The law surrounding United States Food and Drug Administration (“FDA”) Section viii certifications is currently in flux due to two recent decisions of the United States Court of Appeals for the Federal Circuit, Novo Nordisk v. Caraco Pharm. Labs., Ltd. and AstraZeneca LP v. Apotex, Inc. The importance of this area of law is highlighted by the amicus curiae briefs filed by the Solicitor General and five major generic industry groups requesting that the Supreme Court grant certiorari in Novo Nordisk.

Background

A Section viii statement is a certification submitted under 21 U.S.C. § 355(j)(2)(A)(viii). The Section viii certification states that an Abbreviated New Drug Application (“ANDA”) applicant (an applicant for a generic drug equivalent to a patented reference drug) is seeking to market a drug for a method of use that is not covered by any patent listed in the FDA’s Approved Drug Products with Therapeutic Equivalence and Evaluations listing (referred to as the “Orange Book”) for the reference drug. Id. Along with a Section viii statement, the applicant must also submit a proposed label that does not contain any mention of the patented method of use. Id. The proposed label that accompanies a Section viii statement “carves out” the language relating to the patented method of use, which is why such labels are often referred to as “skinny labels.”

The Section viii certification may only be approved if the composition patents covering the reference listed drug have expired, or will expire, prior to the date of the proposed marketing and sale of the generic drug. In addition, there must be no overlap between the proposed carve-out label and the use code narrative submitted by the patentee or “innovator” manufacturer. Novo Nordisk v. Caraco Pharm. Labs., Ltd., 601 F.3d 1359, 1361-62 (Fed. Cir. 2010).

Section viii certification provides an alternative to filing the more common Paragraph I, II, III, and/or IV certifications with an ANDA. One advantage of Section viii certification is that it will not by itself delay the approval of an ANDA, in contrast to a Paragraph III or IV certification.

Recent Case Law

Novo Nordisk v. Caraco Pharm. Labs

In Novo Nordisk v. Caraco Pharm. Labs., Novo owned a patent to a method of treating diabetes using a combination therapy of repaglinide and metformin. 601 F.3d 1359, 1361-62 (Fed. Cir. 2010). The method of treating diabetes was one of three FDA-approved uses of repaglinide. Novo also owned the composition patent covering the reference drug for repaglinide.

Caraco filed an ANDA with a Section viii statement requesting approval for repaglinide as a sole therapeutic agent, without metformin. Two years after this filing, Novo filed an infringement suit against Caraco.

The FDA revised the approved indications for repaglinide and required Novo to change its label. The original use code required a combination of repaglinide and metformin to lower blood glucose. The new use code was broadly directed to a method for improving glycemic control in adults with Type 2 diabetes. The general language encompassed not only Novo’s combination therapy, but also Caraco’s proposed monotherapy label. Since the FDA approves a Section viii statement only where there is no overlap between the proposed label and the use code, the FDA disallowed Caraco’s Section viii statement.

Caraco added a counterclaim requesting that Novo be ordered to reverse its use code to the original code because the new code covered all methods of use, while Novo had a patent covering only one method. Caraco also added a patent misuse defense, asserting that Novo misrepresented the scope of its patent in its use code narrative. Id.

The counterclaim was based on the 2003 Medicare Prescription Drug Improvement and Modernization Act of 2003 (the “Hatch-Waxman Act”), Pub. L. No. 108-173, 117 Stat. 2066 (2003). The Hatch-Waxman Act provides a counterclaim to a charge of patent infringement to permit challenges on the ground that an asserted patent does not claim either “(aa) the drug for which the application was approved; or (bb) an approved method of using the drug.” 21 U.S.C. § 355(j)(5)(C)(ii)(I). The counterclaim provision allows an ANDA filer to request an order compelling an NDA holder to correct or delete “patent information.” Id. The district court granted Caraco’s motion for summary judgment on the counterclaim and entered a mandatory injunction directing Novo to change its use code narrative.

The Federal Circuit granted Novo’s motion for expedited appeal and reversed and vacated the injunction. The Federal Circuit overturned the grant of summary judgment as to the counterclaim, holding that “an approved method” meant “any approved method,” so that the use code on repaglinide was proper because it covered one of the three approved methods of use. Novo Nordisk, 601 F.3d at 1635. Additionally, the “patent information” referenced in the Hatch-Waxman Act’s counterclaim provision was, the court held, limited to patent number and expiration date, and thus did not apply to use codes. Id. Finally, the Federal Circuit refused to address Caraco’s patent misuse defense because the district court had expressly declined to address the issue. Caraco then sought a writ of certiorari from the United States Supreme Court, which was granted on June 27, 2011.

AstraZeneca LP v. Apotex, Inc.

