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TWN Info Service on Intellectual Property and Health
19 November 2024
Third World Network
www.twn.my
Roche’s Patent Strategy Creates a Roadblock to Affordable Pertuzumab for Breast Cancer Patients in India
by Chetali Rao and K M Gopakumar (Third World Network)
In a recent judgement, the Delhi High Court issued an interim injunction against the Indian biosimilar manufacturer Zydus Lifesciences (F-Hoffmann-La Roche AG & Anr. v. Zydus Lifesciences Limited) to prevent the marketing of a biosimilar of Pertuzumab.
Pertuzumab, marketed by Roche under the brand name Perjeta, is a monoclonal antibody used for the treatment of HER2-positive breast cancer. It is typically used in combination with other treatments, such as trastuzumab (Herceptin) and chemotherapy, for both neoadjuvant (before surgery) and adjuvant (after surgery) therapy in patients with early-stage and advanced HER2-positive breast cancer.
Roche’s Infringement Petition
Roche had instituted a patent infringement petition pertaining to its Indian Patent No. IN464646 and IN268632 covering Pertuzumab variants and their pharmaceutical formulations.
As part of the petition, Roche had filed a quia timet action along with an interim application for an injunction.
[A quia timet injunction is a specific legal remedy that allows a party to seek protection against anticipated future harm, particularly in cases involving intellectual property rights. Unlike interim injunctions that may be granted to prevent ongoing or immediate harm, a quia timet injunction is rooted in the apprehension of a potential future injury due to a mere threat of infringing actions that have not yet occurred. Thus a quia timet injunction allows a party to protect its right even before a violation has taken place.]
Roche alleged that Zydus was poised to launch its biosimilar version of Pertuzumab in the market, which allegedly infringed its patents related to Pertuzumab. Roche emphasized the threat of the imminent launch of biosimilar by Zydus and sought an injunction to prevent and restrain Zydus from selling and marketing of the biosimilar version of Pertuzumab.
During the proceedings, Roche stated that Zydus had failed to disclose critical information regarding its regulatory approvals from the regulatory body and the licensing agreements entered between Zydus and Dr. Reddy’s for commercially launching the biosimilar version. Endorsing this argument the Delhi High Court, on 9th July 2024 granted an interim injunction restraining Zydus from marketing the Pertuzumab biosimilar.
The Court viewed that the non-disclosure raised serious concerns about Zydus’s procedural conduct. However, the absence of any claim mapping between the plaintiffs’ and defendant’s patents raised questions on the merit of the decision that was made only on the ground of non-disclosure of certain facts. However, while granting the interim injunction, the Court had not paid any attention to the practice that loss emanating from the infringement can be compensated through monetary damages, and thereby the injunction can be avoided.
On 9th October 2024, the petition was heard by another bench of the Delhi High Court, who issued an order and vacated the 9th July order that granted an interim injunction to Roche. However, later in the day, the Court held the order in abeyance and allowed two weeks for Roche to file an appeal.
Challenging the two-week abeyance order, Zydus appealed the stay. On 15th October, the Division Bench set aside the two-week abeyance order and allowed Zydus to sell and market its biosimilar drug. The Court said that the abeyance order was “not justifiable” and “the order cannot survive even for a second”. Consequently, on 16th October Roche filed an appeal before the Division Bench, and the Division Bench allowed the appeal in favour of Roche and prohibited Zydus from selling Pertuzumab. The Division Bench also directed the single-judge to hear the case afresh. Later, on 5th November, the matter came up for hearing before the single-judge, where Zydus indicated that it had submitted a petition before the Supreme Court against restoration of the injunction.
This is not the first time Roche is using legal options to block the marketing of biosimilar versions of Pertuzumab. In January 2024, Roche requested the Drugs Controller General of India (DCGI), India’s regulatory agency, to inquire into the alleged critical gaps in the clinical trial conducted by Zydus for Pertuzumab. Roche had contended that the reference product used by Zydus during the initial phases of clinical trials was procured from unauthorized sources, and hence, might be of “questionable quality”, “compromised” or “spurious”. It had claimed that Zydus had imported several vials of Perjeta from Germany during August and September 2022, outside of Roche’s official supply chain.
Implication of the Case
Like many other cases, this case also touches the heart of one of the key issues plaguing the system – the high cost of cancer medicines and access to affordable drugs. Biologics, including cancer drugs, are often costly, and biosimilars offer a potential solution to reduce prices and improve access for patients in low- and middle-income countries.
As per Global Cancer Observatory, IARC-WHO, 2022, breast cancer is the most common type of cancer globally with estimated mortality cases of 665,255 for the year 2022 among females. India ranks highest in number of estimated breast cancer deaths (98,337) for the year 2022 among females. According to the National Cancer Registry Program the estimated incidence of female breast cancer cases in India in all states was 221,579.
HER2+ cases account for nearly 15-20 per cent of breast cancer cases. Monoclonal antibodies targeting HER2 are the most ubiquitously used treatments. These include trastuzumab (Herceptin), a modified version of trastuzumab like trastuzumab and hyaluronidase injection (Herceptin Hylecta), Pertuzumab (Perjeta), combination of Trastuzumab, pertuzumab and hyaluronidase injection (Phesgo) and combinations of these with different chemotherapeutic agents. Additionally antibody drug combinations like Ado-trastuzumab emtansine (Kadcyla) and Fam-trastuzumab deruxtecan (Enhertu) are also available treatments.
