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A ray of hope for TB patients Indian authorities’ rejection of a bid to extend the patent monopoly on a vital tuberculosis drug paves the way for more affordable treatment – and for greater involvement by patient groups in opposing such extensions in future. Prathibha Sivasubramanian ON 23 March, in a landmark victory to tuberculosis (TB) patients all over the developing world, the Indian Patent Office (IPO) rejected a patent application relating to fumarate salt of bedaquiline. Bedaquiline is a medicine used to treat drug-resistant TB (DR-TB). It is a component of short and long regimens to treat DR-TB in adults. Before the introduction of bedaquiline, patients diagnosed with DR-TB had a long and tormenting treatment (20 months) with a combination of medicines including daily injections which had adverse side-effects such as permanent hearing loss, psychosis etc. The new bedaquiline-based oral regimen has increased the cure rate of DR-TB and replaced medicines causing severe side-effects. Bedaquiline-inclusive treatment regimens are a boon for DR-TB patients and are used to treat almost every person with DR-TB. In early 2018, the World Health Organisation (WHO) published new treatment guidelines establishing a new, all-oral, bedaquiline-based standard of care for multidrug-resistant TB (MDR-TB).1 It is estimated that globally the incidence of DR-TB increased to 450,000 cases in 2021 from 437,000 in 2020.2 However, only 36% of patients could access treatment.3 India has a high incidence of DR-TB. In fact, India, China and Russia combined contribute more than half of the MDR-TB cases globally.4 There are an estimated 130,000 cases of DR-TB in India every year and currently less than 30% of these patients are diagnosed and put on an appropriate treatment regimen.5 The India TB Report 2022 estimates that in 2021, 48,232 patients were diagnosed (laboratory confirmed) with multidrug- and rifampicin-resistant TB (MDR/RR-TB) and 43,380 patients were put on treatment.6 More than 50% of the DR-TB cases go undetected and untreated in India.7 Bedaquiline was granted accelerated approval by the United States Food and Drug Administration (FDA) in 2012 as part of a combination treatment in adults with pulmonary MDR-TB. Conditional marketing authorisation for bedaquiline was subsequently granted by the European Medicines Agency (EMA) in 2013.8 Bedaquiline is not available in the retail market in India. So far it has been rolled out through the National TB Elimination Programme (NTEP). Currently, a six-month treatment course of bedaquiline costs around $350 for the Indian government.9 It is expected that the cost would come down with the entry of generic pharmaceutical companies. Development of bedaquiline For 50 years, before the introduction of bedaquiline, there were no new medicines for TB. Around 2005, bedaquiline was identified by Janssen, a subsidiary of the pharmaceutical company Johnson and Johnson (J&J). However, further development of bedaquiline involved a lot of public funding and contributions from philanthropic organisations. Academia, non-governmental and humanitarian organisations and governments have played a role in the development of this drug. In 2009, Janssen entered into an agreement with the Global Alliance for TB Drug Development (TB Alliance), a non-profit organisation, to share resources and expertise for the development of bedaquiline.10 Several phase I and II trials of bedaquiline conducted prior to the drug registration were sponsored by the US National Institutes of Health/National Institute of Allergy and Infectious Diseases and the TB Alliance.11 The phase III trials to confirm the efficacy of bedaquiline and to identify potential combinations with other TB medicines were not conducted by Janssen but were undertaken by non-profit organisations such as the TB Alliance, the Union (previously the International Union Against Tuberculosis and Lung Disease), Medecins Sans Frontieres (MSF) and Partners In Health (PIH).12 Apart from the clinical trial costs, other incentives such as tax rebates, orphan drug status and seven years of exclusivity were granted for bedaquiline.13 Since J&J has obtained multiple patents on bedaquiline in many countries, considering the philanthropic contributions to its development, the company should be obligated to provide access to all MDR-TB patients who need it. Secondary patent application Currently, J&J has a monopoly in the market due to the primary patent on bedaquiline. This patent is set to expire in July 2023. Generics can enter the market after July 2023 and provide low-cost versions of bedaquiline. However, J&J has filed multiple secondary patent applications on various forms such as fumarate salt of bedaquiline, dispersible tablet formulation, to treat latent TB, and also for a combination of bedaquiline, pretomanid and linezolid. These secondary patent applications, if granted, will block generic versions of the drug. The applications have been granted in some countries. In India, the patent application relating to the fumarate salt of bedaquiline along with well-known wetting