As of December 5, 2016, the U.S. Food and Drug Administration (FDA) amended its regulations relating to the approval of new drugs.1 The FDA expects the amendments to reduce unnecessary litigation, reduce delays in the approval of generic drug applications, provide business certainty to both pioneer and generic drug manufacturers, and promote transparency. While some of the amendments are minor and likely inconsequential, others warrant consideration.
The FDA approves new drugs under Section 505 of the Federal Food, Drug, and Cosmetic Act (FDCA), codified as amended at Section 355 of title 21 of the U.S. Code (U.S.C.).2 The FDCA and corresponding statutes have been amended multiple times, including by the Drug Price Competition and Patent Term Restoration Act of 1984 (referred to as the Hatch-Waxman Amendments)3 and Title XI of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA).4
The FDA approves pioneer drugs through stand-alone new drug applications (NDAs) under 21 U.S.C. § 355(b)(1). These NDAs must include full reports of nonclinical and clinical investigations showing that the proposed drug is safe and effective, proposed labeling describing the uses for which the drug may be marketed, and a description of the approved method of use (a use code). They also must include patent numbers and expiration dates for any patent claiming the proposed drug or a method of using the proposed drug, for which a claim of patent infringement could reasonably be asserted against a party engaged in the manufacture, use, or sale of the drug. The FDA lists pioneer drugs, their use codes, and their patent information in its Approved Drug Products with Therapeutic Equivalence Evaluations publication, commonly knowrt as the Orange Book.5 Pioneer drugs may be eligible for marketing exclusivities of five years or more and patent term extensions.
The FDA approves generic versions of pioneer drugs through two types of applications: (1) 505(b)(2) applications under 21 U.S.C. § 355(b)(2), and (2) abbreviated new drug applications (ANDAs) under 21 U.S.C. § 355(j). Just as with stand-alone NDAs, 505(b)(2) applications must include full reports of investigations showing that a drug is safe and effective. However, 505(b)(2) applicants need not perform all of the investigations themselves; they may, for example, rely on investigations reported in a stand-alone NDA. ANDAs do not need to include full reports of investigations showing that the proposed drug is safe and effective. Instead, ANDAs must contain information showing that the proposed drug has the same active ingredient(s), route of administration, dosage form, strength, and labeling as a pioneer drug, and that the proposed drug is bioequivalent to that pioneer drug.
If patents covering a pioneer drug are listed in the Orange Book, a generic drug applicant must certify as to each patent that it will not market the proposed generic drug until after the patent expires (a paragraph III certification) or that the patent is invalid or will not be infringed by the manufacture, use, or sale of the proposed generic drug (a paragraph IV certification). If the patents listed in the Orange Book do not cover all of the approved uses of a pioneer drug, a generic drug applicant may seek approval for an approved use that is not claimed by a patent by filing a carve-out statement (sometimes referred to for ANDAs as a section viii statement). The first ANDA applicant who files a paragraph IV certification may be eligible for a 180-day period of marketing exclusivity, during which the FDA cannot approve other ANDAs for the same drug product.
Generic drug applicants must give notice of their paragraph IV certifications to the NDA holder for the pioneer drug and to each patent owner. If the patent owner or its exclusive licensee sues the generic drug applicant for patent infringement within 45 days of receiving the notice, the FDA cannot approve the generic drug application for 30 months or more while the litigation is pending, absent a court order.
Under authority granted to tt m the FDCA, the FDA issues regulations related to Section 505 of the FDCA in title 21 of the Code of Federal Regulations (C.F.R.). Part 314 of title 21 includes regulations relating to applications to market new drugs, and part 320 includes regulations relating to bioavailability and bioequivalence requirements.
On October 6, 2016, the FDA issued a final rule to amend its regulations in parts 314 and 320 to implement portions of Title XI of the MMA, facilitate compliance with and efficient enforcement of the FDCA, and provide clarifications and updates based on court decisions, legislative enactments, and the FDA's practical experience. The amendments took effect on December 5, 2016, and apply to any new submission received by the FDA on or after that date.
Submission of Patent Information by NDA Holders
For the FDA to publish or list patent information, NDA applicants and holders must submit the information on Forms FDA 3542a and 3542, respectively. The FDA revised these forms as of December 5, 2016, to conform to the requirements established by the amendments. For example, the FDA revised Form FDA 3542 to state that a use code must describe a specific approved method of use claimed by a patent. Forms FDA 3542a and 3542 should be submitted to the Central Document Room at the FDA's Center for Drug Evaluation and Research (CDER), not the Orange Book Staff in the Office of Generic Drugs (OGD).
