This article appeared in Pharmaceutical Compliance Monitor, February 14, 2014, and is reproduced with permission.
Despite the lack of recent decisions, in vivo conversion from an unpatented prodrug into a patented metabolite or the administration of an unpatented prodrug for treatment using a patented metabolite still presents inducement concerns.
Titles 35 U.S.C. §271(b) states: “Whoever actively induces infringement of a patent shall be liable as an infringer.” To prove inducement under this section, a patentee must prove that: (1) direct infringement exists; and (2) that the alleged infringer had “knowledge that the induced acts constitute patent infringement.” Global-Tech Appliances, Inc. v. SEB S.A., 131 S.Ct. 2060, 2068 (2011). Moreover, “[i]nducement requires evidence of culpable conduct, directed to encouraging another’s infringement, not merely that the inducer had knowledge of the direct infringer’s activities.” DSU Medical Corp. v. JMS Co., Ltd., 471 F.3d 1293, 1306 (Fed. Cir. 2006). Lastly, the impact of Commil USA, LLC v. Cisco Systems, Inc., 720 F.3d 1361 (Fed. Cir. 2012), holding that a “good faith” belief in patent invalidity may negate the intent to infringe requirement of the §271(b) remains to be seen.
For ease of discussion, the pertinent cases are grouped by whether the patent-in-suit covers a compound/formulation or a method of use.
Compound/Formulation Claims Where a patent covers a metabolite, it has been argued that the sale of an unpatented prodrug that converts to the patented metabolite can induce infringement. In this scenario, the patient is the direct infringer; the seller of the prodrug is the inducer. In an early case, the British House of Lords held that claims to ampicillin were infringed by the sale of hetacillin, which converted to ampicillin in vivo. Beecham Group Ltd. v. Bristol Laboratories, Ltd.,  RPC 153 (House of Lords 1977). In Zenith Labs., Inc. v. Bristol-Myers Squibb Co., 19 F.3d 1418 (Fed. Cir. 1994), a leading Federal Circuit decision, the patent-in-suit covered the pharmaceutical compound cefadroxil monohydrate. The defendant sought to market cefadroxil hemihydrate, which converted to the monohydrate in vivo. In reversing the District Court of New Jersey which had found infringement, the Federal Circuit held that Bristol had not satisfied its burden to prove that the claimed monohydrate was formed in vivo. The court, however, did not explicitly reject the in vivo conversion theory of induced infringement. Indeed, some years earlier the court in Ortho Pharmaceutical Corp. v. Smith, 1990 WL 121353 (E.D. Pa. 1990), had found infringement under the doctrine of equivalents because the accused drug, Norgestimate, converted to the claimed metabolites and achieved essentially the same contraceptive results in the same way. The pertinent evidence included tests showing the levels of the claimed metabolites in the blood. See also Hoechst-Roussel Pharmaceuticals, Inc. v. Lehman, 109 F.3 756 (Fed. Cir. 1997) (conversion theory accepted). The New Jersey District Court again accepted the conversion theory earlier espoused in the Bristol decision in Hoffman-LaRoche, Inc. v. Ranbaxy Labs Ltd., 2009 WL 3261252 (D.N.J. 2009). There, the patent-in-suit covered valganciclovir hydrochloride in crystalline form. The court, however, found that Roche failed to produce adequate proof that the accused Ranbaxy product, which was not crystalline, converted to the claimed crystalline form.
A patent claiming a metabolite was also at issue in Schering Corp. v. Geneva Pharmaceuticals, Inc., 339 F.3d 1373 (Fed. Cir. 2003). There, a prior art patent covered the drug loratadine, the active ingredient in Schering’s CLARITIN.® The patent-in-suit, issued later, covered a metabolite of loradine, “DCL.” Schering attempted to enforce the later-issued metabolite patent against the sale of loratadine, which converted to the claimed DCL in vivo. The conversion theory was again relied upon. However, since the prior art use of loratadine inherently produced the DCL metabolite, the later DCL patent was anticipated. Thus, in vivo conversion is a double-edged sword. If the earlier use of a prodrug produces the patented metabolite, the metabolite patent, even though infringed, would be invalid as anticipated. In this regard, the court in SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331 (Fed. Cir. 2005), held that the prior art production of the claimed hemihydrates through in vivo conversion anticipated the metabolite patent. Yet in Ortho-McNeil Pharmaceutical, Inc. v. Mylan Laboratories, Inc., 348 F. Supp. 2d 713 (N.D.W. Va. 2004), the court did not find anticipation because the defendant failed to prove that prior art use of a prodrug inherently produced the claimed metabolite. There is significant disagreement over the in vivo conversion theory. For example, in Marion Merrell Dow Inc. v. Baker Norton Pharmaceuticals, Inc., 948 F. Supp. 1050 (S.D. Fla. 1996), the patent-in-suit claimed terfinadine acid metabolite or TAM. The patentee alleged that Baker’s terfinadine product converted to TAM in vivo. The district court, however, never addressed conversion because it limited the patent to TAM produced synthetically, not by conversion. This construction was supported by: (1) the other claims, which were limited to pharmaceutical compositions, and therefore, could only be produced synthetically; (2) the failure of the specification to mention in vivo conversion; and (3) the prosecution history that described TAM as “essentially pure.” Similarly, the court in In re Omeprazole, 2001 WL 585534 (S.D.N.Y. 2001), limited the patent to synthetically-produced sulphencimides, not their metabolites.
