On February 6, 2015, the Food and Drug Administration (FDA) published in the Federal Register (FR) a comprehensive proposed rule (80 FR 6802) to amend agency regulations governing Abbreviated New Drug Applications (ANDAs) and 505(b)(2) New Drug Applications (505(b)(2) NDAs) and the patent listing and certification provisions fundamental to the operation of the Drug Price Competition and Patent Restoration Act of 1984 (the Hatch-Waxman Act). The proposed rule would implement portions of Title XI of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) concerning a number of important issues, including:

  • Notice to patent owners and application holders of certain patent certifications made by applicants submitting 505(b)(2) NDAs or ANDAs; 
  • The availability of a 30-month stay of approval on 505(b)(2) NDAs and ANDAs that are otherwise ready to be approved; 
  • Selection of the appropriate reference drug for 505(b)(2) NDAs; 
  • Submission of amendments and supplements to ANDAs and 505(b)(2) NDAs; and 
  • The types of bioavailability and bioequivalence data that can be used to support ANDAs and 505(b)(2) NDAs. 

Comments on the proposed rule are due by May 7, 2015.

The major provisions of the proposed rule include:

  • Submission of patent information. The proposed rule would revise—and purports to streamline—requirements related to the submission of patent information on: (1) patents that claim the drug substance and/or drug product and meet the requirements for patent listing on that basis; (2) drug substance patents that claim only a polymorph of the active ingredient; and (3) certain NDA supplements. 

The proposed rule also clarifies requirements for the submission of reissued patents and describes the agency’s approach to treating original and reissued patents as a bundle of patent rights, an issue that has recently been the subject of litigation in Mylan Pharmaceuticals Inc. v. FDA in the U.S. Court of Appeals for the Fourth Circuit.

In addition, in an apparent effort to address concerns about the agency’s oversight of use codes for method of use patents, raised during the U.S. Supreme Court’s consideration of the issue in Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk, the agency has included a proposal to “restrain overbroad use codes.” FDA’s proposal “would expressly require that if the scope of the method-of-use claim(s) of the patent does not cover every approved use of the [reference] drug, the NDA holder’s use code must describe only the specific portion(s) of the indication or other method of use claimed by the patent.”

  • Timing of submission of patent information. The proposed rule expressly describes the FDA’s current practice with respect to the late listing of patent information, and proposes “to expand the category of untimely filed patent information to include certain amendments to the NDA holder’s description of the approved method(s) of use claimed by the patent, if such changes do not relate to a corresponding change in approved labeling or are submitted more than 30 days after such labeling change.” According to the FDA, this proposed revision “is intended to reduce delays in approval related to manipulation of patent use codes...”

In addition, the FDA proposes to establish that the submission date of patent information provided by an NDA holder after approval would be the earlier of the date on which Form FDA 3542 is date-stamped by the Office of Generic Drugs Document Room or officially received electronically by the FDA. According to the FDA, these proposed revisions “are intended to facilitate prompt listing in the Orange Book and to remove any ambiguity about the date of submission in light of the implications for the patent certification obligations of 505(b)(2) and ANDA applicants that rely upon the listed drug.”

  • Correction or change of patent information. The FDA proposes to enhance its response to challenges to the accuracy or relevance of submissions of patent use code information to the agency, in certain circumstances. “If, in response to such a challenge, the NDA holder confirms the accuracy of the information, fails to timely respond, or submits a revision to the use code that does not provide adequate clarity for FDA to determine whether the scope of a proposed labeling carve-out would be appropriate based on the NDA holder’s use code and approved labeling,” the agency says, then “we are proposing to review proposed labeling carve-out(s) for the 505(b)(2) application or ANDA with deference to the 505(b)(2) or ANDA applicant’s interpretation of the scope of the patent.”

In addition, the FDA proposes to expressly require the correction or change of patent information by the NDA holder if: (1) The patent or patent claim no longer meets the statutory requirements for listing; (2) the NDA holder is required by court order to amend patent information or withdraw a patent from the list; or (3) the term of a listed patent is extended under patent term restoration provisions. According to the FDA, “[t]hese proposed revisions would facilitate implementation of the MMA provision related to patent withdrawal and efficient enforcement of the [FDCA].”

  • Notice of paragraph IV certification (timing). The FDA proposes to clearly delineate the two limitations on the time frame within which Paragraph IV certification notice can be provided to the NDA holder and patent owner: “(1) [t]he date before which notice may not be given (reflecting the FDA’s long-standing practice) and (2) the date, established by MMA, by which notice must be given.” In addition, the agency reiterates that a paragraph IV certification that has been sent prematurely is invalid “and will not be considered to comply with the FD&C Act’s notice requirement.”

The FDA also proposes “administrative consequences” for ANDA applicants who fail to send a Paragraph IV notice within the statutory time frame. Specifically, “[t]he date the ANDA was submitted would be deemed to be delayed by the number of days by which the time frame was exceeded, which may result in the applicant losing eligibility for 180-day exclusivity.”

In addition, the FDA proposes “to establish a date (the first working day after the day the patent is published in the Orange Book) before which an ANDA applicant cannot send valid notice of a paragraph IV certification to a newly listed patent.” According to the FDA, this approach “is intended to promote equity among ANDA applicants seeking eligibility for 180-day exclusivity and to reduce the burden on industry and the FDA associated with serial submissions and multiple notices of paragraph IV certifications related to a newly issued patent.”

