How Gilead is effectively managing past intellectual property and covid-19 anti-viral clinical trials

Non-infectious diseases around which intellectual property is based have a degree of market consistency that viral outbreaks lack. For example, in the United States, 1,000 new cases of cystic fibrosis are diagnosed every year. As this number barely fluctuates, investors in the arena (eg, Vertex) can reliably estimate a drug approval timeline and the ultimate value of their intellectual property. Anti-viral therapies for non-endemic diseases (eg, SARS-CoV, MERS-CoV and potentially covid-19) rarely have this luxury. It can take upwards of a decade to develop a safe, effective anti-viral therapy, in part due to fluctuations in patient numbers and outbreak locations. Indeed, a number of early 2020 clinical trials for covid-19 started in China have been either shuttered or uprooted to other countries due to dwindling case numbers. This delays the drug development timeline and could narrow the window of market exclusivity for therapeutics that are still under patent protection.

Therefore, it is understandable that repurposed or repositioned drugs comprise the near entirety of clinical trials that have either been completed or are ongoing for covid-19 (see Figure 1). It has been just over a year since the first emergence of covid-19 and these ‘second-life’ therapeutics offer advantages to hasten time to market (known toxicity profile). Some compounds that were shown to prevent viral replication in vitro (eg, hydroxychloroquine and ritonavir) have proven ineffective in vivo, while others such as remdesivir and favipiravir have shown promise and are now approved for sale to treat covid-19 in select countries. The variety of previous drug indications for the repurposed compounds undergoing clinical trial is impressive (see Figure 2). Remdesivir was initially developed by Gilead for MERS and ebola. It is a prime example of both the careful positioning and luck necessary to compete in this volatile field.

A group at the Wuhan Institute of Virology was the first to demonstrate remdesivir’s anti-viral activity against covid-19. In the opening days of the pandemic, Wang and others ran an in vitro screen of seven broad anti-viral compounds. This would be the first of many such screens conducted across the globe, some based on scientific understanding of viral mechanism of action, others merely the availability of compounds. At Gilead, the development programme for 11-year-old remdesivir was on pause as the anti-viral treatment for advanced ebola infections was not an improvement on existing therapies. Gilead was awaiting a future ebola outbreak to test the drug earlier in disease pathogenesis. It retained its IP rights in the hope of a future return on investment. Intellectual property for remdesivir (US10251904B2) has claims broadly encompassing both the filoviridae (ebola) and coronaviridae (SARS-CoV, MERS-CoV and covid-19) families.

Although Gilead was not the first to demonstrate potential efficacy in covid-19, it had clear ownership of the compound. Its previous clinical work accelerated time to market for this critical covid-19 therapeutic and analysts now predict upwards of $2 billion in sales. Calculated patience in IP strategy for non-endemic diseases paid off. Gilead is now uniquely positioned to rapidly expand its covid-19 patent portfolio with different methods of remdesivir delivery and combination therapies, among other things. Other pharmaceutical companies are angling to replicate this success. Roche, for example, recently partnered with Atea Pharmaceuticals to advance their repurposed anti-viral compound initially intended to treat hepatitis C (AT-527, US20200179415A1). Where industry sponsors appear to have a major stake is in clinical trials where the compounds were trialed but not yet approved for other indications.          

New anti-viral compounds directed specifically at covid-19 are also making their way through pre-clinical testing. PF-07304814, developed by Pfizer, has entered phase 1 clinical trials. Many of these new compounds draw inspiration from completed studies using repurposed drugs in vitro and in vivo. Whether these therapies will ultimately be commercially applied to covid-19 or to another novel virus is not yet known.     

Accelerating new anti-viral drug development; intellectual property for covid-19 and beyond

Advances in structural biology and computer-assisted drug design have accelerated the anti-viral drug development timeline. The University of California San Francisco Quantitative Bioscience Institute Coronavirus Research Group (QCRG) was able to condense what was a once a decade of basic research into a matter of months. Using a high throughput approach to x-ray crystallography, in April it was among the first to map out how covid-19 interacts with the proteins that it encounters to infect a cell. In June the QCRG detailed how the virus hijacks key host proteins to promote its survival and in July it identified weak points in the virus’s infection mechanisms that could be targeted by drug development. All of this data has been made publicly available. This rapid pace of discovery, while exciting, necessitates corresponding quick moves to secure covid-19-related intellectual property in order to establish non-obviousness in anti-viral drug design.

Recent moves to expand existing in vitro drug screening libraries will likewise have a big impact on IP management. The repurposing, focused rescue and accelerated medchem (ReFRAME) collection developed by the California Institute for Biomedical Research (Caibur) in partnership with the Bill and Melinda Gates Foundation is of particular interest. While other established drug libraries applied to emerging viral outbreaks pull primarily from Food and Drug Administration-approved compounds, off-patent and/or commercially available, ReFRAME is different. The 13,000 library compounds were obtained by Calibur through both purchasing and resynthesis “without regard to mechanism of action, availability, patent status, or cost.” Already applied to covid-19, ReFRAME identified 100 drugs that inhibit viral replication in mammalian cells, 21 for which a dose-response relationship could be established, 13 at concentrations likely to be therapeutically relevant. Several of these hits are already in clinical trial. Calibur has every intention of adding to the library as new compounds are developed, irrespective of disease indication. Library access is determined on a case-by-case basis, depending on factors such as global health relevance and public access to results. Thus, IP managers should be aware of this avenue for the repurposing/repositioning of their compounds and should track accordingly.

Comment

The covid-19 pandemic is unlike any other public health event in recent memory. The quest for treatment is galvanising a generation of intellectual property at an unprecedented rate. At the same time, patent insights derived from a deep understanding of the IP landscape covering anti-rival compounds identified during the previous SARS-CoV and MERS-CoV pandemics have highlighted a path which allows accelerating development of many effective therapeutic remedies to treat covid-19. Companies developing anti-viral cures must be cognizant of the extensive body of prior art filed since 2003 and must effectively differentiate over this work to secure strong patent protection.