This article is written by Ms. Srikrishna Samhita student at ILS Law College, Pune

Abstract

This comprehensive exploration delves into the intricate landscape of polymorph patents in the pharmaceutical industry. Polymorphs, distinct crystalline forms of a drug, wield significant influence over drug solubility and composition. The article scrutinizes the global perspective on polymorph patentability, contrasting the stringent Indian regulations with the multifaceted U.S. framework. The Lumacaftor case study in India exemplifies the challenges faced, emphasizing the necessity to demonstrate enhanced efficacy. The convergence of polymorphism and evergreening, illustrated by Zantac’s strategic delay, adds complexity to the patenting landscape. There comes a need for a redefined approach that prioritizes authentic polymorphs, fostering innovation in drug development while maintaining fair competition.

Introduction

Polymorphs are known as the crystalline forms of a drug which differ in drug solubility and slight variation in composition compared to the original drug. The origin of the word ‘polymorph’ can be traced back to the Greek word ‘polus’ which means many and ‘morph’ meaning different shapes. A single solid compound can manifest in various forms, such as an amorphous state or a crystalline structure. However, the existence of the compound is not limited to only these two solid-state forms. When there are at least two identifiable crystal structures, experts refer to them as ‘polymorphs.’ Additionally, scientists use the term ‘polymorphism’ to describe the occurrence of different amorphous forms of the compound. The significance of polymorphs is established because they can be put into use for their different physio-chemical properties which in turn is an effective strategy for formulating drugs and optimising storage stability.

An emerging question is whether these polymorphs should receive patent protection. Obtaining patent protection for a polymorph in addition to the primary drug has proved to be advantageous for pharmaceutical companies because it’s a good strategy to extend the patent life. In theory, every time a new modification of a clinical candidate is made, the patent protection gets extra time. However, it is not so easy in reality. The Indian patent law, specifically, does not grant patent protection to polymorphs unless it leads to key therapeutic efficacy. On the other hand, even though the US Patent and Trademark Office (USPTO) permits the patentability of polymorphs, it involves navigating through multiple stages which are often complicated. Different countries have different legislations on polymorph patent protection.

Patenting a polymorph requires full disclosure of its composition and distinction from other polymorphic forms to fulfil clarity and sufficiency. It also becomes essential to differentiate between true polymorphs and pseudo polymorphs to avoid illegitimate means of patenting. Therefore, discussing how the patent laws should be redefined to produce intended polymorphs with effective bioavailability is utmost needed. 

Patentability of Polymorphs: A Comparative Analysis

The enigmatic and diverse perspectives within the field of IPR raises considerable debate on the part of those who oppose polymorph patent and those who seek its protection. This is the reason why the patentability of polymorphs is subjected to invalidity in most of the cases. Many developed nations have specific provisions that define the subject matter of patentability for known forms of any compound. For instance, section 3 (d) of the Indian Patent Act doesn’t allow patent protection for those substances which does not result in any enhancement of the known substance (salt, esters, polymorphs, etc.) In the realm of pharmaceuticals, there is an already established significance of patent protection for incentivizing innovation, however, for a polymorph to be eligible for a patent the conditions of novelty necessitate that the polymorph is not disclosed in the prior art and non-obviousness requires that it should not be easily predictable based on existing knowledge. Therefore, patenting a polymorph can put the companies into complexities.

In the US, obtaining a patent for a polymorph is like navigating through multiple steps put forth by the legal framework of the United States Trademark and Patent Office (USTPO). Apart from non-obviousness and novelty, the following conditions are strongly recommended for a hassle-free patent application for polymorphs:

• Detailed description – The patent application should include a comprehensive and detailed description of the polymorph. This encompasses the crystal structure, physical properties, and any unique characteristics that distinguish it from other forms of the compound.
• Supporting data – Providing experimental data and analytical results is crucial. Techniques like X-ray diffraction, infrared spectroscopy, and differential scanning calorimetry can be used to support the identification and characterization of the polymorph.
• Enablement and Utility – The patent application must enable someone skilled in the field to reproduce the polymorph based on the information provided. Additionally, the application should articulate the utility of the polymorph, emphasizing any advantages it offers in terms of stability, solubility, or other relevant properties.

Patenting a polymorph has been a challenge persisting in all the countries. The Europe Patent Office (EPO) addresses the challenge of inventive step by designing a problem-solution approach which essentially involves three stages: 

• determining “the closest prior art” – will disclose the difference between the amorphous form of the known compound or a different polymorph of the compound.
• establishing the “objective technical problem” to be solved – is derived from the technical effect of changing from the closest prior art to a newly claimed polymorph. 
• considering whether or not the claimed invention, starting from the closest prior art and the objective technical problem, would have been obvious to the skilled person. 

Formulating such steps can be easy for the pharmaceuticals if followed diligently. Obtaining a valuable patent for a novel polymorph of a recognized compound is feasible, given that (i) the patent application clearly outlines the characteristics of the polymorph and (ii) a convincing narrative is provided to establish an inventive step, supported by comparative data demonstrating an unforeseen advantage specific to the claimed polymorph.

Polymorphism and Evergreening

Polymorphism is a completely unpredictable phenomenon in the sense a drug manufactured overnight can become highly soluble or less bioavailable. Although a compound’s polymorph might be similar, its physical properties vary tremendously. While evergreening is a strategy adopted by pharma companies to extend the patent life of their drugs beyond the expiration of their patent, polymorphs are the existence of a substance in multiple crystal forms. A common link underlying both these concepts is the extension of patent life. In the case of polymorphs, we have seen countries like the US grant patents for polymorphs and in the case of evergreening, the companies intentionally alter the drugs to increase their efficacy resulting in the addition of patent-protecting years. While the two concepts are separate, they can be complementary. For example, a pharmaceutical company might discover a new polymorph of a drug and subsequently seek to patent this discovery, extending the exclusivity of the drug. Additionally, evergreening strategies may involve obtaining patents for specific polymorphic forms of a drug as part of broader protection.