A second recent Section viii case dealt with the novel question of whether label language was evidence of induced patent infringement. AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042, 1046 (Fed. Cir. 2010). AstraZeneca owned two method-of-use patents covering once-daily budesonide, both listed in the Orange Book. The product label recited both once- and twice-daily administration of the active ingredient. Importantly, budesonide belongs to a class of drugs for which the FDA has mandated language regarding “downward titration.” The downward titration language advised a patient to use the lowest effective dose and to lower the dose as soon as the patient found the dose to be effective.

Apotex submitted an ANDA with a Section viii statement drawn to budesonide for twice-daily administration along with a proposed label removing all mention of once-daily dosing, but containing the “downward titration” language. After the FDA approved this label, AstraZeneca filed a declaratory judgment motion requesting that Apotex’s ANDA be deemed to induce infringement of AstraZeneca’s method of use claims and moved for a preliminary injunction. The district court held that Apotex had demonstrated the requisite acts and specific intent required for induced infringement, and issued a preliminary injunction against Apotex.

Apotex appealed. Treating the issue as a matter of first impression, the Federal Circuit affirmed the district court’s finding of induced infringement and the grant of the preliminary injunction. While the Federal Circuit acknowledged that there might be substantial non-infringing uses of Apotex’s proposed product, the court found that Apotex had evinced the requisite specific intent to induce infringement, and had taken steps to actively induce infringement by users. Regarding active inducement, Apotex was only seeking approval for two dose strengths, 0.25 mg and 0.5 mg. Each dose had to be administered in its entirety and could not be subdivided. The recommended dose on the label for a significant number of patients was 0.5 mg, so the downward titration language would cause at least some patients to use a lower dose, and this could only be accomplished through a once-daily 0.25 mg dose of the Apotex product. Thus, the Federal Circuit held that the label itself suggested an infringing use.

The Federal Circuit noted that a citizen’s petition filed by AstraZeneca, regarding an earlier, and virtually identical, ANDA submitted by IVAX, was evidence of specific intent to induce infringement. In the petition, AstraZeneca had argued that all labels for a budesonide formulation had to include once-daily dosing language, and questioned the necessity of including “downward titration” language. The FDA issued a letter stating that the “downward titration” language did not teach once-daily administration because it did not specify or instruct once-daily administration, although downward titration “could” mean using only one dose a day. Id. at 1057-58. The Federal Circuit found that the citizen’s petition put Apotex on notice that downward titration might involve once-daily dosing. Id. at 1058. After becoming aware of this petition, Apotex attempted to amend its label to remove the downward titration language and to add language specifying that the budesonide should only be administered twice-daily. The FDA rejected both proposed changes.

Given Apotex’s knowledge of potential problems with the label, the court found that its inclusion of the downward titration language and its decision to proceed with its label were both evidence of affirmative intent to induce patients to infringe AstraZeneca’s patents. Id. The Federal Circuit also found that Apotex’s failure to exhaust all administrative remedies, such as appealing the FDA’s denial of its proposed label, was further evidence of this intent.

The Federal Circuit was not persuaded by Apotex’s arguments that it faced a dilemma; either to comply with the FDA requirements and risk a patent infringement action, or to remove the downward titration language and have the FDA deny the ANDA. The Federal Circuit noted that Apotex had other options. Apotex could have waited until AstraZeneca’s patents expired to launch its product, or could have filed a Paragraph IV certification to challenge the patents. Additionally, Apotex could have appealed the FDA’s rejection of its proposed label. Another option would have been for Apotex to propose to launch lower budesonide doses, which would have allowed downward titration with twice-daily administration.

Although the Federal Circuit in AstraZeneca never specifically addressed the issue of induced infringement through “off-label” use (for clinical indications other than those specifically approved by the FDA), an earlier Federal Circuit case cited in AstraZeneca is instructive. In Warner-Lambert Co. v. Apotex Corp., the Federal Circuit held that there was no induced infringement based on a Section viii-certified product that could potentially be used for an infringing non-FDA approved use. 316 F.3d 1348 (Fed. Cir. 2003). The Supreme Court has recently clarified that induced infringement “requires knowledge that the induced acts constitute patent infringement,” and that this knowledge requirement is satisfied by willful infringement but not by “deliberate indifference to a known risk.” Global-Tech Appliances, Inc. v. SEB S.A., 131 S.Ct. 2060, 2068 (2011).

In Warner-Lambert, the innovator owned a patent on a method of treating epilepsy and related disorders using gabapentin (marketed under the brand name Neurontin), which was the only FDA-approved method of using gabapentin. Warner-Lambert also owned a method of use patent to gabapentin for the treatment of neurodegenerative disorders, a use that was listed in the Orange Book, but was not approved by the FDA. Apotex submitted a Paragraph IV certification stating that the product would not be marketed until the epilepsy patent expired, and that Apotex was not seeking approval for any neurodegenerative methods of use. The Federal Circuit characterized the latter statement as “effectively” a Section viii statement with respect to the neurodegenerative method of use. Warner-Lambert at 1360.

