October 2017
Intellectual Property & Technology Law Journal
By Shana K. Cyr, Ph.D.; Li Feng, Ph.D.; Thomas L. Irving
This second part of a two-part article continues a discussion of the U.S. Food and Drug Administration's amendments to the regulations relating to the approval of new drugs. The first part of this article appeared in the September 2017 issue of the Intellectual Property & Technology Law Journal.
Patent Certifications
The amendments provide that a generic drug application must contain an appropriate certification or carve-out statement for each patent listed in the Orange Book, even if the applicant has initiated a patent listing dispute as to that patent. The Federal Drug Administration (FDA) believes that its approach regarding patent certifications strikes an appropriate balance by protecting the patent rights of a holder of a new drug application (NDA) without unnecessarily delaying approval of generic drug applications.
A generic drug applicant is required to amend its patent certification if, at any time before approval, the applicant learns that the previously submitted patent certification is no longer accurate with respect to the pending application or supplement. If an applicant submits an amendment to its application, it must reevaluate whether the paragraph IV certification continues to be accurate.
The amendments clarify the circumstances and time frame in which a generic drug applicant must submit an amended patent certification after an NDA holder has withdrawn the patent and requested removal of the patent from the Orange Book. If the Orange Book reflects that an NDA holder has requested that a patent or patent information be removed from the list and no applicant for an abbreviated new drug application (ANDA) is eligible for 180-day exclusivity based on a paragraph IV certification to that patent, the FDA will remove the patent or patent information. If an ANDA applicant is eligible for 180-day exclusivity based on a paragraph IV certification to that patent, the patent or patent information will remain listed until the 180-day exclusivity based on that patent expires or is extinguished. A 505(b)(2) applicant need not provide or maintain a certification to a patent or patent information that remains listed only for purposes of an ANDA applicant's 180-day exclusivity.
Once the patent or patent information is removed, applicants with pending generic drug applications who have made a certification with respect to the patent must submit an amendment to withdraw the certification. Once that amendment to withdraw the certification is submitted, the ANDA will no longer be considered to contain a paragraph IV certification to the patent. If removal of a patent from the list results in there being no patents listed for the pioneer drug identified in the generic drug application, the applicant must submit an amended certification reflecting that there are no listed patents.
The amendments also clarify the requirements for a generic drug applicant to amend a paragraph IV certification after a judicial finding of patent infringement to reflect statutory changes made by the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA). If a court enters a final decision from which no appeal has been or can be taken, or signs and enters a settlement order or consent decree in the action that includes a finding that the patent is infringed, a generic drug applicant who submitted a paragraph IV certification must submit an amendment to change its certification to a paragraph III certification or a carve-out statement, unless the final decision, settlement order, or consent decree also finds the patent invalid. If the final decision finds the patent infringed and invalid, the generic drug applicant need not file an amended certification.
A 505(b)(2) applicant may not submit an amendment or a supplement to its application to seek approval of a drug that is different from the drug in the original submission of the 505(b)(2) application. A drug is different if it has been modified to have a different active ingredient, route of administration, or dosage form, or a difference in recipients that requires either a separate clinical study to establish safety or effectiveness or, for topical products, that requires a separate in vivo demonstration of bioequivalence. An applicant may, however, amend a 505(b)(2) application to seek approval of a different strength of a drug.
An ANDA applicant may not submit an amendment to its application to seek approval of a drug referring to a listed drug that is different from the reference listed drug identified in the ANDA. This applies if, at any time before the approval of the ANDA, a different listed drug is approved that is the pharmaceutical equivalent to the product in the ANDA and is designated as a reference listed drug. It also applies if changes are proposed in an amendment to the ANDA such that the proposed product is a pharmaceutical equivalent to a different listed drug from the reference listed drug identified in the ANDA. A change of the reference listed drug must be submitted in a new ANDA. However, notwithstanding the limitation described in this paragraph, an applicant may amend the ANDA to seek approval of a different strength.
The FDA reports that the amendments clarify and augment the patent certification requirements for amendments to generic drug applications to ensure that certain types of changes to the drug product are accompanied by an appropriate patent certification (or recertification) or carve-out statement. The regulations continue to require that a patent certification be amended if, at any time before approval, the applicant learns that the previously submitted patent certification or statement is no longer accurate.