While infringement claims for patents claiming metabolites may be possible, patents covering formulations seem to have a more difficult road. As one example, in Novartis Pharmaceutical Corp. v. Eon Labs Manufacturing, Inc., 363 F.3d 1306 (Fed. Cir. 2004), the patent-in-suit covered a specific hydrosol. Novartis, recognizing that Eon’s product did not literally infringe, argued that the claimed hydrosol was formed in vivo. The court limited the term “hydrosol” to a solution prepared outside the body. More recently, in Pfizer Inc. v. Teva Pharmaceuticals, 855 F. Supp. 2d 286 (D.N.J. 2012), the court limited a patented formulation containing a specific compound to the compound itself or its pharmaceutically acceptable salts. Even though the specification stated that the formulation could include prodrugs of the claimed compound, since the claims did not specifically mention prodrugs, they were not included. In sum, in vivo conversion, at least for product claims, may be a possible theory of induced infringement.
Method of Use Claims Infringement of method of use claims via in vivo conversion is even more challenging. In American Home Products Corp. v. Johnson & Johnson, 60 F.3d 843 (Fed. Cir. 1995), the patent-in-suit covered a method of preventing conception in a female by administering a progestationally effective amount of norgestrel acetate. The accused pharmaceutical converted to norgestrel acetate in vivo, but, as Johnson & Johnson argued, not in sufficient amounts to satisfy the “progestationally effective amount” limitation. Thus, infringement under the doctrine of equivalents, the only issue presented, was not found.
The American Home decision accentuates the problem in proving that an “effective amount” of a given metabolite is produced in vivo. Obviously, it would be difficult to establish the amount produced. Moreover, even if the amount could be ascertained, the question remains as to whether that amount is effective, especially when the amount is evaluated over the time of its production (e.g., CMAX, TMAX, etc.). However, despite these difficulties, it may still possible to satisfy the “effective amount” limitation – a limitation this is quite common in method of treatment claims.
In many decisions, however, that limitation is not determinative because courts have limited the term “administering” to “giving” the compound that a patient ingests. Thus, in Schering Corp. v. Mylan Pharmaceuticals, Inc., 2011 WL 2446563 (D.N.J. 2011), the relevant patent covered, inter alia, a method of treating or preventing atherosclerosis by administering an effective amount of ezetimibe. The district court limited the term “administering” “to provid[ing] externally by way of ingestion,” and excluded the metabolite formed in vivo. The court supported this construction by relying on the intrinsic and extrinsic evidence showing only oral dosage forms, e.g., capsules, tablets, and powders. See also Schering Corp. v. Glenmark Pharmaceuticals Inc., 2008 WL 4307189 (D.N.J. 2008). More recently, in Hoffmann-La Roche Inc. v. Apotex, Inc., 2010 WL 1875569 (D.N.J. 2010), the patent-in-suit covered a method of treating a disease by administering an effective amount of particular compounds. Once again, the court limited the term “administering” to the point at which the patient receives the medication, not what occurs thereafter.
It would appear that where patentees’ claim a method of administrating drug X, that’s what they get. Indeed, in In re Buspirone Patent Litigation, 185 F. Supp 2d 340 (S.D.N.Y. 2002), the claim covered the administration of a particular metabolite of buspirone. The court held that the claim was limited to the administration of the claimed metabolite, and not the prodrug. In fact, the court noted that it would be chemically incorrect to refer to a prodrug by the name of its metabolites.
Accordingly, especially with method of use claims, what one claims is exactly what one gets. Careful claim drafting is particularly important here.
If you have any questions about this article or would like to discuss this topic further, please contact the author, Brian Coggio, or your Fish attorney.