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November 30, 2016

ANDA: MMA Final Rule

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Kurt R. Karst provides regulatory counsel to pharmaceutical manufacturers on Hatch-Waxman patent and exclusivity, drug development, pediatric testing, and orphan drugs. He helps clients develop strategies for product lifecycle management, obtaining approval, managing post-marketing issues, and defining periods of exclusivity. As the co-founder and primary author of Hyman, Phelps & McNamara's FDA Law Blog, Mr. Karst often leads the response to new rules and regulations, sharing his interpretation with the broader legal community. Mr. Karst's knowledge of FDA precedents and timely analysis of developments helps clarify and shape the industry's understanding of Hatch-Waxman, in particular. He is a prolific writer, contributing to the blog and publishing articles in major legal journals. Mr. Karst has co-authored and contributed to several text books, including Generic and Innovator Drugs: A Guide to FDA Approval Requirements; Pharmaceutical, Biotechnology, and Chemical Inventions; Fundamentals of US Regulatory Affairs; and FDLI's Drug and Biologic Approvals: The Complete Guide for Small Businesses-FDA Financial Assistance and Incentives. Mr. Karst clerked for Hyman Phelps & McNamara while attending law school and served as articles editor for the American University Law Review. Before joining the firm, Mr. Karst lobbied for F. Hoffmann-La Roche Inc. In 1995, he was awarded a Fulbright Scholarship for post-graduate studies in Germany.

Kurt R. Karst

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Anti-Trust Considerations

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Title XI of the 2003 Medicare

Modernization Act: FDA’s Final

Regulations on ANDAs and 505(b)(2)

Applications

Kurt R. Karst Hyman, Phelps & McNamara, P.C. 700 Thirteenth Street, N.W., Suite 1200

Washington, D.C. 20005, U.S.A. 202-737-7544 – kkarst@hpm.com

November 30, 2016

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Background

• On October 6, 2016, FDA finalized regulations proposed on February 6, 2015 concerning certain provisions of the December 8, 2003 Medicare Modernization Act (“MMA”), Pub. L. No. 108-173, 117 Stat. 2066.

• The Final Rule is the latest – and most significant – in a series of actions intended by FDA to preserve the balance struck with the September 24, 1984 enactment of the Hatch-Waxman Amendments between generic drug availability and rewarding those manufacturers who bring innovative drug products to market.

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Background

• While the focus of the Final Rule is only about 10 pages of MMA statutory text, the document spans 79 triple-column pages in the Federal Register, including about 22 pages of regulations that will be codified in the Code of Federal Regulations as of December 5, 2016.

• Several proposals FDA made in February 2015 are retained in the Final Rule, while a few have been dropped, either because of court decisions, or because FDA decided to move in a different direction.

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References

• MMA, Pub. L. No. 108-173, 117 Stat. 2066 (2003) – http://www.gpo.gov/fdsys/pkg/STATUTE-117/pdf/STATUTE-117-Pg2066.pdf

• FDA, Proposed Rule, Abbreviated New Drug Applications and 505(b)(2) Applications, 80 Fed. Reg. 6802 (Feb. 6, 2015) – https://www.regulations.gov/document?D=FDA-2011-N-0830-0001

• FDA, Final Rule, Abbreviated New Drug Applications and 505(b)(2) Applications, 81 Fed. Reg. 69,580 (Oct. 6, 2016) – https://www.regulations.gov/document?D=FDA-2011-N-0830-0022

• Regulation-by-Regulation Redline of the New Regulations – http://www.fdalawblog.net/MMA%20Final%20Rule%20Reg%20Redline.pdf

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Submission of Patent

Information

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Patent Listing

• Revisions to and streamlining of requirements related to 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.

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Patent Listing

• Codification of FDA’s requirement that the NDA holder’s MOU patent description must contain adequate information to assist FDA and 505(b)(2)/ANDA applicants in determining whether a listed MOU patent claims a use for which the 505(b)(2)/ANDA applicant is not seeking approval.

• If the method(s) of use claimed by the patent does not cover an indication or other approved condition of use in its entirety, the NDA holder’s patent use code must describe only the specific approved method of use claimed by the patent for which a claim of patent infringement could reasonably be asserted.

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Patent Listing

• Patented method of use is broader than an indication or other approved condition of use:

– The use code must only describe a patented MOU that is described in FDA-approved product labeling.

– If the MOU claimed by the patent uses different terminology than the approved labeling and/or is broader than an indication or other approved condition of use, then the use code would need to be phrased more narrowly than the patent claim to only describe the specific patented method of use that is described in FDA-approved product labeling.

