Trend in Pharma Patents From Small Molecules To Biologics

Imagine if you had a patent for a biologic and the same was being infringed by a biosimilar in the market, could you then enforce your patent rights against this biosimilar which is not identical to your patented biologic, as is usually the case with small molecules and generics?

In this article we discuss how the trend has evolved, in relation to both, pharmaceutical industry for generics and biosimilars, and the approach followed by Courts for enforcing small molecules and biologics.

First, let’s answer the most basic questions: How are small molecules and biologics different? And what are similar biologics?

Small molecules are chemically derived, molecularly smaller in size and easier to replicate as a generic drug.

Biologics are generally large, complex molecules created from living organisms and are often more complicated to replicate than small molecule drugs. As a result of which a similar biological product of a biologic (i.e. reference biologic) can be created but not an identical generic.

A “similar biologic” is defined¹ as a biological product which is similar in terms of quality, safety and efficacy to reference biological product licensed or approved in India, or any innovator product approved in International Council of Harmonisation (ICH) member countries.

Pharmaceutical Industry of India: Generics v. Biosimilars

India ranks 3rd worldwide by volume of production of pharmaceuticals and 14th by value, thereby accounting for around 10% of world’s production by volume and 1.5% by value².

In 2024, India ranked 39th in the Global Innovation Index, up from 81 in 2015. One of the major contributors to this growth is the pharmaceuticals industry of India. The total annual turnover of pharmaceuticals in the fiscal year 2021-22 was $42.34 billion³. While, globally, India ranks 4th in terms of generic production⁴, in recent years a shift has been seen in the reproductive capabilities of the biosimilar drug manufacturers. India’s biosimilars’ market size was valued at $349 million in 2022 and is estimated to expand at a compound annual growth rate (CAGR) of 25.2 per cent from 2022 to 2030 and will reach $2108 million by 2030⁵.

With Indian drug manufacturers now creating a biosimilar wave, it is essential to assess the biosimilar legal framework of India.

Legal Framework governing Biosimilars

Under the Indian statutory and regulatory framework, biologics and biosimilars are considered to be drugs and are regulated under the Drugs and Cosmetics Act, 1940, New Drugs and Clinical Trials Rules, 2019 and The Guidelines on Similar Biologics: Regulatory Requirements for Market Authorization in India⁶ (in effect since August 15, 2016) (“the Guidelines”).

The Guidelines – An attempt to regulate the biosimilar wave

The Guidelines prescribe that if the host cell line used for production of reference biologic is disclosed, it is desired to use the same host cell line for manufacturing the biosimilar⁷. Likewise, the Guidelines also prescribe that the active drug substance (active ingredient) of reference biologic and biosimilar must be shown to be similar⁸.

While under the Guidelines, the extent of preclinical and clinical evaluation of biosimilar may be reduced than that required for reference biologic, primarily due to demonstration of similarity in comparative assessment, this, however, does not preclude testing biosimilar to meet levels of safety, efficacy and quality, since after all, a reference biologic is an innovator’s product approved after evaluation of complete dossier.

Pre-clinical phase: In the pre-clinical phase, it is prescribed that the dosage form, dose, strength, route of administration⁹ of biosimilar should be similar to that of biologic. It is after evaluation of preclinical study reports including demonstration of consistency¹⁰ and comparison of similar biologic to reference biologic, RCGM¹¹ will recommend DCGI to allow to conduct next phase of clinical trial as per CDSCO requirements.

Clinical phase: The confirmatory clinical safety and efficacy study can be waived if structural and functional comparability to the referenced biologic is present¹², if biosimilar is comparable in all preclinical evaluations, if PK/PD¹³ study has demonstrated comparability of PD markers, and if comprehensive post-marketing risk management plan has been presented. But the confirmatory clinical safety and efficacy study cannot be waived for large molecular weight biologics¹⁴. Wherever the phase III trial is waived, the immunogenicity should have been gathered in the PK/PD study and will also need to be generated during post-approval Phase IV study.

Check on waiver: The waiver to a biosimilar is kept in check by the Guidelines, which not only provide for a pharmacovigilance plan post-market authorization, which includes submission of periodic safety update reports every six months for the first two years, and annually thereafter for subsequent two years to DCGI¹⁵, but also call for post-marketing safety data “through a pre-defined single arm study of generally, more than 200 evaluable patients and compared to historical data of the Reference product”.

