FDA ‘Monster’ Patent Reg: Brands, Generics Each Want More Options To Pick Fights

PhRMA is concerned about the agency giving deference to generic sponsors in patent use code disputes, while GPhA wants a mechanism to challenge refuse-to-receive letters.

The brand and generic industries are at odds in their criticism of FDA’s proposed rule to implement portions of the Medicare Modernization Act of 2003. While both find fault with provisions dealing with patent certification they disagree on such issues as patent use codes and Orange Book submissions.

FDA issued the 341-page proposed regulation in February. Intended to implement aspects of the MMA that govern approval of 505(b)(2) and ANDA applications, it covers such an array of topics that some in the industry have referred to it as the “monster” rule (Also see "FDA’s ‘Monster’ Proposed Rule Targets Patent Use Codes, Paragraph IV Certification" - Pink Sheet, 5 Feb, 2015.).

The Pharmaceutical Research and Manufacturers of America and Generic Pharmaceutical Association submitted detailed comments summing up the concerns of their members (see chart below). PhRMA is particularly focused on FDA’s plans for handling patent use codes while GPhA is most adamant about the agency’s process for refusing to receive ANDA applications.

The proposed rule does not address provisions of the MMA pertaining to the forfeiture of 180-day marketing exclusivity, which are expected to be implemented in a separate proposed regulation.

Under the proposed rule FDA would give deference to 505(b)(2) and ANDA applicants’ interpretation of the scope of a patent in disputes over the patent’s use code, which is a description of a drug’s method of use that the NDA holder submits to FDA for inclusion in the agency’s Orange Book. Specifically, deference would be granted if the NDA holder does not respond in a timely manner to a challenge or submits a revision to the use code that is not clear enough for FDA to determine if a generic labeling carve-out would be appropriate.

The rule would also require the use code to describe only the specific portions of the indication or other method of use claimed by the patent if the method-of-use does not cover every approved use of the drug. FDA said this provision is intended to restrain NDA holders from providing overbroad use codes.

FDA cited the Supreme Court’s 2012 ruling in Caraco Pharmaceutical Laboratories Ltd. v. Novo Nordisk AS in which the court held that the Hatch-Waxman Act did not intend for one patented use of a drug to prevent the marketing of a generic drug for unpatented uses (Also see "Patent Use Codes For Brands Can Be Challenged By Generics, Supreme Court Rules" - Pink Sheet, 17 Apr, 2012.).

PhRMA Asks For Examples Of How To Set Use Codes

PhRMA's comments recommend that FDA clarify how NDA holders and patent owners should set use codes, describe how it will employ use codes in determining whether the proposed labeling of 505(b)(2) and ANDA applicants properly omits protected information, and re-evaluate its proposal to regard certain use code changes as late-filed. It also asks FDA not to defer to the applicants’ interpretation of a patent’s scope in the event of a use code dispute.

“FDA’s proposed approach imports speculation and imprecision into the process of setting use codes, as it would require the NDA or patent holder to guess what future ANDA and 505(b)(2) applicants would seek to carve out of the labeling of their proposed products in view of the patent claims,” PhRMA states. It says the use code system should not “usurp the responsibility of applicants in ascertaining the scope of a patent from actually looking at patent claims.”

The association recommends that FDA provide hypothetical examples that demonstrate how an NDA or patent holder should set a use code if the patented method-of-use claim is broader, narrower, or co-extensive with approved indications or conditions of use for a drug. It also requests guidance on how to set a use code when the patent and the approved labeling use different terminology, and when the implicated portions of labeling are outside the indications statement.

PhRMA also urges FDA to clarify its position on the listabilty of patents covering devices in NDA approved drug-device combination products. The association says companies should be able to list patents claiming a drug delivery device, including those that do not disclose or claim the active ingredient or formulation of the approved product, in the Orange Book.

GPhA Wants Mechanism To Challenge Refuse To Receive Letters

GPhA's comments urge FDA to modify its “refuse to receive” process for not accepting ANDA applications. The proposed rule would replace the current acceptance criterion of “sufficiently complete to permit a substantive review” to “substantially complete application.”

The association says that FDA has been “transforming substantive, scientific issues into threshold filing issues,” issuing RTR letters based solely on minor, technical errors in electronic submissions, and failing to provide adequate due process to applicants whose ANDAs were not accepted for filing. It says its members are concerned that FDA will use the proposed changes for receipt of an ANDA to justify this trend.