If a patent has been submitted previously for listing, the NDA applicant must identify all changes from the previously submitted patent information and specify whether the change is related to the patent or related to an FDA action or procedure. If an applicant submits information for a patent that claims one or more methods of using a drug product, the applicant also must submit information regarding whether that patent also claims the drug substance or the drug product.
The amended regulations add exceptions to the required submissiom of patent information. If an applicant submits information for a patent that claims a drug substance and meets the requirements for listing on that basis, then the applicant is not required to provide information on whether the patent also claims the drug product. If an applicant submits information for a patent that claims a drug product and meets the requirements for listing on that basis; then the applicant is not required to provide the information on whether the patent also claims the drug substance. If an applicant submits a supplement for a change other than one of the changes listed in the amended regulations, then the patent information submission requirements apply.
According to the FDA, the amendments codify its long-standing requirement that an NDA holder's use code contain adequate information to assist the FDA and a generic drug applicant in determining whether the generic drug applicant seeks approval for a use that is covered by a listed method-of-use patent. When a 505(b)(2) applicant seeks approval for an approved use of a pioneer drug that is not a use protected by a listed method-of-use patent, the FDA decides whether it can approve the 505(b)(2) application with the information related to the protected use omitted from the product labeling.
When an ANDA applicant seeks approval for an approved use of a pioneer drug that is not a use protected by a listed method-of-use patent, the FDA decides whether omitting information related to the protected use from the product labeling renders the product less safe or effective for its remaining nonprotected approved uses.
The FDA states that its regulatory amendments clarify the requirements for an NDA holder's submission of a use code to address overbroad and ambiguous use codes that may delay approval of generic drugs. It expects that the amendments will improve the accuracy of use codes. NDA applicants and holders must submit accurate use codes, subject to verification under penalty of perjury. The FDA states that an inaccurate use code would impede its ability to scientifically determine whether a generic drug application may be approved with labeling that omits information about a protected approved use of the pioneer drug.
NDA applicants and holders must submit information only on those patents that claim uses for which approval is sought or has been granted. For approved NDAs, the use code must describe only a specific approved method of use for which a patent owner or exclusive licensee reasonably could assert patent infringement. The NDA holder must identify with specificity the sections and subsections of the approved labeling that describe the methods of use claimed by the patent submitted. According to the FDA, an NDA applicant or holder that is developing a use code should not speculate about the protected uses that a generic drug applicant may seek to omit from its labeling.
The FDA declined to adopt standardized use codes because they would not accurately capture the nuances of method-of-use patent claims. The FDA also declined to provide hypothetical examples of use codes. It does, however, provide what it refers to as general principles. First, if a patented method of use involves terminology different from the approved labeling or is broader than an approved use, then the NDA holder must phrase the use code more narrowly than the patent claim to describe only the specific patented method of use described in the FDA-approved product labeling. On the other hand, if the patented method of use is narrower than an approved use and it does not cover the approved use in its entirety, then the NDA holder must phrase the use code to describe only the specific approved method of use claimed by the patent.
An NDA holder must separately identify each approved method of use claimed by a patent. The NDA holder also must identify with specificity each section and subsection of the approved labeling that contains information describing the patented method of use. The FDA states that even though the protected use may comprise less than the entirety of the section or subsection of the approved product labeling, an NDA holder need not identify the specific language in the approved product labeling that describes the patented method of use. It states that the use code and the specific sections and subsections are sufficient for it to evaluate a generic drug applicant's proposed labeling. It further notes that it is not bound by the sections and subsections identified by the NDA holder in making its determination, and that it will use its independent scientific judgment to determine which sections and subsections of the approved labeling contain language that must be carved out based on a pioneer drug's use code.
The FDA declined to require NDA holders to resubmit patent information for each of the approximately 10,000 patents listed in the Orange Book as of the amendments' effective date. The FDA reasoned that doing so would impose a significant burden on the FDA and NDA holders without a commensurate benefit, and that a person who disagrees with the listed information can initiate a patent listing dispute as described below.
