Patent Issues and 180-Day Exclusivity

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Generic Firm’s Duties, Triggered By
Patents
• Be Aware Of Patent Status
– Infringement = triple damages
– Search Orange Book and PTO
• Patent Certification, 21 CFR 314.94(a)(12)
• Amend Patent Cert. Until ANDA Approval
• Lack of “Duty of Care” Risks Payment of
Attorney’s Fees

Safe Harbor for ANDA R&D on Patent-
Protected RLD
• History: Court Held “Patent Infringement” Includes Pre-
commercial Testing of Product (Roche v. Bolar, Federal Circuit,
1984)
• Waxman Hatch Act -- Overturned the Court Decision,
Specifically Declaring that Precommercial Testing Is NOT an
Infringement (35 USC Section 271(e)(1))
• Statute Language: Person May Make, Use or Sell a Patented
Drug During the Patent Life If Solely for Uses Reasonably
Related to the Development and Submission of Information
under a Federal Law Which Regulates the Manufacture, Use or
Sale of Drugs

Safe Harbor for ANDA R&D on
Patent-Protected RLD
• Safe Harbor Applies to Innovator and Generic Firms
(Bristol-Myers Squibb v. Rhone-Poulenc Rorer, S.D.N.Y.
2001, aff’d, 3rd Circuit, 2003)
• “Reasonably Related” Means Having a Decent Prospect that
the “Use” Would Generate the Kind of Information Relevant
to FDA Approval Requirements
– (Intermedics v. Ventritex, N.D.Ca. 1991, aff’d, Federal Circuit, 1993 – clinical
trials on intermediates, yes)
– (Integra Life Sciences v. Merck, Sup. Ct., 2005 – preclinical research to identify
future candidate, yes)

ANDA Patent Certifications
No -- Orange Book Patent
• Paragraph 1 – Patent
information not submitted to
FDA
• Paragraph 2 – Patent has
expired
• No Relevant Patents
Statement – No Patents exist
Yes -- Orange Book Patent
• Paragraph 3 – Will not market
until patent expires
• Paragraph 4 – Challenging the
patent as invalid, unenforceable
or not infringed
• Little viii Statement – Patent
not infringed because not
seeking approval for that use;
use will not be on label (Method
of Use Carve-Out)

Labeling Carve-Outs (“Little viii”
Statement)
• Authorized by FFDCA, Sec. 505(j)(2)(A)(v)
– Generic drug must have same labeling as RLD, except for
changes required because of different manufacturers
• Preferred by FDA, 21 CFR 314.94(a)(7), (8)
– Generic labeling may omit an indication or other labeled aspect
that is protected by patent or exclusivity
• Upheld by Courts
– “The statute expresses the legislature's concern that the new generic be safe and
effective for each indication that will appear on its label; whether the label for
the new generic lists every indication approved for the use of the pioneer is a
matter of indifference.“ Bristol Myers Squibb Co. v. Shalala, 91 F.3d 1493, 1500
(D.C. Cir. 1996).
– Sigma-Tau Pharmaceuticals, Inc. v. Schwetz, 288 F .3d 141 (4th Cir. 2002) (orphan
drug exclusivity).

Labeling Carve-Outs (“Little viii”
Statement)
• Differences must not render the proposed product less safe or
effective than the RLD for all remaining, non-protected
conditions of use. 21 CFR 314.127(a)(7)
• Rapamune (sirolimus) – Carve-out Denied
– 3-yr Excl. for cyclosporine withdrawal regimen, extensive info from
clinical study throughout labeling, protected labeling info essential
to safe and effective use of the drug
– FDA: Labeling contains extensive, critical prescribing info that
doctors should receive to determine treatment for any indication.
Sept. 20, 2004, Docket FDA-2003-P-00002.
• Oxandrin (oxandrolone) – Carve-out Upheld
– 3-yr Excl. for geriatric use, clinical study info in labeling
– FDA: all S&E issues within general adult population are adequately
addressed in labeling without geriatric-specific info. Dec. 1, 2006,
Docket FDA-2005-P-0368.

Para. IV Patent Certification
• Submit Completed ANDA
• Receive FDA Letter That ANDA Has Been
Received
• Send Notice To NDA Sponsor/Patent Holder
• Notice Must Contain:
- ANDA No. - Drug Info.
- Patent No. - Expiry Date
- Scientific Rationale why no infringement/invalid
- Offer to Provide Access to ANDA, if no infringement
- Legal Brief supporting position

Para. IV Patent Certification
• Amend ANDA to Inform FDA of Notice
• Get Receipt of Delivery Confirmation and Submit
to FDA, 21 CFR 314.95
• NDA Sponsor Has 45 Days to Sue, Starting Day
After Notice is Received
• Suit Triggers 30-month Stay Against ANDA
Approval
• Amend ANDA “Immediately” to Inform FDA of
Suit

30-Month Stay Rules
• FDA Is Prohibited From Approving The
ANDA For A Period Of:
– Either 30 Months Counted From Day of NDA
Holder’s Receipt of Notice
– Or Until the Day of a Favorable Court Decision
– Whichever Occurs First

30-Month Stay Rules
• Definition of “Favorable Court Decision” Is
Date-Dependent
• Before March 2000: Appellate Court, per FDA
Policy
• From March 2000 to Dec. 8, 2003: District
Court, per Court Ruling
• After Dec. 8, 2003, Any of the Following:
– District Court Judgment or Settlement Order
– Appellate Court Judgment or Settlement Order

