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Aug 9, 2012

Battles Over FDA Use Code Challenge Branded Drug Exclusivity

Brand manufacturers should design their regulatory strategies carefully in light of their patent protection.

  • Successful marketing of pharmaceutical drugs can be put at risk if the approval to market a new drug with the Food and Drug Administration (FDA) is not carefully conducted in parallel with the issuance of patents from the U.S. Patent and Trademark Office (USPTO).

    Two recent Federal Circuit decisions, Novo Nordisk A/S v. Caraco Pharmaceutical Laboratories, Ltd. (2012) and AstraZeneca Pharmaceuticals LP v. Apotex Corp., 669 F.3d 1370 (2012), remind us of the painful outcome—the inability to delay generic-drug competition—when clinical and marketing activities are not fully aligned with patent strategies. Methods-of-use patents may not be effective to delay market entry of the generic drug.

    However, these decisions left unaffected a 2010 decision from the same court more favorable to AstraZeneca in a similar situation against Apotex (633 F.3d 1042). In tandem, these cases show the risk posed by a generic rival’s early market entry when patent protection on methods of use proves deficient. This risk may be lessened by a thoughtful dual-patent regulatory strategy, which would involve seeking patents that take advantage of restriction of use in drug labels.

    Ever since the enactment of the Hatch-Waxman Act in 1984, pharmaceutical companies producing brand-name drugs have been losing their foothold in the marketplace. The Act created a streamlined process for generic manufacturers to get approval for generic versions of drugs (the Abbreviated New Drug Application or ANDA).

    The Act simplifies the requirements for marketing approval with the express aim of lowering the barrier to market entry of generic versions of drugs no longer covered by patents. Since the efficacy of the previously approved drug had already been demonstrated by the brand name manufacturer, the generic manufacturers only need to show that the generic drug has the same bioavailability as the branded drug.

    To further encourage generic manufacturers to file ANDAs and to facilitate the process of navigating the patent minefield, the Act created a register, “the Orange Book,” in which the brand name manufacturer must disclose its patents covering the composition of matter of the drug and its use as stated in the approved indication(s). In exchange for this disclosure, the Act requires the generic manufacturers to make a certification regarding enforceable listed patents: that such patents are invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted.

    The Act made it an act of infringement to submit an ANDA with a paragraph IV. However, the generic manufacturer may choose instead to file a statement under Section viii if the listed enforceable patents for the drug cover only methods of use for an approved indication that the generic manufacturer will “carve out” from his application.

    This last provision came into play in three situations, two of which were unfavorable for the brand-name drug manufacturers.

    Novo Nordisk markets Prandin® (repaglinide) for the treatment of type II diabetes. Prandin® was approved at the FDA for use by itself, or in combination with metformin or TZDs. Novo owned two patents, one on the composition of repaglinide alone, which has since expired in 2009, and one on the method of treatment using repaglinide in combination with metformin, which will expire in 2018. Novo listed the latter patent with a use code reflecting the approved indications. In 2005, Caraco filed an ANDA with a paragraph IV certification to market repaglinide alone once the patent on the composition has expired.

    After Novo initiated suit, the FDA suggested that Caraco amend its ANDA to remove the certification and instead make a statement under Section viii, carving out the combination with metformin. In the meantime, Novo amended its use code for its method patent to read “a method for improving glycemic control in adults with type II diabetes mellitus.” The FDA then refused to grant Caraco marketing approval even under Section viii, because the new use code encompassed the use of the drug alone.

    In a counterclaim, Caraco demanded that Novo amend its use code to reflect the actual coverage of the method patent. Novo challenged the legal basis of the counterclaim and defended its right to the broad use code. The Supreme Court sided with Caraco and remanded the case for further review. The Appeal Court now requires that Novo correct its use code to reflect the scope of the patent.

    AstraZeneca holds three patents covering Crestor® (rosuvastatin calcium), a cholesterol-lowering drug. One covers the composition of matter, a second patent covers a method of treating heterozygous familial hypercholesterolemia (a genetic condition associated with elevated cholesterol), and the third a method for treating people with elevated C-reactive protein at risk of cardiovascular disease. Astra’s approved label was directed to these indications, but also for the treatment of two other conditions that were not covered by the last two patents.

    Apotex and other drug manufacturers submitted ANDAs seeking FDA approval for generic versions of rosuvastatin calcium for the two approved indications that were not covered by Astra’s method-of-use patents. Apotex submitted a Section viii statement asserting that the ANDA carves out all uses claimed in Astra’s patents.

    AstraZeneca sued the generic manufacturers, alleging that they would infringe its patents because, once approved by the FDA, generic rosuvastatin will inevitably be prescribed and administered to treat the indicated diseases covered by AstraZeneca’s patents. The court disagreed, finding that such assertions had no basis under the Hatch-Waxman Act.

    The court said that accepting AstraZeneca’s argument would make it impossible for ANDA applicants to avail themselves of Section viii with a label that “explicitly and undisputedly” excludes the patented indications. The court criticized AstraZeneca’s speculation regarding off-label use, noting that its argument would potentially allow the brand manufacturer to maintain exclusivity indefinitely.

    In a 2010 case, AstraZeneca fared better in challenging Apotex when the latter filed Section viii statements. Astra won a preliminary injunction barring Apotex from marketing a generic version of budesonide, an anti-inflammatory corticosteroid for the treatment of asthma, despite the fact that the FDA had granted approval to Apotex based on a Section viii statement. AstraZeneca had obtained a patent for a method of treating a respiratory disease by administering budesonide in a regimen of “not more than once a day.” Apotex’s Section viii statement requested that the label not mention “once a day” administration. Nonetheless, Apotex’s label required that the drug be titrated down to the lowest effective dose as in the Astra label. The court concluded that titrating would lead at least some patients to a treatment of once a day.

    A brand manufacturer must be watchful when seeking indications that are no longer covered by composition-of-matter patents. A brand manufacturer may be better positioned to fight against carveouts under Section viii if it can obtain a label that is limited to the patented indications. Thus, brand manufacturers should design their regulatory strategies carefully in light of their patent protection.


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