Abstract
Background
Patients with asthma and COPD rely on inhalers to control symptoms. Yet, these products remain expensive, in part because brand-name manufacturers have obtained numerous patents on inhalers, including on their delivery devices. Recent antitrust litigation has raised questions about the boundaries of listing device patents with the US Food and Drug Administration (FDA), particularly when patents do not claim any active ingredients.
Research Question
How have manufacturers relied on device patents to preserve market exclusivity on brand-name inhalers?
Study Design and Methods
We identified patents on brand-name inhalers approved for asthma and COPD between 1986 and 2020 using the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). We extracted information about patents from LexisNexis TotalPatent One and Google Patents and searched device patents for mention of active ingredients or other prespecified features linking the patent to the relevant drug. For each inhaler, we determined the duration of protection added by device patents.
Results
The FDA approved 53 brand-name inhalers for asthma and COPD from 1986 through 2020, 39 of which had at least one device patent. One hundred thirty-seven distinct device patents were in the final cohort, representing 49% of all patents listed on inhalers. Seventy-seven percent of device patents made no mention of active ingredients or their molecular structures, and 72% made no mention of any relevant prespecified feature connecting the device patent to the drug product. For the 39 brand-name inhalers with one or more device patents listed in the Orange Book, device patents extended the duration of market protection by a median of 5.5 years (interquartile range, 0.0-10.5 years) beyond the last-to-expire nondevice patent.
Interpretation
Patent and regulatory reform is needed to promote generic competition and to ensure that patients with asthma and COPD have access to affordable medications.
Key Words: antitrust law, asthma, COPD, Food and Drug Administration, inhalers, patents
Graphical Abstract
Take-home Points.
Study Question: How have manufacturers relied on device patents to preserve market exclusivity on brand-name inhalers?
Results: Thirty-nine inhalers approved from 1986 through 2020 had one or more device patents listed with the Food and Drug Administration, of which 77% made no mention of active ingredients or their molecular structures. Device patents extended periods of market exclusivity by a median of 5.5 years.
Interpretation: Patent and regulatory reform is needed to ensure affordable access to inhalers.
Since first becoming available to US patients in 1956, inhalers have become the primary treatment for asthma and COPD.1,2 Remarkably, however, after > 65 years on the market, they remain expensive3 and contribute to substantial out-of-pocket costs for patients.4 Part of the reason for high prices is that brand-name manufacturers have managed to limit generic competition through extensive patents on their products.5, 6, 7, 8, 9 As with other drug-device combinations featuring decades-old drugs such as epinephrine pens, many of the current patents on inhalers relate to the delivery devices, rather than the active ingredients.5,9 These device patents can serve as obstacles for generic manufacturers seeking US Food and Drug Administration (FDA) approval.10
Pharmaceutical companies that market small-molecule drugs in the United States are required to list key patents on their products in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). The FDA, in turn, is prohibited from allowing approved generic drugs to enter the market if the brand-name reference drug still has active patents listed—unless the generic firm shows that such patents are invalid, unenforceable, or not infringed in what is known as a “paragraph IV certification.”11 The FDA repeatedly has emphasized that its role in maintaining the Orange Book is purely “ministerial” and that it does not assess the merits of patents submitted for listing.12 In recent years, manufacturers of drug-device combination products have chosen to list an increasing number of patents on their delivery devices.5, 6, 7
Without clear FDA policy or enforcement over the types of device patents listed in the Orange Book, problems can arise. In one prominent case, Sanofi Aventis was sued for improperly listing a patent on the drive mechanism of its Lantus SoloSTAR (insulin glargine) pen.13 A federal appeals court ruled in 2020 that, despite regulatory uncertainty, listing certain device patents in the Orange Book may nonetheless constitute anticompetitive behavior. The applicable statute requires that manufacturers list patents on only the relevant drug product, and the court found that the patent at issue failed to meet this bar, having made no mention of insulin glargine or the SoloSTAR pen and only brief mention of treating diabetes. The appeals court sent the case back to the district court for a decision on whether Sanofi’s listing of these patents complied with perceived FDA regulations (asking whether the listing was on a “reasonable basis” and in “good faith”), a key test for determining anticompetitive behavior. However, the appeals court made clear that listing certain types of device patents in the Orange Book, like those without a clear link to particular drug products, may be improper and may constitute violations of antitrust law.
Inhalers represent one of the largest classes of drug-device combinations by market share in the United States, and prior work has noted the numerous device patents covering these products.5,6 When inhaler manufacturers rely on both patent thickets and product hopping (switching from one delivery device to a different delivery device that contains the same ingredients but is protected by new patents), the median duration of patent protection on the line as a whole is > 28 years.6 Several documented device hops were made possible by the FDA’s ban on ozone-depleting chlorofluorocarbons (2009-2013), which enabled manufacturers to introduce newer chlorofluorocarbon-free products with new patents.6,14,15 However, most device hops have involved inhalers with no chlorofluorocarbons. In contrast to inhaled medications that are marketed as drug-device combinations, those sold separately from their delivery devices (nebulized therapies) tend to see far earlier generic competition.7
To understand the nature of device patents contributing to the patent thickets covering inhalers, we evaluated the scope of claims in inhaler device patents, the extent to which they were linked to particular drug products (for example, by reference to active ingredients or specific devices), and the role that they have played in delaying generics. Addressing these issues is particularly relevant given recent antitrust litigation and ongoing efforts by Congress and the FDA to promote competition among drug-device combinations.16
Study Design and Methods
Our goals were to examine all device patents on inhalers approved by the FDA from 1986 through 2020 and to analyze the scope of these patents and the role that each patent has played in manufacturers’ lifecycle management strategies. To do so, we identified inhalers approved for asthma and COPD using the FDA’s Orange Book and product labels from Drugs@FDA and searched annual editions of the Orange Book through 2021 to identify patents on inhalers, their expiration dates, and the manufacturers listed for each product (e-Appendix 1).