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Patent Listing

• Patented method of use is co-extensive with an indication or other approved condition of use:

– The use code must describe only the specific approved MOU claimed by the patent.

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Patent Listing

• Patented method of use is narrower than an indication or other approved condition of use:

– If the method of use claimed by the patent does not cover an indication or other approved condition of use in its entirety, then the NDA holder must describe only the specific approved method of use claimed by the patent, and not the broader indication or other approved condition of use that may include, but is broader than, the use claimed by the patent.

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Patent Listing – Example

• If the patent claims a novel dosing regimen for a particular indication, the use code must specifically describe the protected dosing regimen for that indication and not only the indication to which the dosing regimen relates.

• Thus, if the method(s) of use claimed by the patent does not cover an indication or other approved condition of use in its entirety, an NDA holder’s submission of a use code that describes an entire indication or other approved condition of use would violate FDA's regulations.

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Timing of Submission of

Patent Information

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Untimely Filed Patent Information

• FDA expressly describes the Agency’s current practice with respect to listing patent information that has not been submitted to FDA within 30 days after patent issuance.

– FDA does not require an applicant with a pending 505(b)(2)/ANDA to certify to an untimely filed patent.

– Untimely filed patent information will neither delay approval of a pending 505(b)(2)/ANDA until patent expiration, nor require a carve-out of information related to a patented method of use.

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Categories of Untimely Filed Patent

Information

• FDA expands the categories 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 are not submitted:

– (1) Within 30 days of patent issuance;

– (2) within 30 days of approval of a corresponding change to product labeling; or

– (3) within 30 days of a decision by the PTO or a Federal court that is specific to the patent and alters the construction of a method-of-use claim(s) of the patent.

• This revision is intended to reduce delays in approval related to overbroad or ambiguous patent use codes.

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Patent Information Submission Date

• The submission date of patent information provided by an NDA holder after approval will be the earlier of: (1) the date on which Form FDA 3542 is date-stamped by the Central Document Room; or (2) the form is officially received by FDA in an electronic format.

• These revisions are intended to facilitate prompt listing of patent information in the Orange Book and to remove any ambiguity about the date of submission in light of the implications of untimely filed patent information for the patent certification obligations of 505(b)(2)/ANDA applicants that rely on the listed drug.

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Correction or Change of

Patent Information

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General

• FDA clarifies and enhances the patent listing dispute procedures that govern challenges to the accuracy or relevance of the NDA holder’s submission of patent information to the Agency.

• In addition, FDA requires 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 by the PTO.

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Patent Listing Disputes

• As to the new patent listing dispute mechanism, it is not entirely clear yet how it will work in practice. The following slides describe the process laid out by FDA.

• The process does not ensure that overbroad use codes will not be submitted to FDA, or that they will be corrected. Ultimately, it may be necessary to seek a correction of Orange Book patent information in a counterclaim to a Paragraph IV patent infringement lawsuit (FDC Act 505(j)(5)(C)(ii))).

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Patent Listing Disputes

• For all patent listing disputes, FDA is requiring that the patent listing dispute communication contain a statement of dispute that describes the specific grounds for disagreement regarding the accuracy or relevance of patent information for FDA to send to the applicable NDA holder.

• If a person disputes the accuracy or relevance of submitted patent information regarding an approved method of using the drug product, this statement of dispute must be only a narrative description (no more than 250 words) of the person’s interpretation of the scope of the patent with respect to the MOU.

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Patent Listing Disputes

• FDA intends to forward the statement of dispute (without review or redaction) to the applicable NDA holder using the email address or fax number provided by the NDA holder on the most recent Form FDA 356h submitted to the NDA.

• Therefore, the person submitting the patent listing dispute communication should clearly identify the statement of dispute that he or she intends for FDA to send to the applicable NDA holder, and only include information for which the person consents to disclosure.

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Patent Listing Disputes

• For patent listing disputes directed to MOU claims, the NDA holder must confirm the correctness of the NDA holder’s description of the approved MOU claimed by the patent that has been included as the “use code” in the Orange Book or withdraw or amend the patent information in accordance with 21 CFR 314.53(f)(2).

• In either case, the NDA holder must provide a narrative description (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 . . . .

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Patent Listing Disputes

• The NDA holder must also include the signed verification required by 21 CFR 314.53(c)(2)(ii)(R) and submit its response within 30 days of the date on which the Agency sends the statement of dispute.

• Any response from the NDA holder that is submitted after 30 days will be considered untimely.

• The narrative description must only contain information for which the NDA holder consents to disclosure because FDA will send the text of the statement to the person who submitted the patent listing dispute without review or redaction . . . .