These exclusive therapies for the treatment of HER2+ breast cancer come with very steep price tags placing them out of reach of most of the Indian population. The price of Roche’s vials for Herclon (Trastuzumab); Kadcyla (trastuzumab emtansine); Perjeta (pertuzumab) and Phesgo (pertuzumab, trastuzumab and hyaluronidase) range from INR 61,270 ($689) to INR 491,820 ($6,147).
At the same time, biosimilars for some of these therapies are marketed by multiple Indian biosimilar manufacturers at a price 30-70 per cent below Roche’s Trastuzumab (Herclon) e.g. Zydus markets its Herclon Biosimilar (Vivitra) at INR 35,920 ($404) almost 60% cheaper than Roche.
Secondary Patenting and Maintaining a Market Monopoly
Pharmaceutical innovators employ multiple evergreening tactics to ensure maximum revenue returns, retain their market monopolies and thwart biosimilar competition. Roche has itself employed multiple successful patent evergreening strategies and changed the market dynamics. Such strategies involve adding new formulations, changing the route of administration, and addition of combination products amongst others.
A classic example of a biologic drug subject to evergreening is Roche’s own drug Trastuzumab for breast cancer treatment. Trastuzumab is an immunotherapeutic medicine that is used in treatments for patients with HER2 + early and metastatic breast cancer. Trastuzumab was first registered as Herceptin by Roche in 2000 as an intravenously (IV) administered drug. In a pre-emptive measure, in 2013 Roche decided to abandon its patent on Trastuzumab in India, since the Indian government was considering the issuance of a compulsory license on drug. However, Roche introduced a subcutaneous version of Trastuzumab in India marketed under the name Herceptin SC. Roche filed patent applications on the subcutaneous versions but they later withdrew one application while the other was rejected by the Indian Patent Office. Roche then strategically introduced Pertuzumab in the Indian market in 2015, with indications overlapping Trastuzumab at a steep price of INR 2,49,000 lakh per dose ($2948).
With the introduction of Pertuzumab, Roche potentially attempted to maintain its competitive edge in the HER2-positive breast cancer treatment landscape by reshaping the treatment protocols and market dynamics. A few years later it launched a combination of Pertuzumab and Trastuzumab (Phsego) which became the new standard of care for treatment. Phsego offers similar therapeutic effects as both Tratuzumab and Pertuzumab offer individually, but alters the mode of administration through a single subcutaneous injection. Though, biosimilar versions of Trastuzumab were available at a cheaper price and dented Roche sales, Roche still managed to garner a substantial portion of the market sales and revenues in the HER2+ segment through the sales of its subcutaneous version of Trastuzumab, Pertuzumab and Phsego.
In the current suit at the Delhi High Court, Roche alleged infringement of two of its patents on Pertuzumab, No. IN464646 and No. IN268632 respectively. Patent No. IN268632 relates to an aqueous formulation of Pertuzumab and was granted in 2015, while Patent No. IN464646 which relates to a method of making a composition comprising Pertuzumab and its variants, was granted in 2023. Roche had filed another patent for Pertuzumab related to a method of treatment for HER2 expressing cancer which was rejected by the Indian Patent Office.
While the core patent covering the composition will expire in 2025, the secondary patents covering aspects like method of making a composition, can extend Roche’s monopoly over Pertuzumab till 2034. For its composition application No. IN464646, Roche had filed two corresponding composition applications at the European Patent Office (EPO) with varying claims: one for a Pertuzumab composition and another for a composition specifically incorporating unpaired cysteine variants of Pertuzumab. However, the latter patent application encountered objections in the EPO examination process due to objections concerning lack of novelty. As a result, Roche withdrew the unpaired cysteine variant composition patent application, underscoring the need for rigorous standards for patentability, particularly regarding novelty and inventiveness in biotechnology patents. Such patent layering has enabled Roche to sustain market exclusivity beyond the expiration of its core patents, leveraging additional protections on methods of treatment and manufacturing processes to effectively extend the lifecycle of Pertuzumab and limit competition in the market.
The strategy of evergreening through secondary patenting poses significant challenges in the pharmaceutical landscape, since it impacts both the market dynamics and patient access to medications. While it provides economic benefits for pharmaceutical companies by extending their monopoly period, it raises serious ethical concerns regarding the accessibility and affordability of drugs. This abuse of the patent system has a deleterious impact on public health, as patients are left without access to essential life-saving medicines.
The survival and accessibility of these therapies amongst women ultimately hinge on the cost of these drugs prevalent in the Indian market. Given the alarming rise in breast cancer cases, it is increasingly untenable to delay the entry of more affordable biosimilar versions of these costly therapies, which could provide broader access to life-saving treatments.
The Changing Face of Quia Timet Injunction
The grant of an injunction by the Delhi High Court on 9th July raises some critical issues regarding the conditions under which a quia timet injunction can be granted.
Can an injunction can be granted solely on the conduct of the manufacturer without considering the underlying intellectual property infringement issue surrounding the case? While the conduct of a manufacturer is an important consideration in seeking an injunction, it cannot be evaluated in isolation from underlying intellectual property infringement issues. In the present suit Roche was unable to demonstrate a sufficient claim mapping or evidence of infringement, leading to the conclusion that an injunction could not be granted based solely on a manufacturer’s conduct without clear evidence of intellectual property infringement.
In cases where access to life-saving medicines is at stake, courts must weigh public interest in patent matters, especially concerning access to affordable medications. This factor can significantly influence decisions on whether to grant an injunction extending beyond the manufacturer’s conduct to its implication on access to medicines for the public at large.
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