Review of Patents
We used LexisNexis TotalPatent One and Google Patents to extract the title, application date, and claims for each patent. A patent’s claims define the legal boundaries of an invention. Independent claims, which often are the broadest claims in a patent, stand alone and make no reference to other claims in the patent, whereas dependent claims reference other claims and incorporate all of the limitations of the referenced claim.17 Two authors (S. S. T. and W. B. F.) separately reviewed the independent claims of all patents to determine whether a given patent was on the delivery device (a device patent) or some other aspect of the product (a nondevice patent; agreement, 98.6%; interrater κ, 0.94). Then, two authors (B. J. D. and W. B. F.) separately analyzed all device patents to determine whether the independent claims were on the inhaler as a whole or on components of the device (eg, the canister or dose counter; agreement, 96.5%; interrater κ, 0.85). We further analyzed all claims to determine if the claim made mention of active ingredients, molecular structures of active ingredients, therapeutic class, particular delivery devices, asthma, COPD, emphysema or chronic bronchitis (subcategories of COPD), or the lungs. Disagreements between the reviewers were resolved by consensus.
Extension of Patent Protection by Device Patents
We identified the products in the cohort associated with one or more listed device patents. We then determined the overall duration of patent protection on each product by calculating the time from FDA approval until the last-to-expire patent. We identified which nondevice patents and which device patents were the last to expire, and we determined the duration of added protection from device patents by calculating the duration of time from the last-to-expire nondevice patent to the last-to-expire device patent (or, if only device patents were listed, from FDA approval until the last-to-expire device patent). Because device patents typically have overlapping periods of protection with nondevice patents beginning at FDA approval, our analysis quantified the extra protection that device patents added to inhalers on top of any protection from nondevice patents. Among all device patents, we further distinguished between patents that mentioned active ingredients or their molecular structures in the claims and patents that did not. We determined the duration of added protection from the latter set of patents via a similar process.
Because generic products may enter the market before expiration of patents listed in the Orange Book (after successful paragraph IV challenges), we performed a secondary analysis of the extent to which early generic entry curbed any expected patent protection on inhalers. To determine the calendar quarter of first generic competition, we used publicly available Medicaid files.18,19
Statistical Analyses
All analyses were completed in Excel version 16 (Microsoft). Institutional review board approval was not required because this study did not include human subjects.
Results
From 1986 through 2020, the FDA approved 53 brand-name inhalers for asthma and COPD. Manufacturers listed with the FDA patents on the delivery devices for 39 products (74%) (Table 1). Of the remaining 14 products, seven products were approved before 1997, two products were approved between 1997 and 2008, and the remaining five products were approved after 2008 (Table 2). One hundred thirty-seven distinct device patents were in the final cohort, representing 49% (137 of 278) of all unique patents listed for inhalers. The median number of device patents listed per product was 3 (interquartile range [IQR], 0-9), whereas the median number of nondevice patents was 4 (IQR, 1-7).
Table 1.
Inhalers Approved From 1986 Through 2020 With at Least One FDA-Listed Device Patent
| Product | Active Ingredient(s) | FDA Approval Date | No. of Nondevice Patents | Expiration of Last-to-Expire Nondevice Patent | No. of Device Patents | Expiration of Last-to-Expire Device Patent |
|---|---|---|---|---|---|---|
| Ventolin Rotahaler | Albuterol | 05/04/1988 | 2 | 12/05/1989 | 2 | 04/24/1998 |
| Maxair Autohaler | Pirbuterol | 11/30/1992 | 0 | N/A | 1 | 05/12/2004 |
| Proventil HFA | Albuterol | 08/15/1996 | 6 | 02/25/2014 | 2 | 12/28/2016 |