agents like TWEEN20 was filed in 2009. In 2013, the Network of Maharashtra People Living with HIV (NMP+) filed a pre-grant opposition raising objections on novelty and inventive step under Section 3(d) and 3(e) of the Indian Patents Act, 1970. [A patent is granted only on the satisfaction of three criteria: novelty, inventive step (qualitative improvement from a previous product) and utility. The exact definition of these criteria differs for different countries depending on national laws and standards. Some countries lay down a higher standard, resulting in grant of patents to only genuine inventions, which gives more space for local industries to grow in the particular field of the art. The standard is set according to the needs of the country. In this regard, the international Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) administered by the World Trade Organisation sets only minimum standards and does not define these criteria, leaving this to the individual country.] In 2019, two TB patients also filed a pre-grant opposition pointing out that many parts of the patent specification were copy-pasted from an earlier application relating to an HIV drug, rilpivrine, which the IPO had rejected. The opposition also raised objections on inventive step under Section 3(d) and 3(e) of the Patents Act. The claims were amended after the oppositions were filed. After hearing both parties, the IPO on 23 March rejected the secondary patent application relating to fumarate salt of bedaquiline on the grounds of lack of inventive step in the light of disclosures in prior published documents. The IPO referred to disclosures relating to bedaquiline and suggestions to make a fumarate salt of bedaquiline in the primary patent, as well as the disclosures in the literature about advantages of the salt form over the base compound in terms of bio-availability. It also took into consideration that the use of TWEEN20 as a wetting agent in pharmaceutical compositions in a particular range is well known in the pharmaceutical field. The IPO noted that the affidavits filed in support of the patent application failed to prove that the composition of fumarate salt of bedaquiline and TWEEN20 would show surprising effect over the known composition of bedaquiline disclosed in the primary patent. Thus, combining the teachings and suggestions of the prior art, the IPO concluded that the application is obvious to a person skilled in the art. Additionally, the IPO also found that the applicant had provided data on improved bio-availability to prove Section 3(d). (The bio-availability of a drug indicates the percentage, amount or concentration of the drug that reaches into the systemic circulation and is available at the site of action.) However, the IPO observed that this data was insufficient to satisfy the requirement of enhanced efficacy, as bio-availability is not the same as efficacy. The IPO concluded that ‘improved bio-availability would not constitute enhancement in therapeutic efficacy of the pharmaceutical composition unless it shows significant enhancement in known therapeutic efficacy in terms of efficacy results.’ The IPO also found that the applicant had not proved any synergistic effect of the formulation and considered it as a mere admixture (fumarate salt of bedaquiline and TWEEN20), which is disallowed under Section 3(e) of the Patents Act. The Supreme Court of India, in the case Novartis AG v Union of India (2013), had ruled that ‘efficacy’, a term in Section 3(d) of the Patents Act, means ‘therapeutic efficacy – effect of the drug on the body’. It is not the same as bio-availability. The applicant has to prove that any increase in bio-availability should in turn increase the therapeutic efficacy of the drug. The IPO’s bedaquiline ruling is significant because it not only disallows ‘evergreening’ (i.e., extension) of the patent monopoly on bedaquiline, but also sets a good precedent for subsequent oppositions to secondary patent applications relating to pharmaceutical salts, compositions and tablet formulations. Further, the ruling will encourage the use of pre-grant opposition by not only companies, civil society organisations, academicians or scientists, but also patients who are directly affected by the grant of patent monopoly. The IPO decision will reduce the current high cost that the Indian government has to incur to buy bedaquiline and enable supply of bedaquiline to be scaled up in line with WHO guidelines prescribing the use of bedaquiline-based treatment regimens. This is important not only for India but also for other developing countries as it can facilitate the export of affordable generic bedaquiline. ‘India, being a generic production hub, can count on companies being able to pick up production after the original patent expires in July 2023. This can increase the amount of the medicine available, make it cheaper, and get it to more people,’ Priyam Lizmary Cherian, an intellectual property lawyer who argued the case at the IPO, was cited as saying by Peoples Dispatch. ‘The decision is not important for people in India alone, but also in the rest of the world, since it should