Patent term extension (PTE) provides additional patent term for patents related to U.S. pharmaceutical products to compensate for the effective loss of patent term caused by delay during the drug approval process by the U.S. Food and Drug Administration (FDA).
To be eligible for PTE, a patent must claim a drug product, a method of using a drug product, or a method of manufacturing a drug product, and PTE is only available for the first approval of an “active ingredient.”
The Federal Circuit has addressed the question of what constitutes an active ingredient[1] several times in the context of small molecules. For example, claims directed to a metabolite do not cover the active ingredient,[2] enantiomers of the same compound are different active ingredients,[3] and different salts of the same compound are considered the same active ingredient for purposes of PTE.[4] Although the Federal Circuit case law on small molecules is more developed, it is not clear how the court will apply the current case law and statutory framework to biologics including cell-based therapies and gene therapies.
Recent approval of a cell therapy, YESCARTA®, provides insight into considerations from the U.S. Patent & Trademark Office (USPTO) on what constitutes the active ingredient in the context of biologics.
The YESCARTA PTE application illustrates two challenges for defining the active ingredient in cell-based therapies to meet the first approval requirement.[5] One challenge is how to define the active ingredient for certain cell-based therapies, where the product differs from patient to patient. Moreover, there is the related challenge of providing a detailed enough description of the active ingredient in the PTE application to allow the USPTO to distinguish the active ingredient of the product from previously approved active ingredients.
YESCARTA (Axicabtagene ciloleucel) is an immunotherapy approved to treat B-cell lymphomas. YESCARTA comprises autologous T cells (a type of immune cell that plays a crucial role in detecting and killing cancer cells) derived from an individual patient and engineered specifically to target the patient’s cancer cells. The engineered T cells comprise: (1) T cells harvested from a patient and (2) a foreign protein (i.e., a chimeric antigen receptor (CAR)) specifically targeting a cell-surface protein. The T cells vary from patient to patient, but the CAR is the same for all patients. The T cells containing the CAR are responsible for the anti-tumor activity. All of this raises the question of whether the active ingredient is the T cells and/or the CAR.
In the YESCARTA PTE application, applicant Cabaret Biotech Ltd. (“Cabaret”) defined the active ingredient as the engineered T cells. After reviewing the PTE application, the USPTO issued a letter to Cabaret, stating that (a) the cells could not be the active ingredient because the cells differ from patient to patient and (b) the CAR was not an active ingredient because it was not defined in the application as filed. Aside from the challenge surrounding the question “What is the active ingredient?” the USPTO also indicated that the applicant’s description of the structure of YESCARTA was insufficient. The USPTO requested that the applicant comment on whether an earlier approved antibody that targeted the same cell-surface protein was actually the first approval for the active ingredient in YESCARTA.
The USPTO never squarely addressed what it considered the active ingredient of YESCARTA to be. After multiple communications between the USPTO and Cabaret, and between the USPTO and FDA, the USPTO approved the YESCARTA PTE application. The information the USPTO finally relied upon for determining that YESCARTA was eligible for PTE was the DNA sequence encoding the CAR. It appears that, based upon the differences in sequences between the YESCARTA CAR and the previously approved antibody, the USPTO determined that YESCARTA contained a new active ingredient.
Interestingly, YESCARTA is not the first cell-based product with patient-to-patient variability to receive a grant of PTE. LAVIV® (Azficel-T) is an autologous cell product used for treating moderate to severe wrinkles. In its PTE application, Fibrocell Technologies, Inc. described the active ingredient of LAVIV as an autologous cellular product composed of fibroblasts suspended in a particular cell medium, and listed the active ingredient as “fibroblast cells.”[6] Although LAVIV shares the patient-to-patient variability seen in CAR T cells, the USPTO accepted this designation without further comment.
The YESCARTA PTE application illustrates the challenges in applying the active ingredient analysis developed in the small molecule realm to biologics technologies. Precisely how the USPTO views the question of what constitutes an active ingredient in cell-based therapies remains an open question that will most likely be resolved by the courts. This uncertainty, however, has not impeded the grant of PTE for these cell-based therapies. Thus, patentees should not be deterred from filing PTE applications to secure an additional patent term for biologics products, but should keep these challenges in mind when drafting the description of the active ingredient in the PTE application.
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[1] Title 21 of the Code of Federal Regulations defines an “active ingredient” as any component that is “intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals.”
[2] Glaxo Operations UK Ltd. v. Quigg, 894 F.2d 392 (Fed. Cir. 1990).
[3] Ortho McNeil Pharm. v. Lupin Pharm., 603 F.3d 1377 (Fed. Cir. 2010).
[4] Pfizer Inc. v. Dr. Reddy Labs. Ltd., 359 F.3d 1361 (Fed. Cir. 2004).
[5] U.S. Patent No. 7,741,465; received at the USPTO on December 14, 2017.
[6] U.S. Patent No. 5,591,444; received at the USPTO on August 17, 2011.