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Patent Listing Disputes

• FDA may consider the narrative description from the NDA holder to assist FDA in exercising its scientific judgment to implement FDC Act 505(b)(2)(B) and (j)(2)(A)(viii).

• Is the 250-word narrative essentially an extension of the patent use code?

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Patent Listing Disputes

• To advise prospective and pending 505(b)(2)/ANDA applicants of a patent listing dispute involving a MOU patent, FDA will promptly post information about the patent listing dispute on a Web page linked to the Orange Book.

• FDA intends to provide information such as the relevant drug product, NDA number, NDA holder, U.S. Patent Number, relevant use code(s), and whether the NDA holder has timely responded to the patent listing dispute.

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Paragraph IV Certification

Notice – Timing

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General

• FDA’s regulations will clearly delineate two limitations on the timeframe 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 FDA’s longstanding practice regarding premature notice); and

– (2) the date, established by the MMA, by which notice must be given to be considered timely.

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Original Applications

• For an original application, a 505(b)(2) applicant must send Paragraph IV notice on or after the date on which the application is filed, and an ANDA applicant must send notice on or after the date on which it receives a “Paragraph IV Acknowledgment Letter” from FDA stating that the application is sufficiently complete to permit a substantive review.

• Both 505(b)(2) and ANDA applicants must send notice of a paragraph IV certification not later than 20 days after the date of the “Postmark” on the Paragraph IV Acknowledgment Letter.

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Amendments & Supplements

• For an amendment or supplement, an applicant must send notice of a Paragraph IV certification contained in an amendment to a 505(b)(2) application (that has been filed) or ANDA (that has been received for substantive review) or in a supplement to an approved application at the same time that the amendment or supplement is submitted to FDA.

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ANDAs – Elimination of Serial

Certifications

• The first working day after the day the patent is published in the Orange Book is established as the date before which an ANDA applicant cannot send valid notice of a Paragraph IV certification to a newly listed patent.

• Notice of a Paragraph IV certification that has been sent prematurely is invalid, and will not be considered to comply with the FDC Act’s notice requirement.

• This approach is intended to promote equity among ANDA applicants seeking eligibility for 180-day exclusivity and to reduce the burden on industry and FDA associated with serial submissions.

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Paragraph IV Certification

Notice – Content &

Methods

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General

• FDA revises the Paragraph IV notice content to incorporate requirements added by the MMA.

• FDA also expands the acceptable methods of sending Paragraph IV notice beyond registered or certified mail to include “designated delivery services.”

– Eliminates the need for applicants to request FDA’s permission to send notice by common alternate delivery methods.

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Amended Patent

Certifications

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General

• FDA clarifies the requirements for a 505(b)(2)/ANDA applicant to amend a Paragraph IV certification after a judicial finding of patent infringement to reflect statutory changes made by the MMA.

• FDA also clarifies the circumstances and timeframe in which a 505(b)(2)/ANDA applicant must submit an amended patent certification after an NDA holder has withdrawn a patent and requested removal from the Orange Book.

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General

• The Final Rule codifies FDA’s 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 exclusivity has expired, and exempting 505(b)(2) applicants from providing or maintaining a certification to withdrawn patents.

• In addition, the Final Rule expressly codifies the current requirement for a 505(b)(2)/ANDA applicant to submit a patent certification to a timely filed, newly issued patent that claims the RLD or an approved method of using such drug.

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Patent Certification

Requirements for

Amendments

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General

• FDA clarifies and augments the patent certification requirements for amendments to 505(b)(2)s/ANDAs to ensure that certain types of changes to the drug product are accompanied by an appropriate patent certification (or recertification) or patent statement.

• The regulations maintain the requirement 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.

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Amendments - Changes

• An appropriate patent certification (or recertification) or statement is required to accompany an amendment to:

– (1) add a new indication or other condition of use

– (2) add a new strength

– (3) make other-than-minor changes in product formulation, or

– (4) change the physical form or crystalline structure of the active ingredient.

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Supplements - Changes

• FDA will maintain its current practice of regulating directly from the statute and general patent certification regulations in requiring an appropriate patent certification or statement with a 505(b)(2) or ANDA supplement. – FDA had proposed to reduce the patent certification

requirements by providing that a 505(b)(2) supplement that only seeks approval to add a new indication or other condition of use is required to contain an appropriate patent certification or statement only for patents that are identified as claiming an approved use.

– Also, FDA had proposed not to require a patent certification with a supplement to change the formulation or to change the physical form or crystalline structure of the active ingredient of a product approved in a 505(b)(2)/ANDA.

