The U.S. Food and Drug Administration’s (FDA’s) approach to generic drug applications that seek approval for one or more, but not all, of the uses of a brand name “pioneer” drug has been evolving over time.
Generic drug makers sometimes seek “carve-outs” because of concerns about patent or statutory exclusivity rights that protect the carved-out uses but not the uses for which the generic applicant seeks approval. FDA’s recent Camptosar® decision has apparently resolved—perhaps conclusively—important questions surrounding whether and to what extent a generic drug applicant must match each of the pioneer drug’s labeled uses or whether certain uses of the pioneer drug can be carved out by the generic applicant as a result of patent or statutory exclusivity bars. For more information see FDA July 28, 2008, Decision Letter, Docket No. FDA-2008-P-0069 (denying Citizen Petition, available here .)
Moreover, as FDA’s interpretation of the law has evolved, the law of patent infringement in these circumstances has likewise been developing in parallel.
The Drug Price Competition and Patent Term Restoration Act of 1984, commonly called the Hatch-Waxman Act, Pub. L. No. 98-417, amended the Federal Food, Drug, and Cosmetic Act (FDC Act), to provide for, among other things, an abbreviated pathway for approval of generic versions of brand name drugs. The statute permits the filing of an abbreviated new drug application (ANDA) for a generic version that is the “same” as the approved brand name drug, the so-called “listed” drug, in terms of active ingredient, dosage form, strength, route of administration and, in general, labeling, and that is demonstrably “bioequivalent” to the listed drug.
The Hatch-Waxman Act also provides a mechanism intended to protect the patent rights of the holder of the approved application for the listed brand name drug by requiring that the ANDA applicant “certify” as to the status of patents “claiming” the drug or a “method of using such drug;” by establishing a system for resolving patent challenges in federal district court in a timely manner; and by providing a 30-month stay of FDA approval of the generic (that can be shortened or lengthened by the court) once patent litigation is initiated on certified patents—categorically prohibiting FDA approval of the generic drug even if the ANDA otherwise meets the criteria for approval established by the statute and the agency’s implementing regulations.
However, an ANDA applicant may elect not to certify with respect to each and every method of use patent, and instead may elect to submit a so-called “section viii” statement stating that the applicant is not seeking approval to market the product for one or more patented methods of use covering the listed drug. Where the listed drug is marketed and labeled for a patented method of use for which a section viii statement has been filed by the ANDA applicant, there exists a divergence between the labeling for the listed drug and the labeling for the proposed generic drug subject to the ANDA. This divergence of labeling arguably undercuts the sameness requirement that is the conceptual predicate for generic drug approvals. In other words, in this context, the proposed labeling for the generic drug may well be substantially different from the labeling for the listed drug because it might omit one or more methods of use for which the listed drug is labeled and approved. The question raised is whether this lack of sameness in the labeling precludes approval of ANDAs with method of use labeling carve-outs.
FDA’s Camptosar Label Carve-Out” Decision
Camptosar® (irinotecan hydrochloride) is approved for use in the treatment of patients with metastatic cancer of the colon or rectum. The pioneer drug is approved for both “first line” use in combination with certain other chemotherapeutic agents, and for “second line” use as a “monotherapy.” The first line combination drug use is subject to a method of use patent, whereas the patent for the second line monotherapy use has since expired, as has a period of statutory “pediatric exclusivity.”
A Citizen Petition was filed asking FDA to reject any ANDA that referenced Camptosar® as the listed drug and that attempted to carve-out the still patent-protected first line combination drug method of use. The Petitioner argued, among other things, that any such carve-out ANDA would render the generic drug “less safe or effective” than Camptosar®, even for the non-patent-protected second line use as a monotherapy. Under FDA’s regulations, such a finding of lesser safety or effectiveness for the non-patent-protected use is a basis for the agency’s refusal to approve an ANDA. Indeed, the Petitioner argued that labeling that omits information on the “first line” combination use of irinotecan will render the drug product less safe and effective than Camptosar® for all approved conditions of use because the “pioneer” drug is approved to be used in combination with other chemotherapy agents, any generic version would likely be so used, and the product is toxic if dosed or used improperly in the course of such “combination” drug first line use. In other words, Watson argued that the foreseeable off-label use as a first line combination therapy of a generic irinotecan only approved for second line use as a monotherapy was an independent justification for FDA’s rejection of carve-out ANDAs for the drug, especially in light of mandatory state substitution laws.
FDA had little difficulty rejecting the Petitioner’s arguments on all counts, pointing to a number of recent administrative decisions along the same lines. (See FDA Decision Letter at 12.)
First, the agency, citing court decisions in analogous but slightly different contexts, as well as the literal terms of the Hatch-Waxman Act itself, concluded unequivocally that: “The right to file a section viii statement and carve out from labeling method-of-use information protected by a patent has been upheld by the courts . . . [A] ‘section viii’ statement indicates that a patent poses no bar to approval of an ANDA because the applicant seeks to market the drug for a use other than the one encompassed by the patent.” (Id. at 6.)
Second, FDA also rejected the Petitioner’s argument that because state mandatory substitution laws resulted in the generic drug being used for the carved-out indication, the agency should refuse to approve ANDAs for Camptosar®: “The existence of state generic drug substitution laws, which might require the substitution of a generic irinotecan for Camptosar®, also provides no basis for refusing to approve an irinotecan ANDA. We acknowledge that in some states a generic irinotecan product might be substituted for Camptosar® even when the drug is intended to be used in combination with 5-fluororacil and leucovorin, but we have no control over the operation of these substitution laws.” (Id. at 11.)