| Pulmicort | Budesonide | 06/24/1997 | 0 | N/A | 3 | 09/13/2007 |
| Serevent Diskus | Salmeterol | 09/19/1997 | 5 | 08/12/2008 | 10 | 02/23/2016 |
| Advair Diskus | Fluticasone-salmeterol | 08/24/2000 | 7 | 09/07/2010 | 9 | 02/23/2016 |
| QVAR | Beclomethasone | 09/15/2000 | 6 | 07/07/2015 | 8 | 01/01/2032 |
| Flovent Diskus | Fluticasone | 09/29/2000 | 1 | 05/14/2004 | 9 | 02/23/2016 |
| Foradil Aerolizer | Formoterol | 02/16/2001 | 1 | 11/28/2020 | 1 | 03/08/2019 |
| Ventolin HFA | Albuterol | 04/19/2001 | 3 | 12/19/2016 | 19 | 08/26/2026 |
| Spiriva HandiHaler | Tiotropium | 01/30/2004 | 9 | 07/22/2022 | 3 | 04/19/2030 |
| Flovent HFA | Fluticasone | 05/14/2004 | 3 | 06/08/2018 | 19 | 08/26/2026 |
| ProAir HFA | Albuterol | 10/29/2004 | 5 | 09/12/2023 | 11 | 01/01/2032 |
| Atrovent HFA | Ipratropium | 11/27/2004 | 4 | 11/04/2014 | 3 | 01/17/2030 |
| Xopenex HFA | Levalbuterol | 03/11/2005 | 12 | 10/08/2024 | 1 | 11/17/2015 |
| Asmanex Twisthaler | Mometasone | 03/30/2005 | 7 | 03/17/2018 | 4 | 02/20/2017 |
| Advair HFA | Fluticasone-salmeterol | 06/08/2006 | 8 | 08/19/2014 | 21 | 08/26/2026 |
| Pulmicort Flexhaler | Budesonide | 7/12/2006 | 2 | 01/09/2018 | 3 | 05/08/2018 |
| Symbicort | Budesonide-formoterol | 7/21/2006 | 9 | 07/29/2023 | 9 | 10/07/2029 |
| Foradil Certihaler | Formoterol | 12/15/2006 | 1 | 11/10/2019 | 1 | 12/05/2016 |
| Alvesco | Ciclesonide | 01/10/2008 | 6 | 02/01/2028 | 4 | 05/13/2018 |
| Arcapta Neohaler | Indacaterol | 07/01/2011 | 4 | 02/25/2025 | 1 | 10/11/2028 |
| Combivent Respimat | Albuterol-ipratropium | 10/07/2011 | 0 | N/A | 25 | 10/16/2030 |
| Tudorza Pressair | Aclidinium | 07/23/2012 | 8 | 03/13/2029 | 4 | 04/22/2027 |
| Breo Ellipta | Fluticasone-vilanterol | 05/10/2013 | 8 | 05/21/2025 | 8 | 10/11/2030 |
| Anoro Ellipta | Umeclidinium-vilanterol | 12/18/2013 | 8 | 11/29/2030 | 8 | 10/11/2030 |
| Incruse Ellipta | Umeclidinium | 04/30/2014 | 4 | 12/18/2027 | 7 | 10/11/2030 |
| Striverdi Respimat | Olodaterol | 07/31/2014 | 7 | 01/19/2027 | 18 | 10/16/2030 |
| Arnuity Ellipta | Fluticasone | 08/20/2014 | 2 | 08/03/2021 | 7 | 10/11/2030 |
| Spiriva Respimat | Tiotropium | 09/24/2014 | 1 | 07/30/2018 | 18 | 04/16/2031 |
| ProAir Respiclick/ Digihaler | Albuterol | 03/31/2015 | 0 | N/A | 19 | 08/16/2036 |
| Stiolto Respimat | Olodaterol-tiotropium | 05/21/2015 | 8 | 01/19/2027 | 18 | 10/16/2030 |
| Seebri Neohaler | Glycopyrrolate | 10/29/2015 | 13 | 10/20/2028 | 1 | 10/11/2028 |
| Utibron Neohaler | Indacaterol-glycopyrrolate | 10/29/2015 | 19 | 10/20/2028 | 1 | 10/11/2028 |
| AirDuo RespiClick/Digihaler | Fluticasone-salmeterol | 01/27/2017 | 4 | 10/06/2034 | 21 | 08/16/2036 |
| ArmonAir RespiClick/Digihaler | Fluticasone | 01/27/2017 | 1 | 09/01/2024 | 21 | 08/16/2036 |
| QVAR RediHaler | Beclomethasone | 08/03/2017 | 0 | N/A | 10 | 01/25/2039 |
| Trelegy Ellipta | Fluticasone-umeclidinium-vilanterol | 09/18/2017 | 12 | 11/29/2030 | 7 | 10/11/2030 |
| Duaklir Pressair | Aclidinium-formoterol | 03/29/2019 | 9 | 03/13/2029 | 2 | 04/22/2027 |
FDA = US Food and Drug Administration; N/A = not applicable.
Table 2.
Inhalers Approved From 1986 Through 2020 With No FDA-Listed Device Patents
| Product | Active Ingredient(s) | FDA Approval Date | No. of Nondevice Patents | Expiration of Last-to-Expire Nondevice Patent |
|---|---|---|---|---|
| Atrovent | Ipratropium | 12/29/1986 | 1 | 08/01/1991 |
| Exirel/MaxAir | Pirbuterol | 12/30/1986 | 3 | 11/20/1996 |
| Tilade | Nedocromil | 12/30/1992 | 2 | 10/02/2006 |
| Serevent | Salmeterol | 02/04/1994 | 4 | 08/12/2008 |
| Flovent | Fluticasone | 03/27/1996 | 1 | 05/14/2004 |
| Combivent | Albuterol-ipratropium | 10/24/1996 | 1 | 06/09/2015 |
| Vanceril DS | Beclomethasone | 12/24/1996 | 1 | 10/29/1999 |
| Flovent Rotadisk | Fluticasone | 11/07/1997 | 1 | 05/14/2004 |
| Aerospan HFA | Flunisolide | 01/27/2006 | 2 | 07/07/2015 |
| Dulera | Formoterol-mometasone | 06/22/2010 | 6 | 11/21/2020 |
| Asmanex HFA | Mometasone | 04/25/2014 | 4 | 08/27/2017 |
| Bevespi Aerosphere | Formoterol-glycopyrrolate | 04/25/2016 | 7 | 03/17/2031 |
| Primatene Mist | Epinephrine | 11/07/2018 | 1 | 01/26/2026 |
| Breztri Aerosphere | Budesonide-formoterol-glycopyrrolate | 07/23/2020 | 7 | 03/17/2031 |
FDA = US Food and Drug Administration.