At trial, Warner-Lambert presented evidence that in 1998, the year that the generic applicant filed an ANDA application, only 22% of the prescriptions for gabapentin were for the FDA-approved use. The remaining 78% of prescriptions were for off-label uses, including treating neurodegenerative disorders. Warner-Lambert also presented evidence that the following year, the number of off-label uses had increased to 89%. Warner-Lambert claimed that the generic’s product would similarly be used for off-label use, including the infringing method of use. However, as noted by the Federal Circuit, only about 2.1% of gabapentin prescriptions were for neurodegenerative diseases.

As evidence of induced infringement, Warner-Lambert argued that off-label use is both common and supported by both the FDA and the American Medical Association (“AMA”). Warner-Lambert noted that information about such uses is readily available. Warner-Lambert further argued that pharmacists and other drug dispensers routinely substitute generic drugs for brand name drugs, and in some cases such substitution is mandatory. In addition, Warner-Lambert noted that Apotex expected to get an “A-B” rating for gabapentin, which would allow physicians and pharmacists to substitute it for the name brand drug regardless of the indication for which it is used. Finally, Warner-Lambert argued that Apotex should be assumed to have considered the market size and growth potential of gabapentin when it decided to enter the market.

The Federal Circuit was not persuaded, and upheld the district court’s grant of summary judgment of non-infringement. The Federal Circuit held that even if all of these arguments were true, Warner-Lambert had failed to prove specific intent and actions to induce infringement. In the absence of any evidence that Apotex had promoted its gabapentin product in an infringing manner, or would do so in the future, it was irrelevant whether Apotex knew that doctors would prescribe the drug for the infringing use. Furthermore, the induced infringement statute did not provide for liability in cases in which a generic maker may “someday” induce someone to infringe, since such inducement can only be determined when that infringing act occurs. The Federal Circuit concluded that it “defie[d] common sense” to expect Apotex to actively promote the sale of its gabapentin for a non-approved use that was both infringing and constituted such a small fraction of sales. Id. at 1364.

Discussion

Because a Section viii statement potentially allows an ANDA filer to obtain approval of a generic drug without delay, it is of considerable interest to both innovator and generic companies. In addition, as noted in Warner-Lambert, physicians routinely prescribe generic drugs as a substitute for name brand medications, and some physicians will also prescribe such generics for off-label and patented methods of use.

Until the Supreme Court renders its decision in Novo Nordisk, the Federal Circuit’s decisions in Novo Nordisk and AstraZeneca define the current Section viii jurisprudence. In AstraZeneca, the Federal Circuit found that an implicit mention of an infringing method of use on a label coupled with knowledge that such mention would lead some users to infringe was sufficient to support a holding of induced infringement. In Novo Nordisk, the Federal Circuit held that a use code may be broad enough to delay a Section viii certification even where there are no applicable method of use patents listed in the Orange Book. Additionally, the earlier decision in Warner-Lambert noted that induced infringement may be found when the generic company actively promotes or advertises an infringing use to physicians and/or drug dispensers.

Based on these cases, innovator and generic companies should carefully consider how they manage labels, use codes, and other FDA-related procedures with respect to Section viii statements. Importantly, the labeling decisions made by the FDA may have potentially serious effects on the availability of a Section viii certification. In the Novo Nordisk decision, the FDA changed the repaglinide reference product label and allowed Novo to obtain a broader use code, which caused the FDA to disallow Caraco’s ANDA. Similarly, in the AstraZeneca case, the FDA’s mandate of downward titration language on the budesonide label enabled AstraZeneca to delay any generic product with the same doses from launching.

The AstraZeneca case also demonstrates the importance of FDA administrative procedures. The FDA’s stated belief of non-infringement in a letter responding to AstraZeneca’s Citizen Petition regarding a different applicant’s ANDA was one of the crucial pieces of evidence supporting specific intent to induce infringement. In that decision, Apotex was also penalized for having failed to exhaust all available FDA remedies, including appealing the FDA’s decisions, because the Federal Circuit interpreted this as evidence that Apotex was not trying to avoid infringement. The Federal Circuit was not persuaded by Apotex’s Director of Regulatory Affairs stating, perhaps correctly, that she believed that this appeal was “futile” based on her conversations with the FDA.

The Supreme Court’s decision in Novo Nordisk is likely to provide clarity on the issue of whether a Section viii ANDA applicant may raise a counterclaim to change the use code for a reference drug. Regardless of the outcome of this case, Section viii certifications will continue to be an important area of law for innovator and generic pharmaceutical companies to monitor.