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11th Annual Paragraph IV Disputes

Alan B. Clement

Partner

Locke Lord LLP

(New York, NY)

The REMS Conundrum: Exploring

Challenges for Both Brands and Generics

Tedd W. Van Buskirk

Partner

Lerner David Littenberg

Krumholz & Mentlik, LLP

(Westfield, NJ)

April 24-25, 2017

Tweeting about this conference?

Katharine R. Rice

Corporate Counsel

Gilead Sciences

(Foster City, CA)

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Discussion Points

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• Overview of REMS process:

obstacles to brand and generic

manufacturers in Hatch-Waxman

scenario

• Examining patent infringement scenarios on drug

subject to a REMS and the REMS process itself

• Exploring scenarios of FDA intervention in brand

and generic discord in REMS design

• Understanding antitrust implications

• Status of pending legislative fix

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REMS

• Certain Risk Evaluation and Mitigation Strategies (REMS) restrict access to the drug

• FDA may require REMS:• pre-approval: if FDA determines REMS is necessary to ensure that the

benefits of the drug outweigh risks

• post-approval: if FDA becomes aware of new safety information and determines REMS is necessary to ensure that the benefits of the drug outweigh risks

• Balancing Act• limited access raises issues for generic BE/BA testing

versus

• expanded access outside of REMS raises safety and business issues

• Statute provides, “no holder of an approved covered application shall use any element to assure safe use . . . to block or delay approval of an ANDA or 505(b)(2) application. (505-1(f)(8)).

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REMS – THALOMID and REVLIMID

• Celgene – THALOMID® (thalidomide) and REVLIMID® (lenalidomide) – patented S.T.E.P.S. (System for Thalidomide Education and Prescribing Safety) and RevAssist REMS programs added to Orange Book

• Celgene refused to supply THALOMID to Lannett, despite Lannett having obtained FDA consent to obtain it outside of REMS

• In 2008, Lannett sued in Federal District Court alleging Sherman § 2 violations:

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REMS – THALOMID and REVLIMID

• Celgene moved to dismiss arguing it had no duty to deal with competitor

• Case settled in 2011 after court denied Celgene’s motion 5

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REMS – THALOMID and REVLIMID• Celgene refused to supply REVLIMID to Dr. Reddy’s Labs.

• In 2009, DRL filed Citizen Petition with FDA alleging violation of 505-1(f)(8)

• FDA denied in part and granted in part the CP in August 2013:

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REMS – THALOMID and REVLIMID• Celgene also refused to supply THALOMID and REVLIMID to Mylan

• Mylan filed lawsuit under the antitrust laws in April 2014:

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REMS – SUBOXONE and SUBUTEX

• Reckitt Benckiser – SUBUTEX® (buprenorphine HCl and SUBOXONE® (buprenorphine HCl-naloxone HCl)

• In September 2012, RB files CP, which FDA denies in February 2013:

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REMS – SUBOXONE and SUBUTEX

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REMS – SUBOXONE and SUBUTEX

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REMS – TRACLEER and ZAVESCA• Actelion - TRACLEER® (bosentan) and ZAVESCA® (bosentan) both subject to

REMS

• In September 2012, Actelion filed preemptive DJ action against Apotex, Roxane, and Actavis:

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REMS – TRACLEER and ZAVESCA• Generics then filed counterclaims for antitrust violations

• Actellion then moved for Judgment on the pleadings

• FTC took notice and filed an amicus brief in March 2013:

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• GPhA similarly took notice and sided with the generics in its amicus brief:

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REMS – TRACLEER and ZAVESCA

• In October 2013, Court denied Actelion’s motion

• Case settled and was dismissed in February 2014

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REMS – LETAIRS® (ambrisentan)• Gilead – LETAIRS® (ambrisentan) is subject to an FDA-mandated REMS. The REMS is

part of Gilead’s Letairis Education and Access Program (“LEAP”).

• In August 2014, Natco Pharma sued Gilead and Express Scripts, a specialty pharmacy that distributes Letairis, alleging that the companies denied Natco access to branded Letairs product for BE studies.

• In November 2014, Zydus/Cadila filed a similar suit against Gilead.

• Gilead filed Motions to Dismiss in both suits.

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• Gilead and Express Scripts prevailed in their motion to dismiss in the Natco case and Zydus subsequently dropped its lawsuit.

REMS – LETAIRS® (ambrisentan)

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Single Shared System REMS Issues

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21 USC 355-1Risk Evaluation and Mitigation Strategy (“REMS”)

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• FDA Amendments Act of 2007 gave FDA

the authority to require drug manufacturers

to have a Risk Evaluation and Mitigation

Strategy ("REMS"). See 21 U.S.C. § 355-1

• REMS requests drug manufacturers

demonstrate to FDA that drug's benefits

outweigh its risks. 21 U.S.C. § 355-1(a)

• A REMS may include a medication guide,

communication plans, patient package inserts, potential restrictions

regarding individuals or entities that may dispense the drug, and

other similar illustrations. See 21 USC §§ 355-1(e) and (f).

• ETASU – Elements To Assure Safe Use. 21 USC § 355-1(f)(3)

BENEFITS RISKS

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21 USC 355-1(f)(3)ETASU - Elements to assure safe use

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(A) health care provider training or special certification;

(B) pharmacies, practitioners, or health care settings that dispense

the drug are specially certified;

(C) dispense drug to patients only in certain health care settings, such

as hospitals;

(D) dispense drug to patients with

evidence or other documentation

of safe-use conditions, such as

laboratory test results;

(E) each patient using the drug be

subject to certain monitoring; or

(F) each patient using the drug be

enrolled in a registry.