Characterizing the Device Patents
The 137 device patents included 333 independent claims, with 175 claims (53%) on the inhaler as a whole, 137 claims (41%) on components of the inhaler such as the nozzle, canister, valve, piston pumping system, or other part (e-Table 1), and 21 claims (6%) on a method of use. The most common component referenced was the dose counter, cited in 37 independent claims.
Device Patent Characteristics
Eighty-eight percent of device patents (120 of 137) were listed by four manufacturers: GlaxoSmithKline (31%), Teva (23%), Boehringer Ingelheim (23%), and AstraZeneca (10%). A large majority of patents (105 of 137 [77%]) made no mention of any active ingredients or their molecular structures. Among these patents making no mention of active ingredients or their molecular structures, four patents (4%) mentioned a therapeutic class and three patents (3%) mentioned the lungs, whereas none mentioned particular devices, asthma, COPD, emphysema, or chronic bronchitis. Overall, 72% of the device patents in the cohort (98 of 137) made no mention of any active ingredients, molecular structures, therapeutic classes, disease processes targeted for treatment, or the lungs.
Among the remaining 23% (32 of 137) that listed either an active ingredient or a molecular structure, the median per patent was 2 (IQR, 1.0-5.3). GlaxoSmithKline referenced active ingredients or molecular structures in 42% of its device patents (18 of 43) compared with Boehringer Ingelheim referencing these in 16% (5 of 32), AstraZeneca referencing these in 14% (2 of 14), and Teva referencing these in 13% (4 of 31). Thirteen patents (41%) that referenced an active ingredient or molecular structure also made mention of a therapeutic class; none made mention of a particular delivery device; four patents (13%) made mention of asthma, COPD, emphysema, or chronic bronchitis; and three patents (9%) made mention of the lungs.
Extension of Market Protection by Device Patents
For the 39 brand-name inhalers with device patents listed in the Orange Book, device patents extended the duration of market protection by a median of 5.5 years (IQR, 0.0-10.5 years) past the last-to-expire nondevice patent (Fig 1, Table 3). The last-to-expire patent was a nondevice patent for 11 of these inhalers (28%), a device patent referencing one or more active ingredients for three inhalers (8%), and a device patent referencing no active ingredients for 25 inhalers (64%). Patents in this final category added a median of 7.5 years (IQR, 3.7-10.2 years) of market exclusivity. The longest periods of market exclusivity secured by device patents with no mention of active ingredients or molecular structures were observed for Teva's ProAir Respiclick/Digihaler (21.4 years), Teva's QVAR (16.5 years), and GlaxoSmithKline's Advair HFA (12.0 years).
Figure 1.
Bar graph showing patent protection of inhalers with device patents, 1986 through 2020. This figure includes all brand-name inhalers with one or more device patents approved from 1986 through 2020 (n = 39). It shows how brand-name manufacturers have extended periods of patent protection by listing device patents in the Orange Book with no reference to active ingredients. The red bars represent patent protection obtained from nondevice patents. The blue bars represent added protection from device patents that list one or more active ingredients, beyond any protection from nondevice patents. The gray bars represent further protection from device patents that list no active ingredients, beyond any protection from nondevice patents or device patents that list active ingredients. FDA = Food and Drug Administration.
Table 3.
Patent Protection on Inhalers With FDA-Listed Device Patents, 1986 Through 2020
| Product | Application Date for First Patent Listed on Product | Time From Application Date of First Patent Listed on Product to FDA Approval, y | FDA Approval Date | Patent Protection From Nondevice Patents After FDA Approval, y | Patent Protection Added by Device Patents That Referenced Active Ingredients, ya | Further Patent Protection Added by Device Patents That Referenced No Active Ingredients, yb | Total Patent Protection From FDA Approval, y |