If a generic drug applicant submits an amendment or supplement to its application that includes a paragraph IV certification, it must send notice of that certification, regardless of whether it already has given notice with respect to another such certification.
Generic drug applicants must amend their applications to provide documentation of the date of receipt of the notice by each person provided the notice. The amendment must be submitted to the FDA within 30 days after the last date on which notice was received by the NDA holder or a patent owner. The amendment also must include documentation that the notice was sent on a date that complies with the required time frame.
An amendment to a generic drug application must contain a patent certification or carve-out statement, or a recertification for a previously submitted paragraph IV certification, if approval is sought for any of the following types of amendments:
If the amendment to the 505(b)(2) application does not contain a patent certification or statement, the applicant must verify that the proposed change described in the amendment is not one of these four types. The four instances are intended to address concerns that the factual and legal bases of the applicant's opinion that a patent will not be infringed may have changed. These patent certification requirements are intended to facilitate ongoing compliance with the Federal Food, Drug, and Cosmetic Act (FDCA).
Timing of Notice
The FDA reports that the amendments clearly delineate the two limitations on the time frame within which notice of a paragraph IV certification can be provided to the NDA holder and each patent owner: (1) the date before which notice may not be given (reflecting the FDA's long-standing practice regarding premature notice); and (2) the date,established by the MMA, by which notice must be given to be considered timely. For an original application, a 505(b)(2) applicant must send the notice on or after the date on which the application is filed, and an ANDA applicant must send the notice on or after the date on which it receives a paragraph IV acknowledgment letter newly defined in the regulations) from the FDA stating that the application is sufficiently complete to permit substantive review. Both 505(b)(2) and ANDA applicants must send their notice not later than 20 days after the date of the postmark (as newly defined in the regulations) on the paragraph IV acknowledgment letter.
The amendments newly define "paragraph IV acknowledgment letter" and "acknowledgment letter" to facilitate implementation of the MMA's requirement for an ANDA applicant to send notice of a paragraph IV certification within 20 days after the date of the postmark on the notice with which the FDA informs the applicant that the application has been filed.1 The paragraph IV acknowledgment letter contains information on certain regulatory requirements associated with a paragraph IV certification. The FDA concluded that it is unnecessary to distinguish between an acknowledgment letter and a paragraph IV acknowledgment letter for 505(b)(2) applications. If the 505(b)(2) application contains a paragraph IV certification at any time before the application is filed, the filing communication that the FDA sends to NDA applicants also will be the paragraph IV acknowledgment letter for purposes of determining the date by which notice of paragraph IV certification must be sent.
For an amendment or supplement, a generic drug applicant must send notice of a paragraph IV certification contained in an amendment (to a 505(b)(2) application that has been filed or an ANDA that has been received for substantive review) or supplement (to an approved application) at the same time that the amendment or supplement is submitted to the FDA.
The FDA reports that it is establishing 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 to a newly listed patent. Notice that is sent prematurely is invalid and will not be considered to comply with the FDCA's notice requirement. The FDA intends this approach to promote equity among ANDA applicants seeking eligibility for 180-day exclusivity and to reduce the burden on the industry and the FDA associated with serial submissions and multiple notices of paragraph IV certifications related to a newly issued patent.
With a few exceptions, the notice must be sent on or after the date of filing but not later than 20 days after the date of the postmark on the paragraph IV acknowledgment letter. The 20-day clock begins on the day after the date of the postmark on the paragraph IV acknowledgment letter. If the 20th day falls on a Saturday, Sunday, or federal holiday, then the 20th day will be the next day that is not a Saturday, Sunday, or federal holiday. If notice is sent before the date of filing, it is invalid.
Content of Notice
The FDA reports that the amendments revise the content of a paragraph IV notice to incorporate requirements added by the MMA and to support the efficient enforcement of its regulations. If the applicant alleges that the patent will not be infringed and seeks to preserve the option to later file a civil action for declaratory judgment, then it must include an offer of confidential access to its application for the sole and limited purpose of evaluating infringement of the patent that is the subject of the paragraph IV certification.
