Orange Book

FDA's Orange Book preface says the publication is composed of four parts²:

• the Prescription Drug Product List²;
• the OTC Drug Product List²;
• the list of drug products with approval under section 505 of the FD&C Act administered by the Center for Biologics Evaluation and Research²;
• and the Discontinued Drug Product List².

The preface describes an Addendum that contains patent and exclusivity information for the listed products². FDA says the Orange Book data files are updated monthly¹. The statute separately requires FDA to revise the list every 30 days to include newly approved drugs, and to specify each applicable exclusivity period that has not yet expired³. For how generic exclusivities such as 180-day exclusivity are recorded, see Paragraph IV certification.

The preface says approved drug products are considered therapeutic equivalents if they are pharmaceutical equivalents for which bioequivalence has been demonstrated, and they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling². Generally, prescription drug products that FDA considers multisource have been assigned a therapeutic equivalence code².

The preface also says the Orange Book does not mandate which drug products are purchased, prescribed, dispensed, or substituted for one another². A product that reached the market through the 505(b)(2) route is not necessarily rated therapeutically equivalent to the listed drug it references⁸. See Abbreviated New Drug Application.

Patent information comes from the sponsor of a new drug application, not from FDA. The statute requires the application to include the patent number and expiration date of each patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner engaged in the manufacture, use, or sale of the drug, and that claims the drug as a drug substance or drug product patent, or claims a method of using the drug for which approval is sought or has been granted (21 U.S.C. 355(b)(1)(A)(viii))³.

• Timing. Within 30 days after the date of approval of its NDA or supplement, the applicant must submit Form FDA 3542 for each qualifying patent. FDA will not list or publish patent information that is not provided on that form (21 CFR 314.53(c)(2)(ii))⁴. For a patent issued after approval, the statute requires the holder to file the information not later than 30 days after the patent is issued, and it requires FDA to publish it on submission (21 U.S.C. 355(c)(2))³.
• What FDA publishes. FDA publishes the patent number and expiration date, and for a method-of-use patent the description of the method of use claimed (21 CFR 314.53(e))⁴.
• Extended terms. If the term of a listed patent is extended under 35 U.S.C. 156(e), the NDA holder must submit a correction of the expiration date within 30 days of receiving the certificate of extension (21 CFR 314.53(f)(2)(ii))⁴. See Patent term extension.
• FDA's role. FDA says its patent listing role is ministerial⁵.

These are two different things. A patent challenge goes to whether a listed patent is invalid or not infringed. A listing dispute goes to whether a patent should be listed, or listed with that description of use^3,4.

1. Challenge the patentA generic applicant must certify, for each listed patent that claims the reference drug or a use of it for which approval is sought, that patent information has not been filed, that the patent has expired, the date it will expire, or that it is invalid or will not be infringed. That last option is a paragraph IV certification (21 U.S.C. 355(j)(2)(A)(vii))³. FDA says the first applicant or applicants to submit an application that FDA determines to be substantially complete and that contains a paragraph IV certification to at least one patent listed in the Orange Book are generally eligible for 180-day exclusivity⁶. See Paragraph IV certification.
2. Dispute the listing with FDAA person who disputes the accuracy or relevance of listed patent information, or who believes the NDA holder failed to submit required patent information, must first notify FDA in a communication titled 314.53(f) Patent Listing Dispute⁴. FDA sends the statement of dispute to the NDA holder, who has 30 days from the date FDA sends it to confirm the correctness of the information, with a signed verification, or to withdraw or amend it. Unless the NDA holder withdraws or amends the information in response to a dispute about a drug substance or drug product claim, FDA will not change the Orange Book entry⁴.
3. Counterclaim in an infringement suitIf the patent owner or brand holder sues the applicant for infringement, the applicant may assert a counterclaim seeking an order requiring the holder to correct or delete the patent information, on the ground that the patent claims neither the approved drug nor an approved method of using it. The statute does not allow that claim in any other civil action or proceeding, and no damages are available (21 U.S.C. 355(j)(5)(C)(ii))³.
4. Delisting by the NDA holderIf the NDA holder determines that a patent no longer meets the listing requirements, including after a final judicial finding of invalidity, it must promptly notify FDA to amend or withdraw the patent information. FDA removes a patent from the list only if no first applicant is eligible for 180-day exclusivity based on a paragraph IV certification to that patent, or after that first applicant's 180-day period has expired or been extinguished (21 CFR 314.53(f)(2)(i))⁴.

FDA's Orange Book page also hosts a Patent Listing Dispute List with the relevant drug product information and the disputed patent¹. A 505(b)(2) application or ANDA must contain an appropriate certification or statement for each listed patent, including a disputed one, during and after a listing dispute⁴. For the effect of a challenge on market entry, see Patent cliff.