|---|---|---|---|---|---|---|---|
| Advair Diskus | 02/13/1981 | 19.54 | 08/24/2000 | 10.04 | 0.98 | 4.48 | 15.51 |
| Advair HFA | 08/23/1989 | 16.80 | 06/08/2006 | 8.20 | 0 | 12.03 | 20.23 |
| AirDuo RespiClick/ Digihalerc | 10/22/1999 | 17.28 | 01/27/2017 | 17.70 | 0 | 1.86 | 19.56 |
| Alvesco | 03/04/1993 | 14.86 | 01/10/2008 | 20.07 | 0 | 0 | 20.07 |
| Anoro Ellipta | 06/06/1995 | 18.55 | 12/18/2013 | 16.96 | 0 | 0 | 16.96 |
| Arcapta Neohaler | 01/08/2002 | 9.48 | 07/01/2011 | 13.67 | 3.63 | 0 | 17.29 |
| ArmonAir RespiClick/ Digihalerc | 10/22/1999 | 17.28 | 01/27/2017 | 7.60 | 6.46 | 5.51 | 19.56 |
| Arnuity Ellipta | 06/06/1995 | 19.22 | 08/20/2014 | 6.96 | 7.52 | 1.68 | 16.15 |
| Asmanex Twisthaler | 12/16/1993 | 11.29 | 03/30/2005 | 12.97 | 0 | 0 | 12.97 |
| Atrovent HFA | 03/04/1993 | 11.74 | 11/27/2004 | 9.94 | 5.56 | 9.65 | 25.16 |
| Breo Ellipta | 06/06/1995 | 17.94 | 05/10/2013 | 12.04 | 2.37 | 3.03 | 17.43 |
| Combivent Respimat | 11/19/1992 | 18.89 | 10/07/2011 | 0 | 8.39 | 10.65 | 19.04 |
| Duaklir Pressair | 06/21/2002 | 16.78 | 03/29/2019 | 9.96 | 0 | 0 | 9.96 |
| Flovent Diskus | 02/13/1981 | 19.64 | 09/29/2000 | 3.62 | 7.33 | 4.45 | 15.41 |
| Flovent HFA | 08/10/1994 | 9.77 | 05/14/2004 | 14.08 | 0 | 8.22 | 22.30 |
| Foradil Aerolizer | 09/08/2000 | 0.44 | 02/16/2001 | 19.79 | 0 | 0 | 19.79 |
| Foradil Certihaler | 05/28/1998 | 8.56 | 12/15/2006 | 12.91 | 0 | 0 | 12.91 |
| Incruse Ellipta | 06/06/1995 | 18.91 | 04/30/2014 | 13.64 | 1.14 | 1.68 | 16.46 |
| Maxair Autohaler | 10/25/1984 | 8.10 | 11/30/1992 | 0 | 0 | 11.45 | 11.45 |
| ProAir RespiClick/ Digihalerc | 10/22/1999 | 15.45 | 03/31/2015 | 0 | 0 | 21.39 | 21.39 |
| ProAir HFA | 03/04/1993 | 11.66 | 10/29/2004 | 18.88 | 0 | 8.31 | 27.19 |
| Proventil HFA | 01/30/1991 | 5.55 | 08/15/1996 | 17.54 | 2.84 | 0 | 20.38 |
| Pulmicort | 06/17/1982 | 15.03 | 06/24/1997 | 0 | 0 | 10.23 | 10.23 |
| Pulmicort Flexhaler | 12/16/1988 | 17.58 | 07/12/2006 | 11.50 | 0 | 0.33 | 11.83 |
| QVAR | 03/04/1993 | 7.54 | 09/15/2000 | 14.82 | 0 | 16.50 | 31.32 |
| QVAR RediHaler | 10/22/1999 | 17.79 | 08/03/2017 | 0 | 21.49 | 0 | 21.49 |
| Seebri Neohaler | 10/06/2000 | 15.07 | 10/29/2015 | 12.99 | 0 | 0 | 12.99 |
| Serevent Diskus | 08/23/1989 | 8.08 | 09/19/1997 | 10.90 | 0 | 7.54 | 18.44 |
| Spiriva HandiHaler | 08/15/1994 | 9.47 | 01/30/2004 | 18.49 | 3.99 | 3.75 | 26.24 |
| Spiriva Respimat | 10/04/1996 | 17.98 | 09/24/2014 | 3.85 | 2.07 | 10.65 | 16.57 |
| Stiolto Respimat | 10/04/1996 | 18.64 | 05/21/2015 | 11.67 | 0 | 3.74 | 15.42 |
| Striverdi Respimat | 10/04/1996 | 17.83 | 07/31/2014 | 12.48 | 0 | 3.74 | 16.22 |
| Symbicort | 11/12/1991 | 14.70 | 07/21/2006 | 17.03 | 0 | 6.20 | 23.23 |
| Trelegy Ellipta | 10/02/2001 | 15.97 | 09/18/2017 | 13.21 | 0 | 0 | 13.21 |
| Tudorza Pressair | 06/21/1996 | 16.10 | 07/23/2012 | 16.65 | 0 | 0 | 16.65 |
| Utibron Neohaler | 10/06/2000 | 15.07 | 10/29/2015 | 12.99 | 0 | 0 | 12.99 |
| Ventolin HFA | 08/10/1994 | 6.70 | 04/19/2001 | 15.68 | 0 | 9.69 | 25.37 |
| Ventolin Rotahaler | 09/20/1967 | 20.64 | 05/04/1988 | 1.59 | 0 | 8.39 | 9.98 |
| Xopenex HFA | 01/30/1991 | 14.12 | 03/11/2005 | 19.59 | 0 | 0 | 19.59 |
FDA = US Food and Drug Administration.
Patent protection in this column is equal to the duration of time that elapsed from FDA approval or the last-to-expire nondevice patent (whichever occurred later) until the last-to-expire device patent mentioning an active ingredient.
Patent protection in this column is equal to the duration of time that elapsed from FDA approval, the last-to-expire nondevice patent, or the last-to-expire device patent mentioning an active ingredient (whichever occurred later) until the last-to-expire device patent with no mention of an active ingredient.
The AirDuo Digihaler was listed under the same New Drug Application as AirDuo RespiClick, and patents for both are included here. The same is true of the ArmonAir Digihaler and RespiClick and the ProAir Digihaler and RespiClick.
