Rivaroxaban, marketed under the brand name Xarelto®, has emerged as a pivotal therapeutic option for various cardiovascular conditions, revolutionizing the landscape of anticoagulant therapy. Its approval for the treatment of thrombosis, thromboembolism, and prevention of stroke and atherothrombotic events has significantly improved patient outcomes and reduced the burden of cardiovascular diseases globally. Rivaroxaban belongs to the class of direct oral anticoagulants (DOACs), offering advantages such as predictable pharmacokinetics, fixed dosing regimens, and minimal dietary restrictions compared to traditional anticoagulants like warfarin.

In 2023, Rivaroxaban recorded sales amounting to 4,081 million euros, reflecting its widespread adoption and clinical efficacy. Despite its proven therapeutic benefits, the pricing of Xarelto® varies significantly across different regions, posing challenges in access and affordability for patients. For instance, while the price ranges from $76 to $119 in European countries like Greece and Germany, respectively, it stands at $444 in the United States. Such disparities underscore the complex interplay between healthcare systems, regulatory frameworks, and market dynamics influencing drug pricing strategies.

Patent landscape:

The patent landscape surrounding Rivaroxaban is intricate, with multiple patents governing its market exclusivity and intellectual property rights. The primary EP patent that protects the drug substance – EP1261606 was granted supplementary protection certificate (SPC) and pediatric (PED) extension as well in Europe. The PED extension expired recently on 1st April 2024 in the EU. Its US counterpart US7157456 is set to expire on 26th October 2024. Thus, the market may start seeing Xarelto® generics beginning in 2025. To add fuel to this, it should be noted that in Europe, Xarelto® 10, 15 and 20 mg tablets are protected by a patent granted by the European Patent Office for once-daily dosing until 2026. This secondary patent, EP1845961 protects the dosage regimen of administering Xarelto® once daily for 5 consecutive days for the treatment of thromboembolic disorders. It is set to expire on 19th January 2026 and its US counterpart- US9539218 is valid till Aug 2034 due to PED.

Legal battles and patent challenges:

Recent legal disputes have intensified the scrutiny surrounding Rivaroxaban’s patents, highlighting the complexities of patent litigation and intellectual property rights enforcement in the pharmaceutical industry. From the revocation and subsequent reinstatement of patent EP’961 by the European Patent Office to jurisdiction-specific rulings in France, the Netherlands, and Germany, the patent landscape remains dynamic and subject to ongoing litigation. These legal battles underscore the strategic importance of patent protection and the challenges faced by pharmaceutical companies in defending their intellectual property rights amidst evolving regulatory frameworks and market dynamics.

In consequence, it was understood that if Bayer ideally was successful in defending EP’961, it could monopolise the market until 2026. However, that is not what happened.

The Paris Judicial Court invalidated the EP’961 patent in March 2024. Sandoz, under case number RG n° 22/08612, requested the French Court to invalidate the French part of the patent, which it did. Meanwhile, in separate proceedings against Zentiva (case number: RG n° 24/51632), the court rejected any likelihood of infringement by Zentiva, thereby allowing companies to introduce their generic versions to the French market.

In the Netherlands, the District Court of The Hague prohibited Teva from launching a generic version of Rivaroxaban. Sandoz, the generics manufacturer, challenged EP 961’s validity, arguing that the claimed dosage regimen was obvious from prior art. However, the court dismissed Sandoz’s nullity suit. Simultaneously, the court agreed with Bayer that the market entry of a generic version of Rivaroxaban from April 2024 infringed EP 961. Consequently, Sandoz is prohibited from infringing the Dutch part of EP 961 (case ID: C/09/637811 / HA ZA 22-934). An appeal against this decision is possible.

The German Federal Patent Court recently deemed the patent valid in a preliminary opinion. As a result, the Munich Regional Court issued preliminary injunctions against Zentiva, Stadapharm, and Aliud. These decisions followed a lengthy hearing the previous week, where the companies were co-defendants. However, the court can still revise this provisional opinion until the final judgment, as required by law. The nullity case will be heard in June 2025 (case ID: 3 Ni 11/22). The positive preliminary opinion is crucial for Bayer, as it intends to leverage subsequent patent EP 961 to prevent generic products from entering the market. With the Federal Patent Court’s preliminary opinion, generics manufacturers must now anticipate preliminary injunctions from Bayer, with increased probability of confirmation by German patent courts.