Notices must contain a statement that the applicant has received the paragraph IV acknowledgment letter for the ANDA.
Methods of Providing Notice
The amendments expand the acceptable methods of sending a paragraph IV notice beyond registered or certified mail to include designated delivery services.The FDA expects this amendment will reduce the burden on generic drug applicants who currently must submit requests to the FDA to send notice by alternate delivery methods. In addition to registered or certified mail, with return receipt requested, paragraph IV notices may be sent by a designated delivery service as defined by the amended regulations.
The 45 days as to each required recipient of a paragraph IV notice begins on the day after the date of receipt of the notice. If the 45th day falls on a Saturday, Sunday, or federal holiday, then the 45th day will be the next day that is not a Saturday, Sunday, or federal holiday.
An applicant must submit certain types of information to the FDA, including a copy of any judgment by the court or settlement order or consent decree signed and entered by the court finding a patent invalid, not infringed, or valid and infringed. The generic drug applicant must also notify the FDA in writing within 14 days of any legal action filed within 45 days of receipt of a paragraph IV notice by any recipient.
Generally
The FDA reports that the amendments describe, in a more comprehensive manner, the timing of approval of a generic drug application based on the accompanying patent certifications and statements. The status of listed patents must be considered in determining the first possible date on which a generic drug application can be approved. The regulations set forth criteria to determine, for each relevant patent, the date that patent will no longer prevent approval. The first possible date on which the generic drug application can be approved will be calculated for each patent, and the application may be approved on the last applicable date.
A generic drug application generally may be approved immediately if (1) the applicant certifies that required patent information has not been submitted to the FDA, the relevant patent has expired, the relevant patent is invalid, unenforceable, or will not be infringed except as provided and the 45-day period has expired, or there are no relevant patents; or (2) the applicant submits an appropriate statement explaining that a method-of-use patent does not claim an indication or other condition of use for which the applicant is seeking approval, except that if the applicant also submits a paragraph IV certification to the patent, then the generic drug application may be approved as provided. The application may be approved on the date specified if the applicant certifies that the relevant patent will expire on a specified date.
If an NDA holder submits required patent information after the date that a generic drug application was submitted to the FDA, the applicant must comply with the requirements regarding submission of an appropriate patent certification or statement. If the applicant submits an amendment certifYing that the relevant patent is invalid, unenforceable, or will not be infringed, and complies with other requirements, the application may be approved immediately upon submission of documentation of receipt of notice of paragraph IV certification. The 45-day period provided for in the FDCA does not apply in these circumstances.
If required information was submitted before the date the generic drug application was submitted to the FDA, the applicant makes a paragraph IV certification, and the patent owner or the exclusive patent licensee brings suit for patent infringement within 45 days of receipt of the notice of certification, the generic drug application may be approved 30 months after the later of the date of the receipt of the notice of certification by any owner of the listed patent or by the NDA holder.
If a generic drug application is submitted for a drug or method of using a drug claimed by a patent and the applicant has a licensing agreement with the patent owner, the applicant must submit a paragraph IV certification as to that patent and a statement that the applicant has been granted a patent license. If the patent owner consents to approval of the application (if otherwise eligible for approval) as of a specific date, the generic drug application must contain a written statement from the patent owner that it has a licensing agreement with the applicant and that it consents to approval of the generic drug application as of a specific date.
The FDA may refuse to approve a 505(b)(2) application for multiple reasons, including that the application failed to contain a patent certification or statement with respect to each listed patent for a drug product approved in an NDA that (1) is pharmaceutically equivalent to the drug product for which the original 505(b)(2) application was submitted, and (2) was approved before the original 505(b)(2) application was submitted. The amendments require 505(b)(2) applicants to identify one pharmaceutically equivalent drug product approved in an NDA, if one or more is approved before the original 505(b)(2) is submitted, as a listed drug relied on, and comply with applicable regulatory requirements. The FDA intends this provision 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 could have been approved in an ANDA.
30-Month Stay
The FDA reports that the amendments codify the types of court decisions and other actions that will terminate a 30-month stay of approval for a generic drug application. The FDA intends these amendments to avoid unnecessary delays in approval of generic drug applications while upholding the statutory purpose of the stay as allowing time for patent infringement claims to be litigated prior to approval of the potentially infringing product.
