On October 6, 2016, FDA published a final rule implementing portions of Title XI of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) that govern ANDAs and 505(b)(2) NDAs.1 The 79-page final rule implements a number of important provisions on a range of subjects, including:

  • Submission of patent information by NDA holders;
  • Notice to patent owners and reference product sponsors of certain patent certifications made by 505(b)(2) NDA and ANDA applicants;
  • The availability of 30-month stays of approval on 505(b)(2) NDAs and ANDAs that are otherwise ready to be approved;
  • Submission of amendments and supplements to 505(b)(2) NDAs and ANDAs; and
  • The types of bioavailability and bioequivalence data that can be used to support 505(b)(2) NDAs and ANDAs.

Although there is much to be digested in the coming months, what follows is a summary of some of the significant provisions of the final rule:

The NDA holder must also identify whether the patent has previously been submitted, and if so, whether the changes to the information are related to the patent or to an FDA action. FDA omitted a proposed requirement for an NDA holder to specify whether a patent is a reissued patent.

The enhanced procedure for correcting patent listings is designed to force the NDA holder to create a "road map" to allow the patent challenger to carve protected information out of its labeling. FDA has previously had mixed results in its ability to compel NDA applicants to specifically relate a given patent to the approved labeling. In theory, the narrative requirement forces the NDA applicant to connect the patent to specific language in the labeling. Because the process will now be made public, this "road map" will also be available to other applicants.

  • Submission of Patent Information. In an effort to restrain overbroad use codes, FDA is requiring an NDA holder's use code to describe only the specific approved method of use claimed by the patent for which a claim of patent infringement could reasonably be asserted. For a method-of-use patent, the NDA holder must identify with specificity the sections and subsections of the labeling that describe the use claimed by the patent. Even more, the agency is now requiring that where the patent is broader than the labeled indication or other protected condition of use, the use code must specify the indication or condition of use, rather than reflect the terms of the patent.
  • Timing of Submission of Patent Information. Seeking to deter manipulation of use codes to delay approvals, FDA has expanded the category of untimely filed patent information to include an amendment to a use code that (1) is submitted more than 30 days after patent issuance without a corresponding product labeling change, or (2) is submitted more than 30 days after approval of a corresponding labeling change. This does not apply to updated information submitted within 30 days of a decision by the U.S. Patent and Trademark Office or of a federal court that alters construction of a method-of-use patent claim. Also, if an NDA holder changes its listed patent information within 30 days of the completion of the revised patent listing dispute procedure described below, the change will be considered timely filed.
  • Correction or Change of Patent Information. The final rule establishes additional requirements for patent listing dispute procedures, including:< >An applicant challenging a method-of-use patent must provide a narrative description (fewer than 250 words) describing the challenger's interpretation of the scope of the patent.The NDA holder must respond to the challenge within 30 days, with a narrative description either confirming or amending the patent information, including an explanation of why the existing or amended use code describes the specific method of use for which a claim of patent infringement could "reasonably be asserted." This response must contain a verification of the accuracy and completeness of the submission of patent information, under penalty of perjury.
  • Notice of Paragraph IV Certification – Timing. The regulations will now clearly identify two outside limits on the timing for sending notice of a paragraph IV certification: (1) the earliest date on which notice may be given (codifying FDA's longstanding practice regarding premature notice); and (2) the latest date by which notice may be given and considered timely.
    • A 505(b)(2) NDA applicant cannot send notice of Paragraph IV certification until the date on which the application is filed as described in 21 CFR 314.101(a)(2) or (3); an ANDA applicant cannot send notice until the date on which it receives a "paragraph IV acknowledgment letter" from FDA.
    • Both 505(b)(2) NDA and ANDA applicants must send notice no later than 20 days after the postmarked date of the paragraph IV acknowledgment letter.
    • The sponsor of an amendment or supplement with a paragraph IV certification must send notice at the same time the amendment or supplement is submitted.
    • With regard to patents that are newly listed while an ANDA is pending, the ANDA applicant cannot send notice of a paragraph IV certification before the first working day after the day the patent is published in the Orange Book.
  • Notice of Paragraph IV Certification – Content and Methods. The final rule revises the content of the paragraph IV certification notice to implement MMA provisions. It also reduces the burdens on 505(b)(2) NDA and ANDA applicants by permitting the notice to be sent by "designated delivery services" (in addition to registered or certified mail currently required), and allowing an applicant to submit a single amendment regarding receipt of multiple paragraph IV certification notices (rather than having to submit an amendment with regard to each notice, as is currently required).

FDA had proposed to establish "administrative consequences" for ANDA applicants who failed to send notice within the statutory timeframe, but this is not included in the final rule.

