62 (22-96) active patents at 12 years after FDA approval, of which 52% (118 of 226) were filed after approval. The patent thicket for small-molecule drugs rapidly shrunk thereafter (Figure 3A).

Figure 3. Average Density of Patent Thickets for 4 Small-Molecule Drugs and 6 Biologics.

The vertical line represents the date of US Food and Drug Administration (FDA) approval.

By contrast, biologics were protected by a median (IQR) of 8 (7-20) patents at the time of FDA approval, and the median (IQR) biologics patent thicket reached a peak density of 41 (18-58) active patents at 13 years after approval, of which 76% (197 of 260) came from postapproval patents. Because patent filings were spread out over time, the patent thicket for biologics remained dense for over 25 years (Figure 3B).

The composition of patent thickets varied widely for each drug (eFigure 2 in Supplement 1). For example, Humira’s patent thicket rapidly expanded starting approximately 10 years after FDA approval, reaching 141 active patents. This drug received its first FDA approval in 2002, yet as of June 30, 2022, it was protected by 134 active patents, all but one of which were filed after FDA approval. Similarly, Enbrel has patent protection until 2039, 41 years after its FDA approval in 1998. This drug’s manufacturer began filing applications for device patents 13 years after FDA approval. As of June 30, 2022, almost half (22) of the 45 active patents for Enbrel contained device claims.

The 10 drugs we reviewed have some form of patent protection until a median (IQR) of 27.1 (22.9-32.6) years after FDA approval. All have patents scheduled to remain active for at least another 11 years, and have other patent applications pending.

Characteristics of Issued Patents

Of the 279 issued patents for small-molecule drugs, 92 (33%) had chemical composition claims, 166 (60%) had method of use claims, 22 (8%) had process or synthesis claims, 103 (37%) had formulation claims, and 1 (0.4%) had a device claim. Sixty-three (43%) preapproval patents and 19 (14%) postapproval patents had more than 1 type of claim.

Of the 463 issued patents for biologics, 118 (26%) had chemical composition claims, 141 (31%) had method of use claims, 147 (32%) had process or synthesis claims, 114 (25%) had formulation claims, and 45 (10%) had device claims. Thirty-four (26%) preapproval patents and 52 (16%) postapproval patents had more than 1 type of claim.

For both small-molecule drugs and biologics, most patents with chemical composition claims were filed before FDA approval. Filings of patents with method of use, process or synthesis, or formulation claims decreased after FDA approval for small-molecule drugs but increased after FDA approval for biologics. All patents with device claims were filed after FDA approval (Figure 4). Of all 465 postapproval patents, 86 (19%) had chemical composition claims, 189 (41%) had method of use claims, 103 (22%) had process or synthesis claims, 127 (27%) had formulation claims, and 46 (10%) had device claims.

Figure 4. Claim Types in Patents Issued for 4 Small-Molecule Drugs and 6 Biologics.

FDA indicates US Food and Drug Administration.

Discussion

This study found that among the 10 top-selling brand-name drugs in the US in 2021, almost three-quarters of patents and patent applications related to these drugs were filed after FDA approval. These drugs were protected by a median of 77 issued patents. At their peak, they were protected by thickets consisting of a median of 42 active patents, about two-thirds of which were filed after FDA approval. The majority of postapproval patents covered aspects of the drugs peripheral to their active ingredients, such as methods of use, formulations, and manufacturing processes. Thickets of patents initially sought after FDA approval raise the question of whether these patents cover truly novel and innovative discoveries or were primarily designed to block timely generic or biosimilar competition.

The proportion of postapproval patent applications was higher for biologics (80%) than for small-molecule drugs (58%). Biologics patent applications were filed later, with a median filing date of 5.9 years after FDA approval, which is over 4 years later than the median filing date for small-molecule drugs (1.2 years after FDA approval). The timing of postapproval patent application filings may be strategically related to the anticipated expiration of nonpatent market exclusivities, which differ for small-molecule drugs and biologics. These market exclusivities are provided by statutes other than the Patent Act that block the FDA from approving competing products even in the absence of a patent. For example, under the Drug Price Competition and Patent Term Restoration Act of 1984, new small-molecule drugs can receive at least 5 years of exclusivity before generic applications can be filed.¹⁶ In our study, we found that postapproval filing of patent applications for small-molecule drugs peaked at approximately the first 5 years after FDA approval, as drug manufacturers were building their patent thickets during the regulatory exclusivity years. By contrast, biologics receive 12 years of regulatory market exclusivity before a biosimilar may be considered for FDA approval under the Biologics Price Competition and Innovation Act of 2009 (BPCIA).¹⁷ Among the biologics in our sample, we observed a peak in filing of patent applications in year 12 after FDA approval.