The FDA states that the amendments reflect the MMA's limitation on multiple 30-month stays of approval of a generic drug application containing a paragraph IV certification. The amendments 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 (or its representative). The FDA states that this revision codifies the FDA's current practice and provides an efficient means of ensuring that each patent owner or NDA holder receives the full 30-month stay.
The amendments codify the MMA's clarifications of the types of federal district and appellate court decisions in patent litigation that will terminate a 30-month stay and lead to approval of a generic drug application that is otherwise eligible for approval. First, if before the expiration of the 30-month period (or the seven and one-half years where applicable), the district court decides that the patent is invalid, unenforceable, or not infringed (including any substantive determination that there is no cause of action for patent infringement or invalidity), the 505(b)(2) application or ANDA may be approved on (1) the date on which the court enters judgment reflecting the decision, or (2) the date of a settlement order or consent decree signed and entered by the court stating that the patent that is the subject of the certification is invalid, unenforceable, or not infringed.
Second, if before the expiration of the 30-month period (or the seven and one-half years where applicable), the district court decides that the patent has been infringed and the judgment is appealed, the generic drug application may be approved on (1) the date on which the mandate is issued by the court of appeals entering judgment that the patent is invalid, unenforceable, or not infringed; or (2) the date of a settlement order or consent decree signed and entered by the court stating that the patent that is the subject of the certification is invalid, unenforceable, or not infringed.
Third, if before the expiration of the 30-month period (or the seven and one-half years where applicable), the district court decides that the patent has been infringed and the judgment is not appealed or affirmed, the application may be approved no earlier than the date specified by the district court in an order under 35 U.S.C. § 271(c)(4)(A).
The amendments also address other scenarios in which a 30-month 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 in each pending suit for patent infringement brought within 45 days of receipt of a paragraph IV notice. For example, if before the expiration of the 30-month period (or the seven and one-half years where applicable), the patent owner or the exclusive patent licensee agrees in writing that the generic drug application may be approved any time on or after the date of the consent, approval may be granted on or after that date. If before the expiration of the 30-month period (or the seven and one-half years where applicable), the court enters an order requiring the stay to be terminated, the generic drug application may be approved in accordance with the court order, and if it enters an order of dismissal, with or without prejudice, without a finding of infringement in each pending suit for patent infringement brought within 45 days of receipt of the paragraph IV notice, the application may be approved on or after the date of that order.
180-Day Marketing Exclusivity
Subsequent ANDAs cannot be approved during a 180-day period of exclusivity, but any applicable 180-day exclusivity period cannot extend beyond the expiration of the patent on which the 180-day period was based.
The amendments reflect the MMA provisions that modify the types of events that can trigger the start of the 180-day exclusivity period. A first applicant must notify the FDA within 30 days of the date of first commercial marketing of the drug product. If a first applicant does not, then the FDA will deem the date of first commercial marketing to be the date of 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. If the FDA concludes that the first applicant is not actively pursuing approval of its ANDA, the FDA may immediately approve an ANDA of a subsequent applicant if the ANDA is otherwise eligible for approval.
The FDA reports that it is otherwise implementing the 180-day exclusivity provisions of the MMA directly from the statute and will determine whether further rulemaking is necessary in the future.
It remains to be seen whether the FDA's amendments to Parts 314 and 320 of Title 21 of its regulations will reduce litigation or delays in the approval of generic drug applications. It is also unclear whether the amendments have provided transparency or provided business certainty to pharmaceutical companies. While some of the amendments have provided clarity, others have raised additional questions. Pharmaceutical companies that are developing or marketing new drugs should consider how the amendments may affect them and should pay close attention to further guidance from the FDA.
Endnote
1 Final Rule, 81 Fed. Reg. at 69,591.
505(b)(2) application, new drug application (NDA), Food and Drug Administration (FDA), Hatch-Waxman Act
Originally printed in Intellectual Property & Technology Law Journal in October 2017. This article is for informational purposes, is not intended to constitute legal advice, and may be considered advertising under applicable state laws. This article is only the opinion of the authors and is not attributable to Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, or the firm’s clients.
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