The story so far: On March 23, the Indian Patent Office rejected an application by pharmaceutical giant Johnson & Johnson (J&J) to extend its patent on the drug bedaquiline beyond July 2023. Bedaquiline is a drug in tablet form used to treat drug-resistant tuberculosis (TB). The rejection opens the door for drug manufacturers to produce generic versions of bedaquiline, which are expected to be more affordable and to contribute to India’s goal of eliminating TB by 2025.
What is drug-resistant TB?
As of 2017, India accounted for around one-fourth of the world’s burden of multi-drug-resistant (MDR) TB and of extensively-drug-resistant (XDR) TB.
MDR TB resists treatment by at least isoniazid and rifampicin, the two frontline drugs in TB treatment. XDR TB resists these two drugs as well as fluoroquinolones and any second-line injectable drug. XDR TB is rarer than MDR TB: there were 1,24,000 cases of the latter in India (2021) versus 2,650 cases of the former (2019).
TB incidence in India has been on the decline, but MDR TB and XDR TB endanger initiatives to locally eradicate the disease. During the COVID-19 pandemic, there were indications that TB treatment was hit by disrupted supply chains, availability of healthcare workers for non-pandemic work, and access to drug-distribution centres.
A peer-reviewed 2020 study reported that TB becomes isoniazid-resistant when a person doesn’t fully adhere to the treatment regimen whereas rifampicin-resistance emerges due to other factors. It also found that the incidence of MDR TB (i.e. resistance to both drugs) was “strongly correlated with treatment failure and spread through contact, and not to treatment compliance”.
How is drug-resistant TB treated?
TB is an infection of the bacterium Mycobacterium tuberculosis in the lungs, but often in other organs as well. It can be treated by strictly adhering to the doses and frequencies of drugs prescribed by a physician.
Deviations from this schedule can lead the bacteria to become drug-resistant. Yet they happen because the drugs often have side effects that diminish the quality of life and/or because patients haven’t been afforded access to the requisite drugs on time.
Drug-resistant TB is harder to treat. One important option for those diagnosed with pulmonary MDR TB is bedaquiline.
A person holds up a strip and a bottle of bedaquiline tablets. | Photo Credit: File Photo
In 2018, the World Health Organization replaced two injectable drugs for MDR TB with an oral regimen that included bedaquiline.
At this time, bedaquiline hadn’t completed phase III trials. The recommendation was based on smaller trials, outcomes in TB elimination programmes worldwide, the difficulty of treating MDR TB, and close monitoring of patients receiving the drug.
How good is bedaquiline?
Typically, bedaquiline needs to be taken for six months: at a higher dose in the first two weeks followed by a lower dosage for 22 weeks. This period is shorter than other treatment routines for pulmonary MDR TB, which can last 9-24 months.
One phase II clinical trial observed that culture conversion (turning a patient’s sputum culture from positive to negative) “at 24 weeks was durable and associated with a high likelihood of response at 120 weeks”, due to bedaquiline.
Unlike second-line treatment options that are injected and can have severe side effects, like permanent hearing loss, bedaquiline is available as tablets and is less harmful, although it has potential side effects of its own. Studies until 2018 found that it may be toxic to the heart and the liver. This is part of why it is recommended only when other treatment options for MDR TB have failed.
India’s Health Ministry has guidelines for bedaquiline use as part of the Programmatic Management of MDR TB under the National TB Elimination Program.
The WHO’s decision revitalised a debate about the ethics of making a much-needed but insufficiently tested drug available quickly, on compassionate grounds, versus lowering the safety threshold for pharmaceutical companies producing drugs for desperate patients.
Why was the patent application rejected?
J&J’s patent application was for the production of a fumarate salt of a compound, with which to make bedaquiline tablets. Two groups opposed the patent: 1) ‘Network of Maharashtra people living with HIV’ and 2) Nandita Venkatesan and Phumeza Tisile, both TB survivors, supported by Médecins Sans Frontières.
Both groups argued that J&J’s method to produce a “solid pharmaceutical composition” of bedaquiline is “obvious, known in the art” and doesn’t require an “inventive step”. According to the Indian Patent Act 1970 Section 2(1)(ja), an ‘inventive step’ is an invention that is “not obvious to a person skilled in the art”.
They also objected that J&J’s application didn’t contain information about foreign patent applications, their specifications, and priority dates, among other details, required under Section 8.
The latter also contended that the current application drew significantly from a previous patent, WO 2004/011436, which discussed a similar compound on which bedaquiline is based and whose priority date (2002) well preceded the new application.
The Patent Office rejected the application on these and other grounds, including Sections 3d and 3e of the Act. These pertain to “mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance” and “a substance obtained by a mere admixture resulting only in the aggregation of the properties of the components thereof”, respectively, which are not patentable.
Why is the rejection notable?
India has the largest population of people living with drug-resistant TB. J&J’s patent on bedaquiline meant the drug cost $400 (Rs 33,000) for the six-month schedule, in addition to the cost of other drugs (revised in 2020 to $340). The rejection is expected to lower the cost of bedaquiline by up to 80%.
So far, the Indian government has directly procured the drug and distributed it through state-level TB programmes. Since 2016, India has also availed bedaquiline donated at no cost by J&J and the U.S. Agency for International Development.
The argument based on WO 2004/011436 is also relevant to ‘evergreening’: a strategy whereby a patent-owner continuously extends their rights and/or applies multiple patents for the same entity. Indian law disallows ‘evergreening’.
J&J’s current patent will expire in July 2023.