30-Month Stay Rules
• FDA Amendments Act of 2007
• Signed September 27, 2007
• 30-Month Stay Can Be Extended if FDA Decides
that a Pending Citizen Petition Must Cause a
Necessary Delay in the ANDA Approval
• Extension Equals Length of Time from FDA’s
Receipt of Petition to FDA’s Grant/Denial of
Petition

Later-Listed Patents
• Definition: Patents Listed With FDA After An
ANDA Is Filed With FDA
• Whether They Trigger 30-Month Stay
Depends On Before/After Aug. 18, 2003
• Old FDA Regulation: Submit Patent Cert. To
Later-Listed Patents & Notice To NDA Holder.
Effect Is Multiple 30-Month Stays
• MMA: After Para. IV ANDA Is Filed, Submit
Patent Cert. & Notice, But 45-Day Clock & 30-
Month Stay Are NOT Triggered

180-Day Exclusivity
• Available To ANDAs That Contain a Paragraph
IV Patent Certification
• Awarded For Challenging a Patent (Regardless
Of Success)
• Affect On ANDAs:
– Affects Only Subsequently-Filed ANDAs with
Paragraph IV Patent Certifications
– May Be Filed With FDA, And Reviewed, But Will
Not Be Approved Until Exclusivity Expires
– Results In A Tentative Approval Letter
– May Stop/Restart Due to Pediatric Exclusivity

Requirements for ANDA Exclusivity
• First Person to Submit Complete ANDA
(“First to File”)
• Containing a Paragraph IV Certification
• Challenging a Patent as Invalid or Not
Infringed
• Notice to Patent Holder and NDA Holder
• Eligible for 180 Days of Exclusivity

Medicare Modernization Act of 2003
• Rules Governing 180-Day Exclusivity are
Now Date Dependent
– Para. IV ANDAs filed before Dec. 8, 2003 are under “old”
pre-MMA rules
– Para. IV ANDAs filed after Dec. 8, 2003 are under “new”
MMA rules
– For 2nd and 3rd ANDA Filers, “old” pre-MMA rules apply
if First-to-File was Before Dec. 8, 2003

• Timing of Notice to NDA/Patent Holder
– Before Aug. 18, 2003:
 At ANDA Applicant’s Discretion
– After Aug. 18, 2003:
 Within 20 Days After ANDA Applicant Receives
Word From FDA That ANDA Is Acceptable to
Be Received

• Trigger for Start of Exclusivity
– Before Aug. 18, 2003:
 Earlier of Date of Favorable Court Decision
in a Patent Lawsuit, or Date of First-to-File’s
First Commercial Marketing
– After Aug. 18, 2003:
 First-to-File’s First Commercial Marketing (Only); Includes
Authorized Generic

Forfeiture of 180-Day Exclusivity
• After December 8, 2003, via Medicare Modernization Act
• New Section 505(j)(5)(D)
• By the Following Actions
– Withdrawal of ANDA
– Amendment or Withdrawal of Paragraph IV Cert.
– Failure to obtain Tentative Approval within 30 Months after
submission of ANDA
– Agreement with another ANDA Applicant, NDA Holder or
Patent Owner, where FTC files a complaint and successfully
argues the agreement violates antitrust laws
– Expiration of all patents that had Para. IV certs.

Forfeiture of 180-Day Exclusivity …
• By Failure to Market the ANDA Drug by the Later of 2 Dates:
– Date 1: The earlier of the date that is
 75 days after ANDA approval, or
 30 months after ANDA submission
– Date 2:
 75 days after
 Final Ct. Decision that patent is invalid or not infringed
 Lawsuit Settlement where Court enters final judgment that
states patent is invalid or not infringed
 Patent is withdrawn from Orange Book by NDA Holder
 For all patents with Para. IV Certs.
 By any Para. IV ANDA applicant with Tentative Approval

Historical Controversies Over 180-Day
Exclusivity
• Must First Filer Be Sued?
• What is a “Court Decision” That Triggers 180-Day
Exclusivity?
– 1999: FDA Regulation Said Appellate Court
– 1997-2000: Court Rulings Said Trial Court
– 2000: FDA Guidance Said First Court That Decides the
Patent Is Invalid, Unenforceable or Not Infringed
– After Aug. 18, 2003: No Court (Only Trigger Is First Filer’s
First Commercial Marketing)

Problems Interpreting 180-Day
Exclusivity
• Does Later Filer Ever Get ANDA Exclusivity?
• What About Patents Not Filed Promptly With FDA
(“Late Listed” Patents)?
• Can There Be “Shared” Exclusivity?
– Based on Differing Product Characteristics
– Based on Multiple Patents
– Based on Same-Day Filing of ANDAs
• Can the ANDA Applicant Force a Patent Infringement
Suit?
– Possibly, via Declaratory Judgment Action

Problems Interpreting 180-Day
Exclusivity
• Can exclusivity be “sold”?
• What Are the Potential Consequences of Settling the
Patent Lawsuit?
– Risk of Lawsuit by Plaintiff’s Lawyers, Patient Groups,
Shareholders, Competing Generic Companies, FTC, State
Attorney General
– After Jan. 4, 2004: Must Notify FTC & DOJ Within 10
Business Days of Settlement
– Forfeiture of 180-Day Exclusivity, if settlement “converts”
cert to Para. III

Patent Issues and 180-Day Exclusivity

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