GPhA asks the agency to add language to the preamble of the final rule “to make clear that FDA’s refusal to receive an ANDA must be based solely on a facial assessment of the application’s completeness rather than a review or evaluation of the ANDA’s substantive content or scientific merits.”

In addition, GPhA says applicants should not be penalized when FDA is unable to read an electronic submission due to technical errors and technical challenges facing the agency. For example, it says FDA should not issue RTR letters based on minor issues with hyperlinks and bookmarking in the eCTD format.

The association also asks FDA to provide a mechanism for ANDA applicants to challenge RTR letters. It notes that NDA applicants are able to request an informal conference with FDA to discuss the basis of a refusal to file decision and to file the NDA under protest, but there is no comparable process for ANDA applicants.

FDA outlined its criteria for issuing RTRs in a guidance document published in May. A Teva executive noted at a GPhA workshop last month that the number of RTR letters has increased from 150 in fiscal year 2013 to 216 in the first half of 2015. He also reported that industry has been successful in challenging these decisions as the agency is overturning one RTR for every two challenged (Also see "FDA Urged to Explain ANDA Deficiencies to Avoid RTR Errors" - Pink Sheet, 25 Jun, 2015.).

Paragraph IV Certification Provisions Criticized

FDA also received comments from several companies and law firms. Kirkland & Ellis partner Michael Shumsky made a submission on behalf of an unnamed pharmaceutical manufacturer client that has approved NDAs, ANDAs and 505(b)(2) applications. The company wants FDA to withdraw the proposed provision deeming an NDA holder’s amendment of a use code untimely if it is submitted more than 30 days after patent issuance and is not tied to a corresponding change in the approved product labeling.

The company also objects to a provision barring applicants from notifying the NDA holder of a paragraph IV certification until after the applicant receives a letter from FDA acknowledging receipt of its application or paragraph certification.

The provision is intended to prevent premature paragraph IV notices but Shumsky says that due to the gap between the 60-day deadline at which point 505(b)(2) applications are considered filed and the agency’s 75-day goal for sending acknowledgment letters to 505(b)(2) applicants, the proposal would have the effect of delaying the provision of notice of paragraph IV certification by a 505(b)(2) applicant by approximately two weeks. This would thereby delay the initiation of patient infringement litigation and any corresponding 30-month stay of approval.

Hospira Inc. also objects to the timing of paragraph IV certification notices, saying the lag will have the practical effect of extending an NDA’s holder’s 30-month stay by two weeks.

Hospira further requests a revision to the proposal requiring applicants to submit patent certifications for amendments or supplements to ANDA and 505(b)(2) applications that add a new indication or condition of use, add a new strength, make minor changes in product formulation, or change the physical form or crystalline structure of the active ingredient.

The company recommends that the proposed rule “expressly recognize the fact that a change to an applicant’s ANDA that does not materially affect an applicant’s paragraph IV certification” does not require the applicant to submit an amended certification, except with regard to adding a new strength.

Hospira also objects to FDA’s proposal to penalize ANDA applicants for failing to send timely paragraph IV notifications to patent holders by delaying the date of application submission by the number of days the applicant exceeded the deadline. The company says this is “unduly punitive” and suggests that the agency instead reduce the first filer applicant’s 180-day exclusivity period by the number of days the notice was late.

Choosing The Reference Listed Drug

Hospira also criticizes a provision pertaining to amendments or supplements to ANDAs that reference a different listed drug. The proposed rule states that “if at any time before approval of an ANDA, an NDA is approved for a drug product that is pharmaceutically equivalent to the product in the pending ANDA, and the NDA is designated as an RLD, the applicant is not permitted to amend its pending ANDA” but must submit a new ANDA that identifies the pharmaceutically equivalent product as the basis for its submission.

This “creates an enormous incentive for NDA-holders to attempt to ‘game the system’ and keep lower-cost generic products off the market by identifying new RLDs in order to nullify a pending ANDA,” Hospira states. It suggests that the proposed rule be revised to require the ANDA applicant to submit a new ANDA identifying the pharmaceutically equivalent product if the NDA is approved before submission of the ANDA.

Purdue Pharma LP’s law firm Kleinfeld Kaplan & Becker submitted comments on the proposed rule and separately submitted a citizen petition requesting that FDA ensure that Pfizer Inc.’s 505(b)(2) application for ALO-02, a twice-a-day solid oral dosage form of oxycodone, reference Purdue’s NDAs for OxyContin (oxycodone extended-release) and Targiniq ER (oxycodone/naloxone extended-release).