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ANDA/505(b)(2)

Amendment &

Supplement Submission

Limitation

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Change in Listed Drug

• FDA codifies the Agency’s 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 (FDC Act 505(b)(4)(A)); or

– (2) “a drug referring to a different listed drug” than the drug cited as the basis for ANDA submission (FDC Act 505(j)(2)(D)(i)).

• FDA implements 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.

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Change in Listed Drug – ANDA

• An ANDA applicant may not amend a pending ANDA to reference a listed drug different than the listed drug originally cited in the application.

• This situation might arise, for example in the context of a “petitioned ANDA,” where the petitioned change is approved under a new NDA, resulting in the creation of a new RLD.

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Change in Listed Drug – 505(b)(2)

• According to FDA, a drug is a “different drug” requiring the submission of a new application if the drug product has been modified to have a different active ingredient, route of administration, dosage form, or a difference in excipients requiring a separate clinical study to establish safety or effectiveness (or, in the case of topical products, that requires a separate in vivo demonstration of bioequivalence).

• An applicant may amend a 505(b)(2) application to seek approval of a different strength.

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505(b)(2) Applications

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Listed Drug Identification

• FDA will require a 505(b)(2) applicant to identify one pharmaceutically equivalent drug product approved in an NDA, if one or more is approved before the original 505(b)(2) application is submitted, as a listed drug relied upon, and comply with applicable regulatory requirements.

• This regulation 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 could have been approved in an ANDA.

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ANDA/505(b)(2) Date of

Approval

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General

• The rule describes (more comprehensively) the timing of approval of a 505(b)(2)/ANDA based on the patent certification(s) or statement(s) submitted by the 505(b)(2)/ANDA applicant.

• FDA’s regulations are revised to reflect the MMA’s limitation on multiple 30-month stays of approval of a 505(b)(2)/ANDA containing a Paragraph IV certification to certain patents.

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30-Month Stay – Initiation

• 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(s)).

• This revision codifies FDA’s current practice and provides an efficient means of ensuring that each patent owner or NDA holder receives the full statutory 30-month stay.

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30-Month Stay – Termination

• FDA codifies 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 505(b)(2)/ANDA approval.

• FDA also addresses other scenarios in which a 30-month stay may be terminated: – Written consent to approval by the patent owner or

exclusive patent licensee;

– A court order terminating the stay;

– A court order of dismissal without a finding of infringement in each pending suit for patent infringement brought within 45 days of receipt of the Paragraph IV notice.

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Notice of Commercial

Marketing

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General

• FDA updates its regulations to reflect the MMA provisions that modify the types of events that can trigger the start of 180-day exclusivity.

• A first applicant is required to submit correspondence to its ANDA notifying FDA within 30 days of the date of first commercial marketing of the drug product.

– If a first applicant fails to notify FDA within this timeframe, FDA will deem the date of first commercial marketing to be the date of the drug product’s approval.

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Commercial Marketing – Definition

• Under the amended definition, “commercial marketing” of the drug product refers to a transfer of the drug product outside the control of the ANDA applicant, subject to specified exceptions, and thus does not include a transfer of the drug product within the control of the ANDA applicant.

• The amended definition is intended to clarify that the ANDA applicant’s shipment of a drug product described in an ANDA to any party named in the ANDA for purposes described in the ANDA (e.g., contract packaging) is not “commercial marketing” of the drug product even though such transfer arguably places the drug products outside of the control of the manufacturer.

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Notice of Court Actions;

Consent to Approval

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General

• FDA expands the scope of documentation that an applicant must submit to the Agency regarding patent-related court actions and written consent to approval to ensure that FDA is promptly advised of information that may affect the timing of 505(b)(2)/ANDA approval.

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Documentation

• A copy of any judgment by the court (district court or mandate of the court of appeals) or settlement order or consent decree signed and entered by the court (district court or court of appeals) finding a patent invalid, unenforceable, or not infringed, or finding the patent valid and infringed;

• Written notification of whether or not any action by the court has been appealed within the time permitted for an appeal;

• A copy of any order entered by the court terminating the 30-month or 7½-year period;

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Documentation

• A copy of any written consent to approval by the patent owner or exclusive patent licensee (not a copy of the settlement agreement);

• A copy of any preliminary injunction, and a copy of any subsequent court order lifting the injunction; and

• A copy of any court order pursuant to 35 U.S.C. 271(e)(4)(A) ordering that a 505(b)(2) application or ANDA may be approved no earlier than the date specified.

• All information must be sent to the applicant’s NDA/ANDA within 14 days of the date of entry by the court, the date of appeal or expiration of the time for appeal, or the date of written consent to approval.

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