Do Prodrugs Infringe on Active Pharmaceutical Ingredient (API) Patents?
A prodrug is a precursor chemical compound of a drug, which is metabolized in vivo to produce a derivative or active compound. Prodrugs are often used to improve how a medicine is absorbed, distributed, metabolized, and excreted; to improve bioavailability; or to improve how selectively the drug interacts with cells or processes that are not its intended target. Prodrugs may reduce adverse or unintended effects of a drug, which is especially important in treatments that can have severe unintended and undesirable side effects.
While a prodrug may not directly infringe on a patented active chemical compound, sale of a prodrug may induce infringement by a patient who consumes the prodrug, which then converts into the patented compound. 35 U.S.C. § 271(b) provides that “whoever actively induces infringement of a patent shall be liable as an infringer.” Section 271(b) depends on a showing that the conduct being induced constitutes direct infringement. Under the “conversion theory” of induced infringement, a prodrug might induce infringement when a patent claims a compound or composition and the accused infringing prodrug compound conforms to the claim only upon conversion during use or consumption.1
A chemically distinct prodrug may infringe on a patented active compound when the prodrug is converted into the claimed compound in vivo when ingested by a patient. For example, in Hoechst-Roussel Pharms, Inc. v. Lehman, the court held that a patent claiming 1-hydroxy-tacrine would be infringed by the administration of tacrine hydrochloride which metabolizes into 1-hydroxy-tacrine upon ingestion by addition of a hydroxyl group.2 Similarly in Ortho Pharmaceutical Corp. v. Smith, the court held that a patent claiming the compound norgestrel was infringed by the administration of norgestimate, which metabolized into norgestrel in vivo by the removal of a ketoxime group and an acetyl group.3 Though chemically distinct, a prodrug can thus infringe on a patented compound when ingested and converted into the patented compound in vivo.4
In order to establish infringement by inducement, the plaintiff has the burden to prove that the product ingested is converted into the patented compound in vivo. In Zenith Laboratories, Inc. v. Bristol-Myers Squibb, the court held that infringement may occur if the administered product is converted in vivo into the claimed product.5 In Zenith, the patent-in-suit covered a pharmaceutical compound, cefadroxil monohydrate, and the defendant sought to market the compound, cefadroxil hemihydrate, which converted to monohydrate in vivo.6 While the court in Zenith did not reject the “conversion theory”, the court held that the plaintiff failed to demonstrate that any of the patented crystalline compound was formed in the stomach from the ingested drug.7
While the “conversion theory” has been supported for claims to chemical compounds, the court has not found induced infringement when the claim is directed towards medicinal preparations or formulations.8 Claims that are interpreted as a medicinal preparation or formulation may not use the “conversion theory” to expand the claim as to include compounds formed within the body.
In conclusion, the “conversion theory” of induced infringement is recognized and upheld in the Federal Circuit. When an active compound (A) has been patented, a chemical compound such as a prodrug (A-B), which is converted to the patented compound (A) in vivo, will infringe on the patent for the compound (A). However, the plaintiff must prove that the patented compound is indeed formed in vivo, and the claim language must not limit the compound to its pre-ingested form such as in a claim directed to a medicinal preparation or formulation.
5-16 Chisum on Patents § 16.02, Hoechst-Roussel Pharms, Inc. v. Lehman, 109 F.3d 756, 759 (Fed.Cir. 1997).↩
109 F.3d 759 (Fed. Cir. 1997).↩
1990 WL 121353 (E.D. Pa. 1990).↩
The Federal Circuit has also held that a patent for a metabolite can be anticipated by an earlier patent for a prodrug that is converted into the metabolite in vivo. In Schering, the prior art patent covered the drug loratadine (marketed as CLARITIN®), and the later issued patent-in-suit covered a metabolite of loratadine. Schering Corp. v. Geneva Pharmaceuticals 339 F.3d 1373 (Fed. Cir. 2003). The court held that since loratadine inherently produced the metabolite when ingested, the metabolite patent was anticipated. Id. at 1382.↩
Zenith Laboratories, Inc. v. Bristol-Myers Squibb, 19 F.3d 1418, 1422 (Fed. Cir. 2003).↩
Id. at 1418.↩
Id. at 1421.↩
See Novartis Pharm Corp v. Eon Labs Mfg., 363 F.3d 1306 (Fed. Cir. 2004) (holding that the term “hydrosol” limited the claim to an aqueous medicinal preparation prepared outside the body, and not the product formed after ingestion).↩