  • Notice of paragraph IV certification (contents and methods). The FDA proposes revisions to the content of notice of a paragraph IV certification “to incorporate requirements added by the MMA and to support the efficient enforcement of our regulations.” The FDA also seeks to expand the acceptable methods of sending notice of a paragraph IV certification beyond registered or certified mail to include ‘‘designated delivery services.’’
  • Amended patent certifications. The FDA proposes to “clarify the requirements for a 505(b)(2) or ANDA applicant to amend a paragraph IV certification after a judicial finding of patent infringement to reflect statutory changes made by the MMA,” and to “clarify the circumstances and time frame in which a 505(b)(2) or ANDA applicant must submit an amended patent certification after an NDA holder has withdrawn a patent and requested removal of the patent from the Orange Book.” According to the FDA, the proposed rule “would codify our current practice of not removing a withdrawn patent from the list until FDA has determined that no first applicant is eligible for 180-day exclusivity or such exclusivity is extinguished, and exempting 505(b)(2) applicants from providing or maintaining a certification to withdrawn patents.”
  • Amendments or supplements: patent certification requirements. The FDA proposes to clarify and augment the patent certification requirements for amendments and supplements to 505(b)(2) applications and ANDAs by “requiring a new patent certification with an amendment to make other-than-minor changes in product formulation or to change the physical form or crystalline structure of the active ingredient.” This is a significant issue for matters that are the subject of active patent litigation under the Hatch-Waxman Act, where ANDA applicants may seek to amend their pending applications in response to real-time developments in the patent litigation.”
  • Limitation on submission of certain amendments and supplements to a 505(b)(2) application or ANDA. The FDA proposes to codify its current interpretation of the MMA’s prohibition on submitting an amendment or a 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 ANDA submission. According to the FDA, it is “implementing these parallel restrictions on submission of certain types of changes in an amendment or a supplement to a 505(b)(2) application or ANDA in a manner that is consistent with the statutory text and preserves a meaningful opportunity for a single 30-month stay.”
  • 505(b)(2) applications. The FDA proposes to require a 505(b)(2) applicant to identify a pharmaceutically equivalent product, if already approved, as a listed drug relied upon, and comply with applicable regulatory requirements. According to the FDA, this is “intended to help ensure that the 505(b)(2) pathway is not used to circumvent the statutory patent certification obligations that would have applied if the proposed product was not ineligible for approval in an ANDA.” This issue has been the subject of a series of citizen petitions and, more recently, litigation against the agency. See the FDA Citizen Petition Response, Docket Nos. FDA-2013-P-0869 and FDA-2013-P-0995 (Sept. 18, 2013); see also Takeda v. FDA, Civil Action No.1:14-cv-01668 (D.D.C. 2014).”
  • Date of approval of a 505(b)(2) or ANDA. The proposed rule describes, in a more comprehensive manner, the timing of approval of a 505(b)(2) NDA or ANDA based on the patent certification(s) or statement(s) submitted by the 505(b)(2) or ANDA applicant. According to the FDA, it is proposing “to revise the regulations to reflect the MMA’s limitation on multiple 30-month stays of approval of a 505(b)(2) application or an ANDA containing a paragraph IV certification to certain patents submitted to FDA on or after August 18, 2003.”

The FDA also proposes to clarify that the statutory 30-month stay begins on the later of the date of receipt of notice of paragraph IV certification by any owner of the listed patent or by the NDA holder who is an exclusive licensee (or their representatives). According to the FDA, this proposed revision “codifies our current practice and provides an efficient means of ensuring that each patent owner or NDA holder receives the full statutory 30-month stay.”

In addition, the agency proposes to codify the MMA’s amendments that clarify the type of Federal district and appellate court decisions in patent litigation that will terminate a 30-month stay and lead to approval of a 505(b)(2) application or ANDA that is otherwise eligible for approval.

Further, the FDA proposes to address other scenarios in which a stay may be terminated, including written consent to approval by the patent owner or exclusive patent licensee, a court order terminating the stay, or a court order of dismissal without a finding of infringement. According to the FDA, “[t]his is intended to avoid unnecessary delays in approval of generic drugs while upholding the statutory purpose of the stay (i.e., to allow time for patent infringement claims to be litigated prior to approval of the potentially infringing product).”

  • Notification of commercial marketing. The FDA proposes to update the regulations to reflect the MMA provisions that modify the types of events that can trigger the start of the 180-day exclusivity period. The proposed rule provides:

A first applicant would be required to submit correspondence to its ANDA notifying FDA within 30 days of the date of first commercial marketing of the drug product. If the first applicant does not notify the FDA within this time frame, we are proposing to deem the date of first commercial marketing to be the date of the drug product’s approval. This may have the effect of shortening the 180-day exclusivity period in a similar manner to the current regulatory consequence for failure to provide ‘‘prompt’’ notice of first commercial marketing.

  • Notification of court actions or documented agreements. The FDA proposes to expand the scope of documentation that an applicant must submit to FDA regarding patent-related court actions and documented agreements “to ensure that the FDA is promptly advised of information that may affect the timing of approval of a 505(b)(2) application or ANDA.”

In addition, the proposed rule adds, revises, and relocates many definitions, but does not change the substantive meaning of any definitions, except:

  • The rule proposes to revise the definitions of certain existing terms in 21 CFR 314.3(b) (i.e., ‘‘listed drug’’ and ‘‘the list’’) to conform with other changes the agency is proposing in this regulation and to clarify the distinction between approvals and tentative approvals; and
  • The rule proposes to revise the definitions of “abbreviated application’’ and ‘‘applicant’’ in 21 CFR 314.3(b) to reflect statutory changes made by the Food and Drug Administration and Modernization Act of 1997 (FDAMA).

Other definitions added by the proposed rule include “dosage form,” “active ingredient,” “inactive ingredient,” “component,” and many others. According to the FDA, these added definitions reflect the current uses of the terms and do not change the substance.