Untimely Filed Patent Information
An NDA holder must submit patent information to the FDA within 30 days of patent issuance. The amendments establish that the submission date of patent information provided by an NDA holder after approval will be the earlier of the date on which Fortm FDA 3542 is date-stamped by the Central Document Room or officially received by the FDA in an electronic format. The FDA intends this amendment to facilitate prompt listing in the Orange Book and to remove any ambiguity about the date of submission in light of the implications of untimely fded patent information for the patent certification obligations of generic drug applicants.
The FDA states that while it will list untimely filed patents in the Orange Book, a generic drug applicant that already has submitted an application generally does not need to certify as to untimely filed patents, and thus the patents will not delay its approval. An applicant that submits an ANDA after the untimely filing of patent information, however, or that submits an ANDA beforehand but without the appropriate patent certification or carve-out statement, must submit a certification or carve-out statement as to an untimely filed patent.
The FDA reports that the amendments expand the category of untimely filed patent information to include certain amendments to the use code if not submitted within 30 days of patent issuance, approval of a corresponding change to product labeling, or a decision by the U.S. Patent and Trademark Office (PTO) or a federal court that is specific to the patent and alters the construction of a method-of-use claim of the patent. The use code amendment must contain a copy of the PTO or court decision, and the accompanying Form FDA 3542 must identify the decision as a change related to the patent. The FDA intends this provision to reduce delays in approval related to overbroad or ambiguous use codes. The FDA declined to provide in its regulations that a use code amendment would be timely if based solely on changes in patent law or on an interpretation not specific to the patent. The FDA reasoned that it lacks expertise in patent law and that such a provision could effectively eliminate provisions relating to the untimely filing of method-of-use patent information.
Corrections or Changes of Patent Information—Requests by Others
According to the FDA, its regulatory amendments clarify and improve the procedures that govern challenges to the accuracy or relevance of an NDA holder's submission of patent information to the FDA. The FDA intends to take an incremental approach and evaluate whether the amendments adequately eliminate overbroad and ambiguous use codes before it takes additional steps. It thus declined to finalize its proposal to review a proposed labeling carve-out with deference to the generic drug applicant's interpretation of the scope of the patent in certain circumstances. It will continue to consider whether it needs to finalize the proposal in the future.
Under the amendments, if any person disputes the accuracy or relevance of patent information submitted to the FDA and published in the Orange Book, or believes that an NDA holder has failed to submit required patent information, that person must first notify the FDA in a written or electronic communication titled "314.53(f) Patent Listing Dispute."6 The communication should be directed to the Orange Book Staff in the FDA's OGD. This communication must include a statement of dispute that describes the specific grounds for disagreement regarding the accuracy or relevance of patent information for the FDA to send to the applicable NDA holder. For a dispute regarding the accuracy or relevance of patent inform4tion regarding an approved method of using the drug product, this statement of dispute must be only a narrative description of no more than 250 words of the person's interpretation of the scope of the patent. This statement of dispute must contain omly information for which the person consents to disclosure because the FDA will send the text of the :statement to the applicable NDA holder without review or redaction.
After the FDA sends the statement of dispute to the NDA holder, the NDA holder must confirm the correctness of the information and include the signed verification or withdraw or amend the patent information within 30 days of the date on which the FDA sends the statement of dispute. Unless the NDA holder withdraws or amends its patent information in response to the patent listing dispute, the FDA will not change the patent information in the Orange Book.
For method-of-use claims, the NDA holder also must provide a narrative description of no more than 250 words of the NDA holder's interpretation of the scope of the patent that explains why the existing or amended use code describes only the specific approved method of use claimed by the patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the patent owner engaged in the manufacture, use, or sale of the drug product. The narrative description must contain only information for which the NDA holder consents to disclosure because the FDA will sertd the text of the statement to the person who submitted the patent listing dispute without review or redaction.
If the NDA holder confirms the correctness of the patent information, provides the required narrative description, and includes the required signed verification within 30 days of the date on which the FDA sends the statement of dispute, the FDA will not change the patent information in the Orange Book. If the NDA holder responds to the dispute with amended patent information, provides the narrative, and includes the signed verification within 30 days of the date on which the FDA sends the statement of dispute, the FDA will update the Orange Book to reflect the amended patent information.
Corrections or Changes of Patent Information—Requests by the NDA Holder
The amendments require NDA holders to correct or change patent information 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. The FDA states that these amendments facilitate implementation of the MMA provision related to patent withdrawal and efficient enforcement of the FDCA.
