For biologic drug developers, the period of market exclusivity following FDA approval can be worth billions. Patent term extension (PTE) under 35 U.S.C. § 156 compensates inventors for time lost during U.S. Food and Drug Administration (FDA) regulatory review, allowing up to five years of additional patent protection for approved drug products, including pharmaceutical and biological products. PTE, in some instances, has resulted in significant additional revenue because the period of market exclusivity of an approved product is extended. While this process is generally straightforward for small molecule drugs, PTE applied to biological products has generated significant litigation and uncertainty. A central challenge lies in determining what constitutes the “active ingredient” of an approved biological product, given that patent extension is available only for claims directed to that active ingredient. Unlike small molecule drugs which are discrete chemical entities having defined structures, biologics encompass a wide variety of large, complex molecules that defy simple categorization. For example, in the case of antibody-drug conjugates (ADCs), the active ingredient arguably could be the antibody, the payload, or the entire conjugate. This definitional ambiguity has profound consequences for PTE, as it determines whether a patent qualifies for extension and the scope of exclusivity the extension provides. In this article, we will describe how the “active ingredient” is determined and defined with respect to biologics and provide practical guidance for drafting and prosecuting biologic patent claims that strengthen PTE positions.

What the Law Says—and Where it Falls Short

In PTE, the term “drug product” refers to the active ingredient of a new drug or biological product, including any salt or ester of the active ingredient.¹ The Federal Circuit has examined active ingredients in the context of small molecules;² However, it has not yet addressed the question of active ingredients in the context of biologics.

In biologics, the active ingredient may encompass, for example, a primary amino acid sequence and also may include higher-order structure, post-translational modifications, and functional properties of an approved product. This is because, in biologics, these additional components may affect the function of the drug (e.g., therapeutic efficacy). The difference is further reflected in the regulatory pathways for follow-on products: for small molecule drugs, generic approval requires only a demonstration of bioequivalence to the reference product; for biologics, a biosimilar applicant must demonstrate that its product is highly similar to the reference biologic notwithstanding minor differences in clinically inactive components, with no clinically meaningful differences in safety, purity, or potency..

Lessons from YESCARTA®

The challenge of defining the active ingredient for the purposes of PTE has been illustrated by the cell therapy, YESCARTA® (axicabtagene ciloleucel). YESCARTA® is an individualized immunotherapy comprising T cells derived from a patient engineered to include a chimeric antigen receptor (CAR) to target cancer cells in order to treat B-cell lymphomas. In this instance, the CAR T cells are unique to each patient because the underlying T cells are patient-specific. In this instance, the active ingredient could be the patient-specific engineered CAR T cells or the CAR used to engineer the T cells, which is the same regardless of the patient.

During the PTE application process, the Applicant defined the active ingredient as the T cells. The USPTO issued a letter to the Applicant, noting that the cells could not be the active ingredient because they differ between patients. The USPTO also indicated that the CAR was not an active ingredient because it was not defined in the PTE application and was potentially previously approved as an antibody. Ultimately, the USPTO approved the YESCARTA® PTE application with the DNA sequence encoding the CAR as the active ingredient.

Interestingly, a different individualized cell-based product, LAVIV® (Azficel-T), was granted PTE for an autologous cellular product comprising fibroblasts suspended in a specific cell medium (“fibroblast cells” were listed as the active ingredient in the application). This discrepancy underscores the challenges of defining active ingredients within the PTE framework. Similar challenges arise in gene therapy.

Choosing the Right Patent(s) for PTE

Once the active ingredient is defined, an Applicant must select which patent, or patents, to put forward for extension. The statute permits only one PTE per regulatory review period, so the choice is consequential.

Therefore, a PTE Applicant must carefully consider how to define the active ingredient of a product in order to develop a robust patent portfolio covering the approved product and to select the right patent or patents for a PTE application. In order to be eligible for PTE, a patent must claim the approved drug product, a method of using the drug product, or a method of manufacturing the drug product. It is important to note that, although genus-type claims may be recited in a PTE patent, the extension of term only applies to the approved product (species) itself, not the entire genus.

Getting Strategy Right from the Start

Therefore, effective biologic PTE strategy demands development of a patent portfolio strategy early in the development of the approved product. Continuous communication between regulatory and patent counsel regarding the description of the active ingredient in the Biologics License Applications (BLA) and the language of the product label is important to ensure a successful PTE strategy. In particular, it is important to settle on the right scope to describe the active ingredient: if it is described too narrowly, the definition will foreclose coverage of related forms that competitors might exploit; however, if it is described too broadly, the USPTO may reject the application, or the application may be vulnerable to future litigation.

As biologics continue to reshape the therapeutic landscape, the legal and regulatory frameworks governing PTE will face mounting pressure to keep pace. The foundational questions left unresolved by existing Federal Circuit precedent, including how to define the active ingredient for complex, process-dependent, or patient-specific biologics; how specifically that ingredient must be claimed; and how regulatory descriptions will be used against Applicants in future disputes, will almost certainly be tested in future biosimilar litigation. Applicants who treat PTE strategy as an afterthought, to be addressed only at the moment of FDA approval, do so at considerable risk. By integrating patent and regulatory strategy from the outset, maintaining consistency across all submissions, and staying attuned to the evolving case law, Applicants can position themselves to capture the full value that PTE was designed to provide.

Sources

1. 35 U.S.C. § 156(f)(2)
2. Glaxo Operations UK Ltd. v. Quigg, 894 F.2d 392 (Fed. Cir. 1990); Pfizer v. Dr. Reddy’s Labs., 359 F.3d 1361 (Fed. Cir. 2004); PhotoCure ASA v. Kappos, 603 F.3d 1372 (Fed. Cir. 2010); Ortho-McNeil Pharmaceutical, Inc. v. Lupin Pharmaceuticals, Inc., 603 F.3d 1377 (Fed. Cir. 2010)