Purdue says Pfizer’s NDA includes a study demonstrating the similarity between ALO-02 and reformulated OxyContin that apparently relies on Roxicodone (oxycodone) IR as the reference listed drug. It contends that FDA should require 505(b)(2) applicants to reference the previously approved product that is most similar for 505(b)(2) purposes, which in the case of ALO-02 would be Targiniq ER.

Brand And Generic Divide On Medicare Modernization Act
The Pharmaceutical Research and Manufacturers of America and the Generic Pharmaceutical Association are critical of different provisions in FDA’s proposed rule to implement portions of the Medicare Modernization Act governing the approval of 505(b)(2) and ANDA applications. Below are their primary concerns.
Provision	PhRMA	GPhA
Patent use code content: Use code to be more aligned with patent claims	Objects to proposal that if patent’s method of use claim(s) do not cover every approved use of the drug, then the NDA holder’s use code must contain only the specific portion(s) of the indication or other method of use claimed by the patent	Supports proposal
Patent use code disputes: ANDA or 505(b)(2) applicant’s interpretation of a patent’s scope to be given deference in disputes over the use code	Says FDA should drop proposal as it would incentivize applicants to dispute method-of-use patent listings	Suggests FDA reduce 30-day deadline for an NDA sponsor to respond to a request from FDA about the accuracy of patent information to 15 days
Orange Book submissions: Proposes changes in process for challenging patents	Asks FDA to clarify where and when voluntary delisting requests should be submitted; suggests FDA reconsider its proposal to make patent declaration Form FDA 3542 publicly available on its website prior to an FOIA request	Supports proposals to have each approved method-of-use be separately identified and to have the NDA sponsor identify only the specific sections of product labeling that correspond to specific indication if the scope of the patent does not cover all uses of a drug product
Timing of ANDA and 505(b)(2) approvals: FDA to convert approval to tentative approval if a court orders the approval date be delayed	Says FDA should confirm it will not approve a pending ANDA or 505(b)(2) application if a district court finds patent infringement after a 30-month stay or a 7½ year period has expired; preliminary injunction after these time periods should stay approval through at least the appeal if the district court finds patent infringement	No comment
Paragraph IV certification: Changes timing of when applicants must provide notice of certification to NDA holder or patent owner	Urges Orange Book staff to consider publishing names and addresses for each patent owner and NDA holder; requests that failure of ANDA and 505(b)(2) applicants to send notice letters to these designated names and addresses will render the notice invalid and the 45-day clock for bringing suit will not begin until valid notice has been provided	Says proposal to hold paragraph IV certification invalid if it is sent before the first working day after the patent is listed in the Orange Book would dilute the value of 180-day exclusivity by enabling multiple applicants to be eligible
Patent certifications: New certification would be required if an ANDA applicant seeks approval for a new indication, new strength, change in formulation, or change in the physical form or crystalline structure of the active ingredient	Wants FDA to require ANDA and 505(b)(2) applicants to submit patent certifications for supplements that propose major changes to the formulation or changes to the physical form or crystalline structure of the active ingredient	Says recertification should be determined by ANDA applicant based on modified formulation in relation to the patent
Original patent and reissue patent: To be treated as a single bundle of rights	No comment	Urges FDA to determine if the proposal is valid in light of Fourth Circuit’s 2014 ruling in Mylan v. FDA, which held that a reissue patent is distinct and can yield a separate period of 180-day exclusivity (Also see "Generic Celebrex Dispute Shows Hatch-Waxman’s Legal Wrath" - Pink Sheet, 22 Dec, 2014.)
Date of ANDA approval: Requires first applicant to notify FDA within 30 days of the date of first commercial marketing, which would be the date of ANDA approval	Advocates that FDA define the “date of approval” for purposes of NCE exclusivity of controlled substances as the date on which the company could begin commercially marketing the drug, not the date stamped on the NDA approval letter	Says this proposal is inconsistent with FDA’s proposed definition of “commercial marketing,” which requires an approved drug to be introduced into interstate commerce
Refuse to receive process: ANDA acceptance criteria would be revised from “sufficiently complete to permit a substantive review” to “substantially complete application”	No comment	Asks FDA to clarify that refusal to receive an ANDA is based solely on assessment of an application’s completeness rather than evaluation of its substantive content or scientific merits; wants FDA to provide a mechanism for applicants to challenge RTR letters