In February, the Stockholm Patent and Market Court upheld Bayer’s European patent EP’961 in its entirety, indicating Sandoz’s failure to challenge the Swedish part of the patent (case ID: PMT 16592-22).

Bayer also received a favorable ruling in Belgium, where the Enterprise Court of Brussels confirmed EP’961 (case ID: A/22/02947). Sandoz may appeal the judgment, which is highly likely.

In a very recent news, London’s High Court ruled that EP’961 is invalid due to the lack of an “inventive step” in developing the drug, following legal challenges brought by Sandoz and other rival manufacturers (Case numbers: HP-2022-000029, HP-2022-000032, HP-2022-000034, HP-2023-000005, HP-2023-000006, HP-2023-000017). Bayer intends to appeal this decision and interim injunctive relief to prevent the launch of 10mg, 15mg, and 20mg generic Rivaroxaban products.

Inventive step and patent validity:

The concept of inventive step has been central to the validity of Rivaroxaban’s patents, with courts scrutinizing whether the drug’s development involved sufficient innovation to warrant patent protection. Recent rulings, such as the decision by London’s High Court invalidating Bayer’s patent, underscore the significance of inventive step in patent litigation and the complexities involved in assessing the novelty and non-obviousness of pharmaceutical inventions. These legal precedents shape the landscape of patent law and intellectual property rights enforcement in the pharmaceutical industry, influencing innovation, competition, and market dynamics. As per the UK patent law, “An invention shall be taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art by virtue only of section 2(2) above (and disregarding section 2(3) above). The question of whether an invention is obvious is a matter which is normally decided on the technical facts of the case rather than on any general legal principles, but insofar as any such principles can be derived from decisions given under previous legislation, they will generally continue to be relevant.”

The court established a structured method consisting of four steps to evaluate obviousness:

1. Define the claimed inventive concept.

2. Assume the perspective of an ordinarily skilled but not imaginative individual in the field at the priority date, considering the common general knowledge of the relevant art at that time.

3. Determine any disparities between the cited “known or used” material and the purported invention.

4. Determine, without prior knowledge of the alleged invention, whether these disparities represent advancements that would have been obvious to the skilled individual or if they necessitate a degree of inventive step.

Inventive step issue in the Bayer vs Sandoz case in the UK:

The documents forming the two groups of prior art, all originated from Bayer. A skilled team reviewing each group at the priority date would have noted that they all detailed the outcomes of phase I trials, specifically involving Rivaroxaban. Bayer acknowledged that the skilled team, having reviewed the cited prior art, would have not only considered advancing to conduct a phase II trial but would have had the incentive and capability to do so. Bayer contended that for the skilled team to select rapid-release Rivaroxaban and implement a once daily dosing regimen, as specified in claim 1 of the patent, would require additional inventive steps. However, it was widely accepted that the phase II trial would likely involve a once daily dosing regimen, and the dispute centered on whether such a regimen would be reasonably expected to succeed. Despite differing opinions, the prevailing consensus across various jurisdictions is that the Patent does not lack an inventive step, except for dissenting rulings from the South African court and the Paris Tribunal, which deemed the equivalent patent invalid over the prior art of Harder and the Kubitza posters. The cited items of prior art, namely Harder and the Kubitza posters, collectively led to the patent’s invalidation in the UK.