First, if an NDA holder determines that a patent or patent claim no longer meets the FDCA requirements for listing (including if there has been a judicial finding of invalidity for a listed patent, from which no appeal has been or can be taken), the NDA holder must promptly notify the FDA to amend the patent information or withdraw the patent or patent information and request that the patent or patent information be removed from the list.
Second, if the NDA holder is required by court order to amend patent information or withdraw a patent from the list, it must submit an amendment to its NDA that includes a copy of the order within 14 days of the date that the order was entered to the CDER's Central Document Room. The amendment to the NDA must bear the required identification. The FDA will remove a patent or patent information from the list if there is no ANDA applicant eligible for the 180-day exclusivity period based on a paragraph IV certification to that patent or after the 180-day period has expired or been extinguished.
Third, if the term of a listed patent is extended pursuant to 35 U.S.C. § 156(e), the NDA holder must submit on Form FDA 3542 a correction to the expiration date of the patent. This correction must be submitted within 30 days of receipt of a certificate of extension or documentation of an extension of the term of the patent as described in 35 U.S.C. § 156(e).
Corrections or changes to previously submitted patent information, other than withdrawal of a patent and requests to remove a patent from the list, must be submitted on Form FDA 3542a or 3542, as appropriate, in nn amendment or supplement to the NDA. The amendment or supplement must bear the required identification. Withdrawal of a patent and requests to remove a patent from the list may be submitted by letter, but it must include the NDA number to which the request applies, each product approved in the NDA to which the request applies, and the patent number.
The FDA decided not to finalize its proposed single-bundle-rights approach for reissued patents. Instead, the FDA considers a reissued patent as separate and, distinct from the original patent for patent certification requirements, 30-month stays, and 180-day exclusivities. When a patent reissues, the original patent is surrendered and ceases to have legal effect. An NDA holder must then withdraw the original patent and request that the FDA remove it from the Orange Book.
The FDA will assess whether a reissued patent is timely listed based solely on whether the NDA holder has submitted the required patent information within 30 days of reissuance (provided that the patent is reissued after the date of approval of the NDA) or otherwise meets the requirements for timely filing of patent information. Similarly, the date on which patent information on the reissued patent (and not the original patent) is submitted to the FDA determines whether a paragraph IV certification to the reissued patent could give rise to a 30-month stay if other criteria are met. This means that the FDA evaluates eligibility for 180-day exclusivity based on whether the criteria are met for an original patent (irrespective of whether it subsequently is reissued) or for a reissued patent. The FDA does, not require an NDA holder to indicate whether a patent it submits for listing is a reissued patent of one that was previously submitted.
Disclosure of Information
The FDA intends to list in the Orange Book the date that pateruts and patent information are submitted on a prospective basis beginning as soon as practicable. It does not intend, however, to separately publish a list of untimely filed patent information. The FDA also declined to undertake the burden of notifying individual ANDA applicants when patents are listed in the Orange Book, but states that it is committed to facilitating public access to the Orange Book and notes that it generally posts electronic updates to the Orange Book on a daily basis.
The FDA does not intend to publish Form FDA 3542s, noting that the forms may be obtained on an individual basis through a Freedom of Information Act (FOIA) request. The amendments provide that submitted patent information and requests to remove a patent or patent information from the Orange Book may be subject to public disclosure. The FDA states that it will prompdy post information on its website regarding whether a patent listing dispute has been submitted for a published description of a patented method of use for a drug product and whether the NDA holder has timely responded to the dispute.
1 U.S. Food and Drug Administration, Abbreviated New Drug Applications and 505(b)(2) Applications, 81 Fed. Reg. 69,580 (Oct. 6, 2016) (to be codified at 21 C.FR. pts. 314, 320) (Final Rule).
2 Federal Food, Drug, and Cosmetic Act, Pub. L. No. 75-717, § 505, 52 Stat. 1040, 1052-1053 (1938) (codified as amended at 21 U.S. C. § 355).
3 Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585 (1984) (codified as amended at 21 U.S.C. § 301 et seq.).
4 Medicare Prescription Drug, Improvement, and Modernization Act of 2003, Pub. L. No. 108-173, tit. XI, 117 Stat. 2066, 2448-69 (2003) (codified as amended at 21 U.S.C. § 301 et seq.).
5 U.S. Food and Drug Administration, Approved Drug Products with Therapeutic Equivalence Evaluations, https://www.accessdata.fda.gov/scripts/cder/ob/.
6 Final Rule, 81 Fed. Reg. at 69,646.
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