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21 USC 355-1(f)(8)

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No holder of an approved covered application shall use any

element to assure safe use required by the Secretary under

this subsection to block or delay approval of an application

under section 355(b)(2) or (j) of this title or to prevent

application of such element under subsection (i)(1)(B) to a

drug that is the subject of an abbreviated new drug

application.

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21 USC 355-1(i)(1)(B)Abbreviated new drug applications (ANDA)

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(B) Elements to assure safe use, if required under subsection

(f) for the listed drug.

• ANDA and the listed drug shall use a single, shared

system under subsection (f).

• The Secretary may waive single shared system

requirement and permit the applicant to use a different,

comparable aspect of the elements to assure safe use,

• if the Secretary determines that—

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21 USC 355-1(i)(1) - Waiver Exceptions

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(i) the burden of creating a single, shared system outweighs

the benefit of a single, shared system health care providers,

patients, ANDA applicant, NDA holder; or

(ii) an aspect of ETASU claimed by a patent or entitled to

trade secret protection, and ANDA applicant certifies it

sought license for ETASU but not able to obtain.

• Certification to describe license efforts

• Secretary may seek to negotiate a voluntary

agreement between NDA holder and ANDA applicant

for such covered ETASU

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Recent Case StudyXyrem® REMS Distribution Patents

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A computerized method of distributing a prescription drug under exclusive control

of an exclusive central pharmacy, the method comprising:

• receiving in a computer processor all prescription requests, … ;

• prescription info entered into exclusive computer database at exclusive central

pharmacy … ;

• checking doctor credentials with computer processor …;

• confirming patient read educational material …;

• checking exclusive computer database for potential prescription abuse…;

• mailing prescription drug to the patient

only if no potential abuse …;

• confirming receipt by the patient of the

prescription drug; and

• generating with the computer

processor periodic reports ….

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Recent Case StudyXyrem® Distribution Patents

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• CBMs denied – not financial transaction

• IPRs – mostly granted (system claims of ‘963 patent not

instituted) – on appeal to Federal Circuit – based on

Advisory Committee prior art

• Citizen Petition – full REMS not a requirement for ANDA

acceptance for filing

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Xyrem Litigation and FDA Waiver

• Recently first filer Roxane settled patent litigation with Jazz

• Waiver granted on REMS distribution system in January 2017 – benefits of separate system outweighed burdens

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Another XYREM® REMS patents (non-OB)US Patent No. 7,797,171

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A method of obtaining FDA approval for a

prescription drug comprising:

• maintaining with a computer processor an

exclusive central computer database;

• determining potential abuse patterns from

information entered into the exclusive central

computer database

• selecting certain multiple controls for

distribution with the computer processor

• displaying the selected controls to an output device; and

• receiving negotiation input from the FDA and adding with the computer processor

further controls from the group until approval is obtained;

• wherein the prescription drug is a scheduled drug in Schedule II-V of FDA subpart

4 regulation embodied in Title 21, CFR Part 314, existing on Apr. 1, 2005.

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Current State of Legislation

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FAST Generics Act – Hard to Obtain

• “Fair Access for Safe and Timely Generics” Act introduced in House of Representatives.

• Effect is to prohibit use of REMS to block eligible drug developers from obtaining REMS-protected products for development of testing

• Reasonable quantities at

• Commercially reasonable, market-based prices

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• The House of Representatives introduced

legislation “to ensure that eligible product

developers have competitive access to approved

drugs.”

• 114 H.R. 2841: “Fair Access for Safe and Timely

Generics Act of 2015’’

• Reintroduced on April 7, 2017 as FAST Generics

Act of 2017

• License holders to negotiate in good faith towards the prompt

development of a single shared system on commercially reasonable terms

• 120 day negotiation period

FAST Generics Act of 2015 – Single Shared System

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CREATES Act of 2016

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• The Senate Judiciary Committee introduced

legislation “To provide for certain causes of action

relating to delays of generic drugs and biosimilar

biological products.”

• 114 S. 3056: “Creating and Restoring Equal Access to

Equivalent Samples Act of 2016’’

• Sec. 3. Actions for delays of Generic Drugs and

Biosimilar Bilologocal Products

(b) Civil Actions

1) Failure to provide sufficient quantities of a

covered product –

2) Failure to reach agreement on shared

REMS system –

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Status of Pending Legislative FixCREATES Act § 3(b)(2)

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Sec. 3. (b) (2) Failure to reach agreement on shared system –

A. An eligible product developer (ANDA or 351(k) applicant), may bring a civil action

against the license holder for a covered product …

i. failed to reach agreement with respect to a single, shared system of

elements to assure safe use with respect to the covered product; or

ii. refused to allow the eligible product developer to join a previously approved

system ….

B. Elements to prevail, by preponderance of the evidence, that:

i. the eligible product developer sought approval

ii. the covered product is subject to a REMS

iii. 120 days after the developer seeks agreement with license holder

iv. No agreement reached allowing product developer to participate in a single,

shared systems

v. the Secretary has not waived the requirement for the covered product to be

part of such a single, shared system

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“Low Drug Costs through Competition Act”

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• The House Judiciary Committee introduced

legislation “To increase competition in the

pharmaceutical industry.”

• 115 H.R. 749: January 30, 2017

• Sec. 3. Study of REMS

(a) The Comptroller General shall conduct a

review of the implementation and

effectiveness of REMS program

(b) Contents of Study

(c) Elements under review, e.g.,

3) The burdens associated with REMS

4) The Standards and policies applied by FDA to require, modify,

add, or remove REMS

5) The effect of REMS programs on generic entry

6) The effect of REMS programs on pharmaceutical prices

(d) Report – not later than May 1, 2018.