TWN Info Service on Health Issues (Mar23/05)
27 March 2023
Third World Network

A Ray of Hope for TB Patients: Indian Patent Office Rejects a Secondary Patent on TB drug Bedaquiline

By Prathibha Sivasubramanian (Legal Researcher, Third World Network)

On 23 March 2023, in a landmark victory to tuberculosis (TB) patients all over the developing world, the Indian Patent Office (Mumbai) rejected a patent application relating to fumarate salt of Bedaquiline.

Bedaquiline is a drug used to treat drug resistant (DR) TB. It is a component of all the short and the most long regimens to treat DR-TB in adults. Before the introduction of Bedaquiline, patients diagnosed with DR-TB had 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 regimen is a boon for DR-TB patients and is used to treat almost every person with DR-TB.

MDR-TB is related to the condition where Mycobacterium tuberculosis is resistant to isoniazid and rifampicin.  In early 2018, the WHO published new treatment guidelines establishing a new all-oral, bedaquiline-based standard of care for MDR-TB.[1]

It is estimated that globally the incidence of DR-TB increased to 450,000 cases in 2021 as compared to 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 multi-drug resistant tuberculosis (MDR-TB) cases globally.[4]

There is an estimated 130,000 cases of drug-resistant TB in India every year and currently less than 30% of these patients are diagnosed and put on appropriate treatment regimen.[5] The India TB Report 2022 estimates that in 2021, 48,232 patients were diagnosed (laboratory confirmed) with multi-drug 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] Currently the treatment for a six-month course of bedaquiline costs around USD 350 for the Indian Government.[8] It is expected that the cost would come down with the entry of generic pharma companies.

Bedaquiline was granted accelerated approval by the US 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.[9] Bedaquiline is not available in the retail market in India.  So far it has been rolled out through the National TB Elimination Program (NTEP).

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, the 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] Consequently Janssen did not conduct the phase III trials of bedaquiline. Several phase I and II trials conducted prior to the drug registration were sponsored by the U.S. 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 are being undertaken by other non-profit organisations such as TB Alliance, the Union (previously the International Union Against Tuberculosis and Lung Disease), Médecins Sans Frontières (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.  

Multiple secondary patents extend market monopoly

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, also for a combination of bedaquiline, pretomanid and linezolid—with many of them being granted in some countries. These secondary patent applications if granted will block generic versions of the drug.

Patients opposed patent application in 2013

In India, the patent application relating to the fumarate salt of bedaquiline along with the well-known wetting agents like TWEEN20 was filed in 2009 [1220/MUMNP/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 Patents Act, 1970.

[A patent is granted only on the satisfaction of three criteria: novelty/new, inventive step (qualitative improvement from a previous product) and utility. These criteria differ 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 giving more space for local industries to grow in the particular field of the art. It is set according to the needs of the country. In this regard, the Trade-related Aspects of Intellectual Property Rights Agreement (TRIPS) administered by the World Health Organization sets only minimum standards and does not define these criteria.]

In 2019, two TB patients also filed a pre-grant opposition pointing out that many parts of the patent specification have been copy-pasted from an earlier application relating to an HIV drug, rilpivrine, which the Indian Patent Office (IPO) had rejected. The second opposition also raised objections on inventive step under Section 3(d) and 3(e) of the Patents Act, 1970. The claims were amended after the oppositions were filed.

After hearing both parties, on 23 March 2023, the IPO 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 (220/DELNP/2005) and also the disclosures in literature about advantages of the salt form over the base compound in terms of bioavailability.

The IPO 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 by the Applicant company 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 bioavailability to  prove Section 3(d). Bioavailability of drugs indicates the percentage, amount or concentration of 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 bioavailability is not the same as efficacy. The IPO concluded that “improved bioavailability 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 has 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, 1970.  The Supreme Court of India in Novartis AG v Union of India (2013), had ruled that “efficacy”, a term in Section 3(d) of the Patents Act, 1970 means “therapeutic efficacy – effect of the drug on the body”. It is not the same as bioavailability. The Applicant has to prove that increase in bioavailability should in turn increase the therapeutic efficacy of the drug.

The bedaquiline ruling is relevant not only because it disallows evergreening of patent monopoly on bedaquiline, but it also sets a good precedent for subsequent oppositions on secondary patents relating to pharmaceutical salts, compositions and tablet formulations. Further it encourages the use the public health safeguards such as pre-grant opposition by not only companies or civil society organisations or academicians or scientists, but also patients who are directly affected by the grant of patent monopoly.

This decision is in line with the current WHO guidelines, whereby pretomanid, (another new TB medicine) is to be used in combination with bedaquiline/linezolid/moxifloxacin (BPaL or BPaLM regimens) for DR-TB and possibly depending on the outcome of clinical trial results, a combination of bedaquiline/moxifloxacin/pyrazinamide (BPaMZ regimen).

Once India adopts the new WHO guideline, the Government will have scaled up the production of bedaquiline. Hence, this order of the IPO is significant as it will reduce the current expensive cost that the Indian Government has to incur to buy bedaquiline. Rejection of the fumarate salt of bedaquiline is not only important for India but also for other developing countries as it may facilitate the export of generic bedaquiline.

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 companiess in India – Viatris (formerly Mylan) and Macleods.[14] With these sub-licenses in place these companies could only supply bedaquiline for DS-TB and not DR-TB. Since these agreements are not available in the public domain, it is not clear whether these licenses have any unbundling clause in the sub-licence. However, other companies who have not entered into licenses are now free to develop the generic bedaquiline.

Indian patent offices must disallow evergreening patents

This decision was given by the Mumbai Patent Office. (There are four Patent Offices in India: Mumbai, Delhi, Chennai and Kolkatta). Ideally this decision needs to be followed by other Patent Offices. However, according to the practice of the Patent Offices, there is no consistency in following precedents. The decision of the Mumbai Patent office should be followed by other patent offices in a uniform and consistent manner. While we celebrate this order, 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, polymorph, compositions etc. For instance, the IPO had granted a patent to the combination of tenofovir and emtricitabine in May 2022 (IN 201817001590). Both tenofovir and emtricitabine are known and their combinations were earlier rejected by the IPO.[15] Despite the glaring disclosures in the previously published documents the IPO has granted the patent without applying the inventive step or Section 3(d) appropriately.

Further a patent for a bilayer tablet[16] comprising of old HIV drugs – rilpivrine and tenofovir –  was granted in 2019 (4424/DELNP/2013).[17] Many of these orders granting secondary patents of the existing drugs have no reasoned decision by the IPO. It appears that the IPO has been lowering the inventive step criteria and granting more and more patents and not implementing the Supreme Court judgement on section 3(d) in their bid to compete with their counterparts in China and the United States.   

Apart from the potential benefits in the context of bedaquiline, this recent ruling’s significance is broader and deeper. It is an exemplar of how patient groups can effectively use legal safeguards to oppose frivolous secondary patent applications even when the generic pharmaceutical companies are not part of the process.+