Third, and interestingly given the government’s concern about off-label use in a variety of unrelated contexts, FDA rejected the Petitioner’s off-label foreseeability argument. According to the agency, adopting the Petitioner’s argument “. . . would create new approval requirements beyond those established by Congress and the Agency. In addition, it would be inconsistent with our long-standing policy of not interfering with the practice of medicine, in particular with physicians’ ability to prescribe approved drug products for their patients for any purpose deemed appropriate in their professional judgment.” (Id. at 13.) Of course, this language does not give the ANDA holder the right affirmatively to promote its product for the unapproved, carved-out use, which may well amount to an “inducement” to patent infringement, as discussed below, as well as constituting an independent FDC Act violation. At the same time, it does reinforce FDA’s ambivalence about off-label use generally that may well be relevant in different contexts beyond the scope of this article.
Lastly, and as a factual matter, FDA likewise rejected Petitioner’s lesser safety or effectiveness argument, concluding in this instance the “. . . information regarding the protected [indication] is not necessary to make irinotecan safe and effective for the remaining, second-line, non-protected conditions of use.” (Id.)
Based on FDA’s analysis, it appears that the only argument likely to gain much traction in a future label carve-out controversy is one that persuades the agency that there is an affirmative safety or effectiveness problem with the generic drug as contrasted with the pioneer drug when the generic is labeled only for the non-protected uses.
Inducing Patent Infringement and the Hatch-Waxman Act
Even though there may be no FDA remedy in these circumstances, this does not foreclose the possibility of patent infringement litigation against the ANDA holder (either before FDA approval or after marketing of the drug) for inducing infringement by promoting its product for the carved-out, patent-protected use. “Inducement” means that although the “infringer” has not directly practiced the patented method, it has actively and knowingly caused others to use the same. In the context of method-of-use patents covering particular treatment uses, someone will be deemed an inducer of infringement if the person actively encourages purchasers of the drug to use it in a way that is patented, albeit that the particular use in question is either carved-out of the label or otherwise unapproved by FDA. Such patent inducement lawsuits can be pursued against ANDA holders or even doctors for prescribing the drug for a patent protected use for which the generic drug is not approved. However, doctors are almost never sued, both because they are “customers” of the patent holders, and because lawsuits against doctors are impractical inasmuch as they would require countless actions against countless defendants to counter widespread infringement effectively.
The courts have recognized limited statutory bases for jurisdiction to hear patent inducement cases involving uses of a drug for carved-out or unapproved (i.e., off-label) indication.
Patented but Not FDA-Approved Uses (Off-Label)
For example, where the generic applicant has sought approval for only one use of a drug, and other uses are patented but not FDA-approved, a patentee can sue for infringement pursuant to the basic inducement-to-infringement statute, 35 U.S.C. § 271(b). In this circumstance, there is generally no infringement suit permitted pursuant to the Hatch-Waxman Act, 35 U.S.C. § 271(e)(2).
A section 271(b) lawsuit brought before actual marketing of the generic drug has occurred (e.g., during the ANDA application process) might conceivably be brought as a Declaratory Judgment Act action—seeking a declaration that the generic manufacturer will induce infringement when it ultimately markets its product.
Patented and FDA-Approved Uses (Label Carve-Out)
Where the generic applicant seeks approval for a particular use of a drug and other uses are patented and also FDA-approved, the patentee can allege inducement pursuant to both 35 U.S.C. §§ 271(b) and 271(e)(2).
Proof of Inducement: the Specific Intent Requirement
Despite recognizing some statutory bases for potential theories of inducement, the courts require specific proof of intentional acts before infringement will be found. Thus, in one leading case, the court stated that “[M]ere knowledge of possible infringement by others does not amount to inducement; specific intent and action to induce infringement must be proven. . . . Thus if a physician, without inducement by [the generic manufacturer], prescribes a use of gabapentin in an infringing manner, [the generic manufacturer’s] knowledge is legally irrelevant. . . . Especially where a product has substantial noninfringing uses, intent to induce infringement cannot be inferred even when the defendant has actual knowledge that some users of its product may be infringing the patent.”
FDA’s Camptosar® label carve-out decision appears to be the final word from the agency on the approvability of ANDAs in these circumstances. At the same time, the possibility of litigation against an ANDA holder for inducing “patent infringement,” as well as the prospect of violating the prohibition against off-label promotion, may well temper the enthusiasm that ANDA holders might otherwise have for encouraging use beyond the scope of the approved ANDA.
Moreover, FDA’s decision in this case is not dispositive of how Congress may address label carve-outs in the context of follow-on biologics, which are currently not covered by the Hatch-Waxman Act but are the subject of pending legislation. Given the greater complexity of biologics and the greater possibility of safety and effectiveness concerns, the label carve-out problem may pose an array of different considerations in that context and may well be resolved differently. Manufacturers of pioneer biologics might usefully seek to persuade Congress to resolve the carve-out problem differently from how it has been resolved by FDA under the Hatch-Waxman Act in whatever follow-on biologics approval pathway is ultimately enacted.