pave the way for export of generics.’14 However, MSF reports that J&J has licensed bedaquiline to treat drug-sustainable TB (DS-TB) to the TB Alliance, who in turn sub-licensed it to two generic companies in India – Viatris (formerly Mylan) and Macleods.15 With these sub-licences in place, these companies could only supply bedaquiline for DS-TB and not DR-TB. Since the licensing agreements are not available in the public domain, it is not clear whether there are any unbundling clauses in the sub-licences. However, other companies which have not entered into licences will now be free to develop the generic bedaquiline. Increased patent grants The 23 March decision was handed down by the Mumbai Patent Office. (There are four Patent Offices in India: Mumbai, New Delhi, Chennai and Kolkata.) Ideally this decision needs to be followed by the other Patent Offices, although there is currently no consistency among the Patent Offices in following precedents. Further, while this latest ruling is cause for celebration, the increased grant of patents to existing drugs by the IPO is still a huge problem. Lack of uniformity in decisions is a crucial issue which leads to conflicting decisions in the grant of secondary patents to salts, polymorphs, compositions etc. For instance, the IPO granted a patent to the combination of tenofovir and emtricitabine in May 2022. Both tenofovir and emtricitabine are known and their combinations were earlier rejected by the IPO.16 Despite the glaring disclosures in the previously published documents, the IPO granted the patent without applying the inventive step or Section 3(d) appropriately. In addition, a patent for a bilayer tablet17 comprised of old HIV drugs – rilpivirine and tenofovir – was granted in 2019. Many of these orders granting secondary patents on existing drugs have no reasoned decision by the IPO. It appears that the IPO may be lowering the inventive-step criterion, granting more and more patents, and not implementing the Supreme Court judgement on Section 3(d) in a bid to compete with its counterparts in China and the United States. Amid this backdrop, the recent bedaquiline ruling has a significance that extends beyond the potential benefits in terms of TB treatment. It is an exemplar of how patient groups can effectively use legal safeguards to oppose frivolous secondary patent applications even when generic pharmaceutical companies are not part of the process. Prathibha Sivasubramanian is a legal researcher with the Third World Network. Notes 1. World Health Organisation. Rapid communication: Key changes to treatment of multi-drug- and rifampicin-resistant tuberculosis (MDR/RR-TB). 2018. https://www.who.int/publications/i/item/WHO-CDS-TB-2018.18 3.
The reported number of people started on treatment for MDR-TB
and rifampicin-resistant TB (RR-TB) in 2021 was 161,746, covering
only about one in three of those in need. https://cdn.who.int/media/docs/default-source/hq-tuberculosis/global 4. World Health Organization. Global Tuberculosis Report 2020. https://apps.who.int/iris/bitstream/handle/10665/336069/9789240013131-eng.pdf 6. https://tbcindia.gov.in/WriteReadData/IndiaTBReport2022/TBAnnaulReport2022.pdf 8. https://msfaccess.org/open-letter-jj-calling-affordable-access-critical-tb-drug-bedaquiline 11. Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis With(J-M-Pa-Z) (NC-001), https://clinicaltrials.gov/ct2/show/NCT01215851; Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis (TMC207-CL001), https://clinicaltrials.gov/ct2/show/NCT01215110; https://clinicaltrials.gov/ct2/show/NCT01341184; https://clinicaltrials.gov/ct2/show/NCT00992069 12. https://msfaccess.org/open-letter-jj-calling-affordable-access-critical-tb-drug-bedaquiline 13. Gotham, D., McKenna, L., Frick, M. & Lessem, E. Public investments in the clinical development of bedaquiline. 2020. PLoS One, 15(9), e0239118. https://doi.org/10.1371/journal.pone.0239118 14. Singh, J. & Vračar, A. Yes, we can stop patents getting in the way of TB treatment. Peoples Dispatch, 24 March 2023. https://peoplesdispatch.org/2023/03/24/yes-we-can-stop-patents-getting-in-the-way-of-tb-treatment/ 15. MSF Access Campaign. DR-TB Drugs Under the Microscope 2022, 8th Edition. Issue Brief. https://msfaccess.org/dr-tb-drugs-under-microscope-8th-edition 16. This combination is of tenofovir alafenamide fumarate and emtricitabine; earlier combinations of tenofovir disoproxil fumarate and emtricitabine were rejected. Patent applications relating to tenofovir alafenamide were also previously rejected. Further, the combination of tenofovir alafenamide fumarate and emtricitabine was very obvious in light of the literature and disclosures in the prior art. Basically the active ingredients tenofovir and emtricitabine and their combinations are well known in the art. 17. Bilayer tablets, sometimes called double-layer tablets, are a combination of two or more active pharmaceutical ingredients in a single dosage form. It is a technology for controlled release formulation and the use of bilayer tablets is growing. *Third World Resurgence No. 355, 2023, pp 6-9 |
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