  • Amended Patent Certifications. Codifying FDA's established practice, the final rule provides that FDA will not remove a withdrawn patent from the Orange Book until the agency has determined that there is no first ANDA applicant eligible for 180-day exclusivity, or that any 180-day exclusivity period based on the patent has expired or been extinguished. Additionally, a 505(b)(2) NDA applicant is not required to provide or maintain a certification to withdrawn patents. The final rule also codifies 505(b)(2) NDA and ANDA applicants' obligation to certify to a timely filed, newly issued patent that claims the listed drug or an approved method of using such drug.
  • Patent Certification Requirements for Amendments and Supplements. The final rule identifies the types of amendments to an application that require patent certification or recertification, or a "carve-out" statement: those that propose to add a new indication, other condition of use, or strength; make other-than-minor changes in product formulation; or change the physical form or crystalline structure of the active ingredient.
  • Limitation on Submission of Certain Amendments and Supplements to a 505(b)(2) NDA or ANDA. In the final rule, an applicant will be permitted to amend or supplement its 505(b)(2) application to identify a new or different listed drug as long as the applicant is not seeking approval for a different drug from the drug in the original submission. This affirms FDA's interpretation of the MMA's prohibition from the proposed rule with regard to submitting an amendment or supplement to seek approval of: (1) "[A] drug that is a different drug" than the drug identified in the original 505(b)(2) application; or (2) "a drug referring to a different listed drug" than the drug cited as the basis for the 505(b)(2) submission.
  • Listed Drug for 505(b)(2) NDAs. If there is an approved product that is a pharmaceutical equivalent to a 505(b)(2) NDA, it must be identified as the "listed drug" relied on. If there is more than one such approved product, the 505(b)(2) NDA is required to identify only one of them as the listed drug. There is no requirement to identify as the listed drug a pharmaceutical equivalent that is approved after the 505(b)(2) NDA was submitted.
  • Suitability Petition ANDAs. The final rule codifies FDA policy in this regard: FDA will not approve an ANDA submitted under a suitability petition if, while the ANDA is pending, the agency approves an NDA for a product that has the characteristic that led to the suitability petition in the first instance. The ANDA applicant will have to withdraw the pending application, and submit a new ANDA with the newly-approved, pharmaceutically equivalent product as the reference listed drug.
  • Filing an NDA and Receiving an ANDA. If a 505(b)(2) NDA or an ANDA contains a paragraph IV certification, FDA will send a Paragraph IV acknowledgment letter to notify the applicant that the application is regarded as filed (NDA) or received (ANDA).
  • Date of Approval and Related Issues. The final rule addresses a number of issues regarding the approval date of 505(b)(2) NDAs and ANDAs:
    • An application "becomes effective" on the date it is approved.
    • An application is eligible for approval on the last applicable date for all relevant patents listed in the Orange Book.
    • An application containing a "505(b)(2)(B)" or "section viii" statement to a method-of-use patent may be approved immediately.
    • An application that includes a paragraph IV certification cannot be approved until 45 days after the NDA holder or patent owner receives notice of the certification. (This is not the case if the patent was submitted after the 505(b)(2) NDA or ANDA, and thus cannot give rise to a 30-month stay.)
    • An application that is amended to contain a paragraph IV certification to a newly listed patent may be approved immediately, if otherwise eligible.

A 30-month stay (or a delay in approval for a 7.5-year period where applicable) is available only when the patent owner or exclusive patent licensee sues for patent infringement within 45 days after receiving notice of a paragraph IV certification.


  • The 30-month stay begins on the latest date of receipt of the paragraph IV certification notice by any patent owner, NDA holder, or its representative(s).

The final rule revises regulations regarding the effect on approval timing of various judicial actions, such as court decisions, appeals, preliminary injunctions, orders, and dismissals.The effect on approval timing of other types of exclusivity (e.g., orphan, pediatric) on approval timing is also addressed.

The scope of documentation a 505(b)(2) NDA or ANDA applicant must submit regarding court actions and patent settlement is expanded. Among other things, a court judgment on the validity or enforceability of a patent (i.e., either that the patent is invalid, unenforceable, or not infringed, or that it is valid and infringed) must be submitted within 14 calendar days of entry by the court.

The sponsor of a first-filed ANDA with a paragraph IV certification must notify FDA within 30 days of the date of first commercial marketing of the drug. If marketing is initiated and timely notice not made, FDA will deem the date of first commercial marketing to be the approval date, which likely will shorten the 180-day exclusivity period.

  • Assessing Bioavailability and Bioequivalence for Drugs Not Intended to Be Absorbed Into the Bloodstream. The regulation regarding bases for measuring in vivo bioavailability or establishing bioequivalence is revised to allow the use of scientifically valid methods to assess bioavailability and bioequivalence for drugs not intended to be absorbed into the bloodstream.This reflects current practice and corresponds to changes made by the MMA.