Most patents filed after FDA approval among the 10 drugs in our sample covered methods of use, formulations, and methods of manufacture, rather than variations on the active ingredients (such as derivatives). Other research has shown that patents on methods of use or other peripheral aspects contribute to most litigation brought against biosimilars manufacturers seeking market authorization.¹⁸ In addition, previous research has shown that patents protecting the formulations and methods of use are often weaker patents and less likely to be upheld after being challenged in litigation by manufacturers of generic drugs.¹⁹ In our study, biologics had a larger proportion of process or synthesis claims than small-molecule drugs, particularly when patents were filed after FDA approval. This might be explained by the more complex manufacturing processes of biologics that provide the opportunity to file more patents with regard to methods of manufacture, which are often not product specific.²⁰ Our results also reflect the growing practice of patenting biologics delivery devices.²¹ While device patents constituted only 10% of biologics patents in our sample, all were filed after FDA approval.

Patent thicket density peaked about 13 years after FDA approval. At peak patent thicket density, drugs were protected by a median of 42 active patents; manufacturers of competing generic or biosimilar drugs would have to assess each patent to determine whether their product infringed patent protection. Regardless of the validity of each patent, the overall density of patent thickets can deter competition^22,23 by raising the perceived cost of market entry. Competitors will have to predict the probability that each patent will be found valid, enforceable, and infringed,²⁴ and weigh the costs of challenging administratively or in litigation.²³ This process might be even more challenging for manufacturers of biosimilars that might have to identify and challenge non–product-specific manufacturing patents enforced by brand-name manufacturers.²⁰ While patent thickets in the pharmaceutical industry are strategically used to prevent competition (for example, in the case of adalimumab [Humira]),²⁵ challenging patent thickets is an uphill battle.²⁶

Previous research has revealed similar patent thicket density profiles for 4 of the drugs included in this sample.²⁷ But the number of active patents at peak thicket density in our study is higher than previously reported. We found that patent thickets for biologics contained more patents overall and remained dense longer than those for small-molecule drugs. These results are in line with previous data that patent thickets are larger and median market exclusivity is longer for biologics than for small-molecule drugs (21.5 vs 14.4 years).²⁸

Limitations

Our study has several limitations. We reviewed patent landscapes covering 10 blockbuster drugs, and these results may not be generalizable to drugs for rare diseases or low-revenue products. Postapproval data covered a longer period for some drugs than for others. Manufacturers have continued to file patent applications after we stopped collecting data, and some currently pending applications may become issued patents. Because of this, we may underestimate the impact of postapproval patents. Because the USPTO website may be incomplete, we also may not have accounted for all patent term extensions, thus potentially underestimating the impact of postapproval patents. It is further possible that our patent list was overinclusive, as it included more patents than listed in the Orange Book or Purple Book. Neither FDA-published compendium is comprehensive or contains all patents related to a product; in particular, the Purple Book has only recently started listing patents and is limited to those asserted at certain stages in manufacturer-specific litigation related to the BPCIA, while the Orange Book excludes method of manufacture patents. There are various techniques third parties can use to avoid reaching the point at which their patent lists become subject to the requirement to submit it to the FDA’s Purple Book.²⁹ Similarly, if the biosimilar manufacturer chooses to move outside the BPCIA context and launch at risk, there is no requirement for the brand-name biologics manufacturer to publish its patents in the Purple Book.

Finally, we did not independently review each patent or patent application to determine its relevance or strength of its claims. We did, however, identify patents in the dataset that were litigated but were not listed in the Orange Book or Purple Book, indicating that relevant patents go beyond those disclosed to the FDA. In our analysis of filing practices, we included both issued patents and patent applications. Analysis of patent applications may be unreliable, since the claims may change over time and ultimately be unrelated to the drug. But patent applications will still be relevant for potential competitors seeking to enter the market, as they will have to predict whether the patent application will ultimately result in an issued patent.²⁴ Furthermore, some of the patents may have narrow claims or may be invalid. However, this reflects the patent landscape that manufacturers of competing generic or biosimilar drugs will have to assess when considering whether to enter the market.³⁰

Conclusion

In this study, among the 10 top-selling prescription drugs in the US in 2021, patents filed after FDA approval and containing claims peripheral to the active ingredient contributed to dense patent thickets. Careful scrutiny of patent applications and of patents filed after FDA approval is needed to facilitate timely generic and biosimilar competition.

Supplement 1.

eMethods

eFigure 1. Patents and Applications Filed per Year for Individual Drugs

eFigure 2. Density of Patent Thickets for Individual Drugs

Supplement 2.

Data Sharing Statement