In the race to bring generic drugs to market, Paragraph IV patent challenges are now an unavoidable fact of life. The question is no longer if there will be a patent challenge, but when and by whom. In the current hypercompetitive environment, no company can pursue all possible targets, so understanding the potential competitive landscape is crucial to allocating limited product development resources.
Many of the most promising generic targets are subject to New Chemical Entity (NCE) exclusivity. ANDAs can be filed for older drugs anytime, but ANDAs for NCE products can be filed no earlier than one year before the expiration of the exclusivity, so every applicant in the hunt for the 180-day generic drug exclusivity has the same filing date in its sights. When multiple filers submit applications on that date, the exclusivity is shared and any advantage it confers is diluted. Even blockbusters with branded sales in the billions may become significantly less attractive targets when the field is crowded and every player qualifies as a first filer. In April 2017, for example, Bristol-Myers Squibb and Pfizer sued 25 potential first filers for generic versions of Eliquis (apixaban) tablets.
Eliquis may be an extreme example, but many enticing products raise targeting questions. For rich targets, is a crowded field unavoidable? Can any generic hope to reap the expected profits in a saturated market?
Potential patent challengers
With an NCE-1 date in November 2019, Gilead’s tenofovir alafenamide fumarate products for treatment of HIV and hepatitis B could be facing patent challenges very soon. According to Gilead, U.S. sales of Vemlidy (tenofovir alafenamide fumarate) in 2018 amounted to $245m, a healthy but not overwhelming figure. However, in some combination therapies we see significantly more impressive numbers:
Source: Gilead Form 10-K covering 2018.
Will these products, which represent billions in branded sales, attract crowds of challengers?
One indicator of generic interest is API availability. As of this writing, more than ten companies have filed Drug Master Files (DMF) for tenofovir alafenamide fumarate. A closer look shows that several of those DMF holders are also vertically integrated finished dose manufacturers who have pursued challenges to similar products in the past. Mylan, for example, holds DMFs for all the compounds in the products mentioned above and has been involved in patent challenges to products such as Complera (emtricitabine/rilpivirine HCl/tenofovir disoproxil fumarate), Stribild (cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil fumarate), and Truvada (emtricitabine/tenofovir disoproxil fumarate). In that light, it would be surprising if Mylan were not among the filers for tenofovir alafenamide fumarate products.
The patent challenge ‘challenge’
While the number of DMFs points to significant generic interest, it should be noted that historically, Paragraph IV challenges to antiviral products have been less numerous than they have been in other areas with similar sales. There could be many reasons for this, but one possible explanation is that patent challenge timelines can be long and HIV treatments have shifted relatively rapidly. Generic challengers risk devoting resources to a product that may not be the standard of care by the time it reaches the market. For example, Complera’s 2018 US sales were $276m, but Gilead reports a 32% year over year decline in worldwide sales for that product. Thus far, Mylan is the only known Paragraph IV filer for Complera. Given the sales figures for tenofovir alafenamide fumarate combination products, it would be surprising to see only one or two generic challengers, but evolving standards of care are certainly a consideration when projecting a generic’s potential years in advance of market entry.
Of course, patents themselves are a major consideration when evaluating a product for patent challenge. According to Gilead, it expects to lose patent protection for Vemlidy and Descovy in 2022, Odefsey in 2025, Genvoya in 2029. It is unlikely that challenges could result in generics before the expiration of the 2022 patents, but later-expiring patents listed in the Orange Book invite patent challenges nonetheless. The shorter timelines for Vemlidy and Descovy may mitigate some of the inherent market uncertainty facing the therapeutic class, which could encourage additional filers. Odefsey and Genvoya are also covered by patents expiring before Gilead’s expected loss of patent protection, which complicates potential challenge strategies.
It will be interesting to note if the longer timelines and greater IP complexity affect the number of companies that choose to pursue those products. History and evidence show that patent challenges to these products are inevitable. The specifics remain to be seen, but wise competitors will surely have used the best available information to guide their decision to join the scrum or stay on the sidelines.