The patent debate surrounding PrEP, the game-changer in HIV prevention

Last year, Gilead sparked controversy with the airing of a commercial during a live broadcast of Rent, the landmark musical about AIDS, for its HIV prophylactic Truvada. Truvada prophylaxis (PrEP) is a potential game changer in the fight against the global AIDS pandemic. However, Gilead has faced considerable criticism from AIDS activists for the high price of Truvada, particularly in the US. This criticism has been heightened by the significant amount of government funding that contributed to the development of Truvada for HIV prophylaxis. Whilst Gilead owns the basic patents for Truvada, the US Government (USG) owns the patents for use of Truvada in PrEP. In a recent move, that is unlikely to improve its popularity, Gilead announced that it plans to challenge the USG Truvada PrEP patents.

What is PrEP?

Truvada is a combination therapy of emtricitabine and tenofovir disoproxil fumarate (TDF), both inhibitors of the HIV reverse transcriptase. If taken daily, Truvada pre-exposure prophylaxis (or PrEP) prevents HIV infection in individuals who are at a high risk of HIV exposure. Without PrEP, the risk of contracting HIV from unprotected sex with an HIV infected individual can be as high as 20%. According to clinical studies, Truvada can reduce the risk of contracting HIV from sex by more than 90%. Truvada PrEP therefore has the potential to eradicate HIV.

Gilead manufactures and owns the patents for Truvada (Orange Book, US 6642245 and US 6703396). Gilead has been accused by AIDS activists of abusing its monopoly and inflating the price of Truvada in the U.S., where Truvada was, until very recently, the only FDA approved PrEP regime. The annual cost of Truvada in the U.S. is currently around 20 billion US dollars (about $70 per pill). This is in contrast to the price of PrEP in Africa, where open-label PrEP is deliverable in a public setting at a cost of less than $100 a year (Mugo et al.).

Researching...

In its defence, Gilead points out that it took 10-15 years to develop Truvada, at a cost of $1.1 billion, and that it is currently plowing the profits from Truvada into further research for an HIV cure. Gilead also argues that the greatest barriers to Truvada for PrEP access is not the price of the drugs, but the limited awareness of the potential benefits of PrEP. Additionally, as tweeted by President Trump, Gilead has also agreed to donate Truvada to up to 200,000 uninsured, at risk individuals. However, pressure groups such as PrEP4All have dismissed this donation as a token gesture, and continue to call for a reduction in the price of PrEP for those at risk. The controversial issue of PrEP pricing was recently the subject of a fascinating U.S. congressional hearing on drug pricing (as reported over on IPwatchdog).

Gilead's Truvada basic patents

Truvada was originally developed for use in patients already infected with HIV. Gilead owns patents for the anti-retrovirals forming Truvada combination therapy (US6642245). The U.S. patents for Truvada will expire in 2021. Gilead has brought a number of infringement actions in the U.S. based on its Truvada patents in order to keep generics off the market - although notably Gilead has also recently agreed a settlement with Teva that will allow Teva to launch a Truvada generic in September 2020 (Gilead March 2019 quarterly report, page 35).

The U.S. government's PrEP patents

The second medical use of Truvada as a prophylaxis, as opposed to a treatment for individuals already infected with HIV, was developed by Gilead in collaboration with the USG (Center for Disease Control and Prevention, CDC) and The Gates Foundation. Gilead received around $50 million grant funding from the NIH to conduct the clinical trails for PrEP necessary for FDA approval (granted in 2012).

A front page story by the Washington Post earlier this year drew attention to the surprising fact that it is the USG, and not Gilead, who owns the patents for the use of Truvada in PrEP. U.S. patent 9,044,509 claims a process of protecting a primate host (e.g. human) from HIV comprising administering directly to an uninfected primate host emtricitabine and TDF, wherein the combination is administered prior to an exposure to the virus.  Lobby groups have put the USG under pressure to leverage these patents against Gilead, in order to force a reduction in the cost of PrEP.