Needless to add that the patents for Biologics are governed by The Patents Act, 1970.

Infringement by Biosimilars

Unlike smaller molecules, where the law is settled in Roche v. Cipla¹⁶ and Merck v. Glenmark¹⁷. We know from Roche v. Cipla that test of infringement is to map Defendant’s product against patent claims, and the limited evaluation is to assess presence of same Active Pharmaceutical Ingredient. We further know from Merck v. Glenmark that the use of same API in Defendant’s product amounts to an admission to infringement.

The question which arises for consideration is whether such a basis of infringement can be applied to biosimilars and reference biologics, which are not identical but similar, and if not, then what constitutes the threshold infringement of a reference biologic by a biosimilar?

The court has been posed with questions pertaining to biosimilars in different scenarios, such as:

1. In Roche v. Cadila¹⁸, currently the Court is answering the question whether the Defendants are attempting to ride on the goodwill of the referenced biologic to take unfair advantage of same in selling their drug as a biosimilar of it, in absence of conducting requisite tests. Roche, being the innovator of drugs Trastuzumab (which is sold as Herceptin) and Bevacizumab (which is sold as Avastin), filed suits seeking declarations that approval granted by DCGI to Cadila and Hetero for pre-clinical/clinical protocols and marketing their drug claimed to be a biosimilar of Trastuzumab and Bevacizumab, be declared invalid and further sought permanent injunction restraining them from representing their drugs as biosimilar versions of Roche’s Trastuzumab and Bevacizumab.

2. Recently, the Delhi High Court is posed with the question of infringement of patented reference biologic by a biosimilar in F-Hoffmann La Roche AG & Anr. v. Zydus Lifesciences Limited¹⁹, which is currently pending adjudication.

Pertinently, the Court in Roche v. Zydus recognised duality of intellectual property in a biologic, first being the molecular structure and the second being the process required for its reliable, safe and consistent large-scale manufacturing within living systems²⁰.

Claim Mapping – aid to infringement?

In Roche v. Zydus, the Court, after noting that the Defendant had applied for a patent for the formulation of its biosimilar, observed that claim mapping could be a way to assess infringement and invited Parties to show infringement by claim-by-claim analysis/claim mapping of the suit patents to the Defendant’s patent application. Arguments on this are currently being heard before Court and a conclusion on this is awaited.

How can infringement be assessed in biosimilars?

In the meantime, in a quia timet action, where a biosimilar is yet to be made available in the market and not yet the subject matter of a patent application, on a prima facie view, can be argued to be infringing on the basis of the admissions made by the applicant of a biosimilar:

a. First: Before the CDSCO for obtaining approval to conduct trials in reference to the referenced biologic,

b. Second: before the CDSCO to obtain approval for manufacturing and marketing the biosimilar based on the results of the above comparative clinical trial, and

c. Third: To the public (consumer) at large when the product is claimed to be a biosimilar of the referenced biologic.

Therefore, borrowing from Merck v. Glenmark, the reference to the referenced biologic can be argued as an admission on part of the Defendant.

We have seen this line of argument being accepted in GSP Crop Science Pvt. Ltd. v. Devender Kumar²¹, wherein the Court dealt with Section 9(4) of The Insecticide Act, 1968. The Court granted ad-interim relief to the Plaintiff by observing that the “me too” registration of the Defendant’s product amounted to an admission that the Defendant was aware of the suit patent and Defendant’s product comprised of formulation identical to suit patent. The same argument is also advanced in SEP matters, where the claim mapping on the standards is considered as evidence of infringement.

Globally, this aspect has been examined by the U.S. District Court for the Northern District of West Virginia in Regeneron v. Formycon²², which while granting a preliminary injunction prohibiting the commercial sale by Formycon of its proposed biosimilar EYLEA (aflibercept), observed that the standard of proof will be “preponderance of evidence” and relied on expert evidence led by Regeneron and came to a finding of infringement and observed that Formycon’s product met each and every limitation of patent claims. This decision has been appealed by Formycon and arguments are yet to be concluded in appeal.

It will be of interest to see the test developed by Courts in India for assessing infringement by a biosimilar, in quia timet action and otherwise, where two batches of the same biosimilar may not be identical to each other.

Disclaimer – The views expressed in this article are the personal views of the authors and are purely informative in nature.