However, to point out a star difference between the two; polymorphism focuses on variations in the crystalline forms of the drug while evergreening involves making incremental changes to the drug often beyond its crystalline composition. A major problem that persists in the field of polymorphs is the lengthy court battles regarding its ownership (which also coincides with evergreening). Zantac, the widely successful anti-ulcer medication containing ranitidine hydrochloride, attained blockbuster status. During the drug’s development, Glaxo (now GSK) identified a second polymorph of ranitidine hydrochloride and obtained a patent for it. This alternative form, which was easier to produce, became the active ingredient in Zantac. When the patent for the initial polymorph expired, generic companies sought to create their own versions. However, the continued patent protection of the second polymorph posed a significant challenge for competitors trying to manufacture the first form without contamination. This scientific obstacle granted GSK valuable time, delaying the market entry of generic Zantac versions.

Polymorphism and evergreening are essential concepts in the pharmaceutical industry, influencing drug development, market exclusivity, and competition. While polymorphism deals with the diverse crystalline forms of a drug, evergreening involves strategic efforts to prolong market exclusivity through various patenting tactics. Both concepts are integral to the complex landscape of pharmaceutical innovation, patent law, and ethical considerations in providing access to essential medicines.

Case Study

As mentioned earlier, The Indian Patent Act, of 1970 does not accept polymorphs or other like substances for patent application and this has been reflected in the case of the rejection of Lumacaftor (Polymorph) patent application in India. The case involves the patent application for Lumacaftor, used in conjunction with Ivacaftor for treating cystic fibrosis. The First Examination Report (FER) was issued in August 2014, citing objections based on prior art and sections 3(d), 3(i), and 3(n) of the Patents Act, 1970, along with procedural grounds. Despite a twelve-month allowance period, the application was found non-compliant after the deadline, leading to objections communicated in the year 2016. A hearing addressed nine objections, including major technical concerns related to novelty, inventive steps, and non-patentability under section 3(d) of the Act.

Section 3(d) prohibits the patenting of new forms of known substances unless they significantly enhance efficacy. The controller’s decision, rejected the application under section 15, emphasizing that the technical data provided during the hearing was beyond the complete specification and didn’t alter the rejection decision. The applicant’s argument about the novel and inventive aspects of Lumacaftor’s Form I was dismissed, with the controller stating that better pharmacokinetic properties didn’t necessarily imply enhanced efficacy. Additionally, the rejection was considered a pre-grant opposition filed by the Indian Pharmaceuticals Alliance under section 25(1), leading to the refusal of the patent application. In summary, the rejection was based on the controller’s findings that the provided technical data was not part of the complete specification and the claimed Form I of Lumacaftor did not demonstrate sufficient novelty or inventiveness, as per the requirements of section 3(d). The pre-grant opposition also contributed to the refusal of the patent application.

In the Indian context, filing experimental data becomes crucial for granting a patent. Also, the Indian examiners insist on the disclosure of experimental data in all the applications claiming polymorphs of known compounds. It has been well established from the above case study that although bioavailability may be increased, the efficacy may not necessarily increase. Polymorphs are not the only means to increase drug efficacy because they are largely dependent on unpredictable external factors like temperature, atmosphere, etc. Determining the eligibility of a patent application for a novel polymorph of an active pharmaceutical ingredient falls within the jurisdiction of a country’s intellectual property laws. However, there is room for adjusting patent legislation to encourage the patenting of authentic polymorphs, those that present genuine technological advancements over existing knowledge, rather than endorsing pseudo polymorphs created solely to expand a company’s portfolio. In the upcoming era, organizations are advised to prioritize research efforts towards discovering stable polymorphs that offer superior quality and efficacy, recognizing the paramount importance of this aspect in the drug development process.

Conclusion

In the realm of pharmaceuticals, the patenting of polymorphs is a complex interplay between scientific advancements and legal frameworks. The diverse crystalline forms of a drug, known as polymorphs, significantly impact its efficacy and stability. While some countries, like India, impose stringent criteria for patenting polymorphs, others, such as the United States, navigate a multifaceted process. The case study of Lumacaftor in India illustrates the challenges faced in obtaining patent protection for polymorphs, emphasizing the importance of demonstrating enhanced efficacy. The intersection of polymorphism with evergreening adds another layer of complexity, as seen in the strategic delay of generic versions in the case of Zantac.

Looking ahead, there is a need to redefine patent laws to incentivize the protection of authentic polymorphs with substantial technological advancements. Organizations are encouraged to prioritize research in discovering stable polymorphs with superior quality and efficacy. Balancing innovation incentives with fair competition remains a dynamic challenge that requires continuous refinement of patent laws and a nuanced understanding of both scientific and legal intricacies.

References

1. The article was originally written by Runjhun Tandon, Nitin Tandon & Rajesh Kumar Thapar published on FutureScience. The link for the same is herein. https://www.future-science.com/doi/10.4155/ppa-2017-0039
2. The article was originally written Arwed Burrichter, Natalie Kirchhofer and Melanie Lödige published on IAM. The link for the same is herein. https://www.iam-media.com/guide/global-life-sciences/2022/article/tips-and-tricks-how-obtain-patent-protection-polymorphs
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