Given that the USG owns the patents for the use of Truvda in PrEP, why has Gilead not been paying royalties to the USG? If payable, some have predicted that these would be in excess of $1 billion. Of course, the USG very rarely brings patent infringement suits, weakening its bargaining position. In 2016, the USG unsuccessfully approached Truvada with a request for royalty payments.

Gilead has now pre-empted further action by the USG by the unusual move of requesting inter-partes review of the PrEP patents (Gilead press release). Gilead argues that the use of Truvada as a preventative therapy was known before the priority dates of the patents. Gilead particularly cites the guideline published by CDC in 2005 recommending Truvada prophylaxis immediately after exposure to HIV. Gilead's decision to challenge the PrEP patents is unlikely to make Gilead more popular among AIDS activists. However, Gilead insists that the patent issues are a distraction from efforts to reduce barriers to PrEP. Gilead argues that the primary barrier is not the cost of the drug, but the lack of public awareness of the benefits of PrEP.

In the meantime, Gilead has been developing an alternative drug for use in PrEP, Descovy (emtricitabine and tenofovir alafenamide (TAF)), that has fewer side effects and lower manufacturing costs (Gilead press release). Descovy has recently been granted FDA approval for use in PrEP. The patent term for Descovy is set to expire in 2032 (Orange Book). However, Gilead's move against the USG patents for Truvada PrEP may also be influenced by the unclear issue of whether a recently granted PrEP USG patents may also cover Descovy PrEP.

What about Europe?

In the UK, generics of Truvada are already available. Gilead's SPC for Truvada based on the European patent EP0915894 was found by Mr Justice Arnold in the UK High Court to contravene Article 3(a) of the SPC Regulation (Teva v Gilead [2018] EWHC 2416 (Pat)). Particularly, Mr Justice Arnold, following a CJEU ruling (IPKat post here), found that Truvada was not in fact protected by the EP patent because the patent only related to one of the drugs in Truvada. The patent on which the SPC was based did not mention the other drug or suggest the combination therapy. Truvada was therefore found not to embody the technical contribution of the patent. Generics for Truvada are thus now available in the UK and Europe (e.g. Mylan's Ricovir)

Notably, however, Turvada for use in PrEP is still not currently available on the NHS in England (a PrEP Impact Trial has been running for the past 2 years). PrEP is available on the NHS in Scotland for individuals satisfying certain criteria of high HIV risk. NHS England cites the cost of PrEP as the main factor for not making the treatment more widely available. However, the hope is that the NHS will review this position in view of Gilead's loss of its SPC for Truvada. The USG also owns a European second medical use patent for Truvada PrEP, EP2015753. The patent was opposed by Mylan and maintained in amended form. However, the USG does not appear to be enforcing its European patents. Of course, given that Descovy has been shown to have significantly fewer side effects compared to Truvada (particularly a lower risk of kidney damage), the NHS is likely to face pressure to provide Descovy instead of Truvada.

A debate to be had

Is the price of PrEP really that prohibitive for developed nations? The use of PrEP has been shown in study after study to be economical in the long run (as the cost of Truvada PrEP is minimal compared to the cost of life-long AIDS treatment). Notably, recent guidance issued by the U.S. Preventive Services Task Force classified PrEP as Grade A, meaning that insurers will now be obligated to cover the medication at no cost to their policyholders. Perhaps the issue with PrEP access runs deeper than Gilead's alleged over-pricing and is a function a dysfunctional U.S.'s healthcare system. Particularly, the inability of the USG to negotiate drug prices centrally.

Furthermore, if Gilead was not permitted to reap some rewards from its investment, would therapies such as PrEP ever be brought to market? Gilead has so far been able to profit from the time-limited market-exclusivity for PrEP awarded by its Truvada patents. As dictated by the patent system, Gilead's exclusivity has (in Europe) or will shortly (in the U.S.) come to an end. The limited patent term thus opens the gates for generic manufactures of Truvada such as Mylan. It will be interesting to see if Gilead's aim of introducing a new and improved PrEP drug, in the form of Descovy, will have any impact on the sales of Truvada generics.

In the meantime, Gilead's challenge of the USG patents will be watched closely. It is rare for large pharma to challenge government held patents. If Gilead is successful, this may encourage other companies to follow suit.