Bayer’s strategies for managing setbacks:

Bayer’s ambitious plans to transform Asundexian into a 5 billion euro ($5.5 billion) per year medication faced a setback. The phase 3 trial revealed that the Factor XIa inhibitor had “inferior efficacy” compared to Eliquis, a drug jointly developed by Bristol Myers Squibb and Pfizer, prompting Bayer to halt the study prematurely. Despite this setback, Bayer intends to continue advancing the asset in a different indication. Asundexian was initially ahead in development compared to Bristol Myers Squibb’s Factor XIa inhibitor, Milvexian, which is not expected to complete Phase 3 trials for FDA approval until 2026 or 2027. However, Asundexian’s performance in clinical trials has been disappointing. In 2022, the drug candidate failed to outperform a placebo in midphase trials involving patients recovering from heart attacks and a type of stroke. The molecule faced another setback in November 2023 when it failed a phase 3 trial (OCEANIC-AF). Despite these challenges, Bayer remains committed to investigating Aasundexian and will proceed with its trial for stroke prevention. Bristol Myers expressed confidence in its trial plans for Milvexian, asserting that it differs from other oral Factor XI inhibitors.

Competitive landscape and market dynamics:

The competitive landscape for Rivaroxaban is evolving, with competitors such as Eliquis (Apixaban), Pradaxa (Dabigatran etexilate), and Savaysa/Lixiana (Edoxaban) vying for market share in the rapidly growing anticoagulant market. Legal challenges, patent expirations, and the emergence of generic versions further contribute to the dynamic nature of the market, shaping pricing strategies, market access, and commercialization pathways for pharmaceutical companies. These market dynamics underscore the importance of strategic positioning, innovation, and regulatory compliance in navigating the competitive landscape and achieving sustained growth and profitability.

Eliquis (Apixaban): Within the EU, the composition of matter patents and associated SPCs for Apixaban are set to expire in 2026. Generic companies have contested these patents and SPCs in multiple jurisdictions, with trials either underway or scheduled in certain European nations. During these ongoing legal proceedings, generic manufacturers have commenced the sale of generic Eliquis in select EU countries and may pursue further marketing in additional EU countries before the expiration of apixaban patents and related SPCs. This situation could result in additional legal actions concerning Eliquis patents, including claims of infringement and invalidity, being initiated across various European countries.

Pradaxa (Dabigatran etexilate): Pradaxa generics started entering the EU market in 2023 with first generic approval to Accord.

Savaysa/Lixiana (Edoxaban): The SPCs granted on the molecule patent expire in June 2027, which may then allow generic entry in the EU market.

Generic manufacturers with litigation cases against Bayer for Xarelto® in Europe:

• Sandoz
• Medisorb
• Teva
• Hexal
• Accord
• Genepharm
• KrKa
• Abdi Farma
• Polpharma
• STADA
• Ratiopharm

Xarelto® situation in India:

In 2015, Bayer filed for a preliminary injunction against Dr. Reddy’s Labs to block the company from launching its patented drug Xarelto®’s generic version. However, the case concluded without an injunction being passed against Dr. Reddy’s. It was speculated that Dr. Reddy’s had no immediate plans to commercially launch the generic drug, as the patent for Xarelto® had not yet expired. In India, Bayer distributes Xarelto® through its equally owned joint venture, Bayer Zydus, formed with Ahmedabad-based Zydus Cadila. This joint venture handles the marketing and distribution of Xarelto® in the Indian market. However, the Indian patent for Xarelto® held by Bayer expired in December 2019, paving the way for potential generic competition in the market.

So currently, generics of Xarelto® present in India are:

• Ixarola
• Rivaban
• Rivaflo
• Rpigat
• Ricosporin
• Rovor
• Gloves

Xarelto® situation in the US:

The anticoagulant has been listed as one of the drugs in the negotiation list of Inflation Reduction Act. This thus may again impact the revenue generation in the US market.

Conclusion:

The journey of Rivaroxaban, epitomized by the brand Xarelto®, reflects the intricate interplay between patent protection, legal challenges, and market dynamics in the pharmaceutical industry. As stakeholders adapt to evolving landscapes, the legacy of Rivaroxaban continues to unfold, leaving an indelible mark on cardiovascular medicine and patient care. The future holds both challenges and opportunities for pharmaceutical companies like Bayer, as they navigate the complexities of patent litigation, market competition, and regulatory scrutiny to achieve sustainable growth and advance the frontiers of innovation in cardiovascular therapy.