Secondary Analyses
Only three products in the cohort faced generic competition through 2021 in the United States: Advair Diskus (first generic available in the first quarter of 2019), ProAir HFA (first generic available in the first quarter of 2020), and Proventil HFA (first generic available in the second quarter of 2020). Only ProAir HFA saw early generic competition before the expiration of its patents. This product had 27.2 years of expected patent protection to end in 2032, including 18.9 years from nondevice patents and an additional 8.3 years from device patents alone (none of which made mention of active ingredients). Generic entry occurred in 2020, 15.3 years after FDA approval of ProAir HFA. Removing the 8.3 years of device patent-related protection on ProAir HFA, device patents extended market exclusivity on inhalers in the cohort by a median of 5.4 years (IQR, 0-10.8 years) compared with 5.5 years in the primary analysis. Among the 24 last-to-expire device patents with no mention of active ingredients or their molecular structures (with the last-to-expire device patent of ProAir HFA excluded), the median duration of added protection was 6.9 years (IQR, 3.7-10.3 years) compared to 7.5 years in the primary analysis.
Discussion
High inhaler prices in the United States have been sustained over the past 3 decades by patents on the products’ delivery devices. Among 39 brand-name inhalers approved during that time with one or more patents on the delivery device, these device patents extended periods of market exclusivity on inhalers by a median of 5.5 years. Less than one-quarter of all device patents (and just over 10% of last-to-expire device patents) made mention of active ingredients or their molecular structures.
Although device patents have proliferated over the past several decades, clinical guidelines for asthma and COPD remain open on which delivery device physicians should prescribe given the paucity of clinical evidence favoring one device type over another.1,2 Device patents certainly may protect innovation; however, the financial rewards for these innovations often exceed their clinical value and may rival the financial rewards for new therapeutic breakthroughs. From 2000 through 2021, for example, manufacturers earned $111 billion on inhalers after patents on their active ingredients expired compared with just $67 billion when these patents were still active.14 With only one generic inhaler in the study entering before expiration of patents, device patents seem to have played an important role in blocking generic competition.
Several studies have identified an increasing number of device patents in the patent portfolios of drug-device combination products.5, 6, 7, 8, 9 These studies fit within a broader literature documenting the growing problem of patent thickets in the pharmaceutical industry.20,21 Our study builds on prior work by characterizing the scope of claims on inhaler device patents and revealing the disconnect between these patents and the drugs that inhalers deliver. In so doing, the study offers a broad, systematic analysis of how recent developments in antitrust law might apply to a prominent class of drug-device combinations.
FDA regulations prevent certain patents from being listed in the Orange Book, namely, patents that do not claim the drug product.13 The recent federal appeals court ruling on Lantus mentioned above held that merely claiming an integral component of a drug product was not tantamount to claiming the drug, rejecting the chain of reasoning “whereby an integral part of the injector pen becomes the pen itself, and in turn is a drug.”13 As with that patent, the vast majority of device patents on inhalers surveyed in this study failed to mention any active ingredients or other relevant characteristics that might connect the device patent to a drug such as the therapeutic class or disease being treated.
Our findings raise two key concerns with Orange Book listings on drug-device combinations. First, FDA regulations remain ambiguous on which device patents may be listed. Drug manufacturers specifically have asked the FDA for guidance on whether device patents that make no mention of active ingredients are suitable for listing, and the FDA has chosen to remain silent on this question.13 The FDA has long maintained that it “lacks both the resources and the expertise to police the correctness” of patents submitted for listing in the Orange Book, and the agency generally has resisted setting precise parameters on the various types of pharmaceutical patents that may be listed.22,23 The recent ruling against Sanofi found that the company had gone too far in listing a patent on the drive mechanism of its SoloSTAR injector pen and yet acknowledged that different courts may reach different conclusions.13,24 The acceptable bounds for listing device patents in the Orange Book remain unclear, and the legal implications for listing such patents remain unsettled.
To address this, the FDA should develop comprehensive regulations about which types of device patents, if any, are suitable for listing in the Orange Book. In addition, Congress could require the FDA to work with the US Patent and Trademark Office (PTO) and take on more than a ministerial role with respect to Orange Book listings. Specifically, Congress should task the FDA and PTO with determining whether a patent is sufficiently tied to a given drug product before permitting the manufacturer to list the patent in the Orange Book. The FDA and PTO took the first steps toward directly collaborating in 2022,25 and we believe that regulation of drug-device combinations could be a key area for future joint initiatives.
A second important concern raised by our findings is the substantive worry that manufacturers have listed inappropriately broad patents on drug-device combinations in the Orange Book. The bulk of inhaler device patents listed over the past 3 decades have failed to claim any particular active ingredients, and almost half have claimed components of delivery devices (eg, dose counters and nozzles), rather than delivery devices as a whole. Manufacturers have adopted broad interpretations of FDA regulations and, in many cases, have listed patents on the same component of a delivery device for multiple products in the Orange Book. Congress, the FDA, and the PTO should work together to ensure a tighter link between the patents listed in the Orange Book and the specific products under which those patents are listed.
Better regulation of Orange Book listings for inhalers and other drug-device combinations may expedite generic entry in several ways. The listing of fewer patents in the Orange Book would reduce the likelihood that generic manufacturers would need to pursue costly patent challenges via paragraph IV certifications. Paragraph IV certifications tend to lead to 30-month stays in the marketing of generic products, and thus stricter requirements for Orange Book listings may improve the timeliness of generic competition.11 A potential downside of blocking more device patents from being listed in the Orange Book is that such patents can still be raised in court, so generic manufacturers may face a heightened risk of litigation for patent infringement if, for example, they are unaware of the patents. However, generic manufacturers tend to be skilled at identifying the patent landscapes of the products that they are developing. Congress also could take a further step and require full transparency of all relevant patents for FDA-approved products without linking disclosures to the possibility of earning 30-month stays, as the Orange Book does.
Patent and regulatory reform is vital to improve the care of patients with asthma and COPD. The American Thoracic Society has recognized high prescription drug prices as a significant public health threat for patients with chronic lung disease.26 Financial toxicity leading to medication nonadherence and poor outcomes is only exacerbated by patent thickets extending periods of market exclusivity on brand-name inhalers. With patents on two highly used classes—the long-acting muscarinic antagonist-long-acting β agonist class and the triple therapy (long-acting muscarinic antagonist-long-acting β agonist-inhaled corticosteroid) class—not set to expire until the late 2020s or early 2030s3,6 and more environmentally friendly inhalers associated with new patents under development,27,28 reform is needed to ensure that patients with asthma and COPD have access to affordable medications.
Study Limitations
First, we did not analyze which patents were most vulnerable to antitrust liability. Some of the device patents in our study may not have been directly responsible for preventing generic competition because, for example, no generic competitor was ready to enter the market for a given inhaler. Rather than demonstrating antitrust liability, our findings instead suggest the need for further investigation into individual inhaler patents. Second, generic manufacturers may have been dissuaded from entering the market for a variety of reasons beyond patent thickets. One such reason is the high costs of developing drug-device combinations.29 Another is the high bar set by the FDA for approving generic versions of complex products like inhalers; the FDA applies an aggregate "weight-of-evidence approach" that requires in vitro, pharmacokinetic, and pharmacodynamic or comparative clinical end point studies.30,31
Interpretation
In the past 3 decades, brand-name manufacturers of inhalers have listed numerous device patents with claims that are disconnected from the corresponding drugs. These device patents have contributed to longer periods of market exclusivity, slower generic competition, and higher prices for payers and patients.
Funding/Support
This work was funded by the Commonwealth Fund. W. B. F.’s work is also funded by the National Heart, Lung, and Blood Institute (K08HL163246), W. B. F.’s and A. S. K.’s work by Arnold Ventures, and S. S. T. work by West Virginia University's Hodges Research Grant.
Financial/Nonfinancial Disclosures
The authors have reported to CHEST the followng: A. S. K. reports serving as an expert witness in litigation against Gilead relating to tenofovir-containing products. Outside the scope of the work W. B. F. serves as a consultant for Alosa Health and as an expert witness in litigation against inhaler manufacturers. W. B. F. also served as a consultant to Aetion and received an honorarium for a presentation to Blue Cross Blue Shield of Massachusetts. None declared (B. J. D., S. S. T., M. A. C.).
Acknowledgments
Author contributions: All authors were involved in the conceptualization of the manuscript, data analysis, interpretation of the results, and critical revision of the manuscript. B. J. D. drafted the manuscript. W. B. F. and A. S. K. provided supervision and secured funding for the work. W. B. F. takes responsibility as the guarantor of the manuscript.
Additional information: The e-Appendix and e-Table are available online under “Supplementary Data.”
Supplementary Data
References
- 1.Global Initiative on Chronic Obstructive Lung Disease Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2023 report. Global Initiative on Chronic Obstructive Lung Disease website. https://goldcopd.org/2023-gold-report-2/
- 2.Global Initiative for Asthma (GINA) 2022 Annual report. Global Initiative for Asthma website. https://ginasthma.org/gina-reports/
- 3.Feldman W.B., Gagne J.J., Kesselheim A.S. Trends in Medicare Part D inhaler spending: 2012-2018. Ann Am Thorac Soc. 2021;18(3):548–550. doi: 10.1513/AnnalsATS.202008-1082RL. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Patel B., Mayne P., Patri T., et al. Out-of-pocket costs and prescription filling behavior of commercially insured individuals with chronic obstructive pulmonary disease. JAMA Health Forum. 2022;3(5) doi: 10.1001/jamahealthforum.2022.1167. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Beall R.F., Kesselheim A.S. Tertiary patenting on drug-device combination products in the United States. Nat Biotechnol. 2018;36(2):142–145. doi: 10.1038/nbt.4078. [DOI] [PubMed] [Google Scholar]
- 6.Feldman W.B., Bloomfield D., Beall R.F., Kesselheim A.S. Patents and regulatory exclusivities on inhalers for asthma and COPD, 1986-2020. Health Aff (Millwood) 2022;41(6):787–796. doi: 10.1377/hlthaff.2021.01874. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Feldman W.B., Bloomfield D., Beall R.F., Kesselheim A.S. Brand-name market exclusivity for nebulizer therapy to treat asthma and COPD. Nat Biotechnol. 2022;40(9):1319–1325. doi: 10.1038/s41587-022-01451-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Beall R.F., Nickerson J.W., Kaplan W.A., Attaran A. Is patent “evergreening” restricting access to medicine/device combination products? PLoS One. 2016;11(2) doi: 10.1371/journal.pone.0148939. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Sinha M. Costly gadgets: barriers to market entry and price competition for generic drug-device combinations in the United States. Minnesota Journal of Law, Science & Technology. 2022;23(1):293–361. [Google Scholar]
- 10.El-Gendy N., Bertha C.M., Abd El-Shafy M., et al. Scientific and regulatory activities initiated by the U.S. food and drug administration to foster approvals of generic dry powder inhalers: quality perspective. Adv Drug Deliv Rev. 2022;189 doi: 10.1016/j.addr.2022.114519. [DOI] [PubMed] [Google Scholar]
- 11.US Food and Drug Administration Patent certifications and suitability petitions. Food and Drug Administration website. https://www.fda.gov/drugs/abbreviated-new-drug-application-anda/patent-certifications-and-suitability-petitions
- 12.US Food and Drug Administration Report to Congress: the listing of patent information in the Orange Book. Submitted Under Section 2(e) of the Orange Book Transparency Act of 2020. Food and Drug Administration website. https://www.fda.gov/media/155200/download
- 13.United States Court of Appeals for the First Circuit. In re Lantus Direct Purchaser Antitrust Litigation, No 18-206.
- 14.Feldman W.B., Tu S.S., Alhiary R., Kesselheim A.S., Wouters O.J. Manufacturer revenue on inhalers after expiration of primary patents, 2000-2021. JAMA. 2023;329(1):87–89. doi: 10.1001/jama.2022.19691. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Wouters O.J., Feldman W.B., Tu S.S. Product hopping in the drug industry—lessons from albuterol. N Engl J Med. 2022;387(13):1153–1156. doi: 10.1056/NEJMp2208613. [DOI] [PubMed] [Google Scholar]
- 16.United States Congress Orange Book Transparency Act of 2020. Public Law 116-290. United States Congress website. https://www.govinfo.gov/app/details/PLAW-116pub1290
- 17.Chisum D.S. LexisNexis Digital Library; 1978. Chisum on patents: a treatise on the law of patentability, validity, and infringement. [Google Scholar]
- 18.Centers for Medicare and Medicaid Services 2019 Medicaid state drug utilization data. Centers for Medicare and Medicaid Services website. https://data.medicaid.gov/dataset/daba7980-e219-5996-9bec-90358fd156f1
- 19.Centers for Medicare and Medicaid Services 2020 Medicaid state drug utilization data. Centers for Medicare and Medicaid Services website. https://data.medicaid.gov/dataset/cc318bfb-a9b2-55f3-a924-d47376b32ea3
- 20.Feldman R. Cambridge University Press; 2019. Drugs, Money, and Secret Handshakes: The Unstoppable Growth of Prescription Drug Prices. [Google Scholar]
- 21.Feldman R. May your drug price be evergreen. J Law Biosci. 2018;5(3):590–647. doi: 10.1093/jlb/lsy022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Winkler A.M., Weingarten M.D., Cyr S.K. Requirements, benefits, and possible consequences of listing patents in FDA’s Orange Book. BNA’s Pharmaceutical Law & Industry Report. July 3, 2018. Finnegan, Henderson, Farabow, Farrett & Dunner, LLP website. https://www.finnegan.com/en/insights/articles/requirements-benefits-and-possible-consequences-of-listing-patents-in-fdas-orange-book.html
- 23.Tu S.S., Duan C. Pharmaceutical patent two-step: the adverse advent of Amarin v. Hikma type litigation. Intell Prop & Ent L. 2023;12(1):1–46. [Google Scholar]
- 24.Organon, Inc. v. Mylan Pharm., Inc., 293 F. Supp. 2d 453, 459–460 (D.N.J. 2003), (2003).
- 25.United States Patent and Trademark Office USPTO-FDA collaboration initiatives. United States Patent and Trademark Office website. https://www.uspto.gov/initiatives/fda-collaboration#
- 26.Patel M.R., Press V.G., Gerald L.B., et al. Improving the affordability of prescription medications for people with chronic respiratory disease. An official American Thoracic Society policy statement. Am J Respir Crit Care Med. 2018;198(11):1367–1374. doi: 10.1164/rccm.201810-1865ST. [DOI] [PubMed] [Google Scholar]
- 27.AstraZeneca AstraZeneca progresses Ambition Zero Carbon programme with Honeywell partnership to develop next-generation respiratory inhalers. AstraZeneca website. https://www.astrazeneca.com/media-centre/press-releases/2022/astrazeneca-progresses-ambition-zero-carbon-programme-with-honeywell-partnership-to-develop-next-generation-respiratory-inhalers.html
- 28.Rabin A.S., Furie G.L. The cruel irony of inhalers that make climate change worse. New York Times. July 23, 2022. New York Times website. https://www.nytimes.com/2022/07/23/opinion/inhalers-climate-pollution.html
- 29.Sagonowsky E. A $442M failure: after years of work and an FDA rejection, Novartis calls it quits on Advair copy. Fierce Pharma website. https://www.fiercepharma.com/pharma/after-years-development-and-fda-rejection-novartis-calls-it-quits-advair-generic-and-takes
- 30.Newman B., Witzmann K. Addressing the regulatory and scientific challenges with generic orally inhaled drug products. Pharmaceut Med. 2020;34(2):93–102. doi: 10.1007/s40290-020-00327-y. [DOI] [PubMed] [Google Scholar]
- 31.Newman B., Babiskin A., Bielski E., et al. Scientific and regulatory activities initiated by the U.S. Food and drug administration to foster approvals of generic dry powder inhalers: bioequivalence perspective. Adv Drug Deliv Rev. 2022;190 doi: 10.1016/j.addr.2022.114526. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.