Leveraging Pharmaceutical
Patent Exclusivities
Michael R. Dzwonczyk
Sughrue Mion, PLLC
Global Perspective on Pharma and Biotech Patents
Taj Residency, Ummed
Ahmedabad, India
April 19, 2007
Sources of Exclusivity
Patent Exclusivity
• Patent Term Extension
Non-Patent (Regulatory) Exclusivity
• New Chemical Entity (NCE) (5 years)
• First ANDA patent challenger (180 days)
• New Clinical Investigations (3 years)
• Orphan Drug (7 years)
• Pediatric (6 months)
First ANDA Patent Challenger Exclusivity
• Under Hatch-Waxman:
• First ANDA Para IV filer (under §505(j)) obtains
180-day exclusivity against other ANDA filers
• FDA precluded from approving second ANDA
covering same drug product for 180 days after
start of first exclusivity period
• Several issues arising under Hatch-Waxman
have been addressed by the Medicare
Modernization Act (“MMA”)
3
180-Day Exclusivity Eligibility
• The drug includes the listed drug
• First applicant includes all ANDAs filed on
the same “first” day (shared exclusivity for
same-day filings)
• First applicant is the first ANDA with a PIV
to any patent (no shared exclusivity for
different patents)
NOTE: NOT applicable to 505(b)(2) applications
4
180-Day Exclusivity Trigger
Is 180-day exclusivity triggered by trial court or
appellate decision?
• Pre-MMA, FDA policy that exclusivity was
triggered by district court decision; Created
difficult choice for ANDA applicants:
• launch at risk of appellate reversal and
face potential lost profits damages, or
• potentially lose benefit of 180-day
exclusivity
180-Day Exclusivity Trigger
Post-MMA
For ANDAs with no Para IV prior to Dec. 8, 2003:
• trigger is first commercial marketing of
generic drug or brand drug by any “first
applicant”
• court decision is no longer a trigger but may
be a “forfeiture” event
6
Post-MMA Forfeiture
First applicant’s 180-day exclusivity forfeited by first
applicant’s:
1. Failure to market
2. Withdrawal of ANDA (either voluntarily or by FDA)
3. Amendment/withdrawal of qualifying Para IV as to
all patents
4. Failure to obtain tentative approval within 30
months
5. Agreement with another ANDA applicant, NDA
holder or patent owner adjudicated to violate
antitrust laws
6. Expiration of all the patents that are subject of
qualifying Para IV of first applicant
Post-MMA Failure to Market Forfeiture
For failure to market the drug by the later of:
• If no PIV litigation, the earlier of:
75 days after ANDA approval; or
30 months after ANDA submission
• If PIV litigation:
– 75 days after favorable court decision on all
qualifying patents (appeals court, or unappealed
district court decision); or
– 75 days after favorable court settlement or
consent decree on all qualifying patents; or
– 75 days after all qualifying patents are delisted
Generic Strategies re 180 days
• Under MMA, ANDA applicant can file
declaratory judgment action for invalidity/noninfringement if patentee does not bring suit
during 45-day period)
• Case or controversy must be proven
“Courts shall, to the extent consistent with
the Constitution, have subject matter
jurisdiction” over such actions.” 35 U.S.C.
§ 271(e)(5)
Generic Strategies re 180 days
• For years, patent holder would not sue at all
within 45-day period or bring suit on less
than all of the listed patents
• ANDA applicants sought DJ relief based on:
– Patent listing in Orange Book
– Failure to sue within 45-day period
– Refusal to grant a covenant not to sue
– Patent holder litigation history
Generic Strategies re 180 days
• DJ relief denied based on failure to establish
“reasonable apprehension of imminent suit”
under Federal Circuit standard
Teva v. Pfizer, Inc., 395 F.3d 1324 (2005)
• Pre- and Post-MMA courts routinely denied DJ
jurisdiction to generic companies
• Resulted in a patent listing/litigation strategy
by patent holder for delaying patent dispute
Generic Strategies re 180 days
• The U.S. Supreme Court criticized the Federal
Circuit’s standard for DJ jurisdiction in
Medimmune v. Genentech (Jan. 2007)
• Controversy established by a definite and
concrete dispute between parties having
adverse legal interests
• In response, Federal Circuit dispenses with its
own Teva standard (“reasonable apprehension
of imminent suit”) in Teva v. Novartis (March 30,
2007)
Teva v. Novartis (March 30, 2007)
• DJ Jurisdiction established where:
1.
2.
3.
4.
five patents listed in Orange Book
suit brought on 1 of 5 listed patents
Novartis refused to grant a covenant not to sue
Novartis had an aggressive litigation history
• Lower threshold for future generics seeking
“patent certainty” through DJ action
• Must establish definite and concrete controversy
• All circumstances may be considered
Generic Strategies re 180 days
• MMA permits ANDA applicant to bring a
counterclaim in an infringement suit to delist
patents from Orange Book
• Counterclaim only; no independent right of
action
• Previously, ANDA applicant had no private
cause of action against NDA holder
• First Para IV ANDA filer likely will not want to
do this because it would lose 180-days
exclusivity, but subsequent ANDA filer may
14
Orange Book Patent Delisting
Mylan Pharm. v. Thompson, 268 F.3d 1323 (Fed.
Cir. 2001) ( Generic applicants are unable to sue
the NDA sponsor to delist a patent)
Andrx Pharm. Inc. v. Biovail Corp., 276 F.3d 1368
(Fed. Cir. 2002) (Right of Action exists against
FDA under the APA for improper patent listing)
Alphapharm v. Thompson, 330 F. Supp. 2d 1
(D.D.C. 2004) (Affirmed FDA’s ministerial role in
declining to list certain patents in the Orange
Book).
Orange Book Patent Delisting
Patentee strategy:
Can an NDA holder delist its own patents
from the Orange Book after P IV
certifications have been filed, in order to
deprive the ANDA applicant of 180-day
exclusivity?
Orange Book Patent Delisting
NO!
• The purpose of the statute is to allow delisting when
a generic drug maker files an ANDA containing a
paragraph IV certification and the NDA holder has
not filed a lawsuit to contest the certification
• FDA may not delist Orange Book patents at the
request of the NDA holder after PIV certifications
have been filed
• NDA holders must prepare to litigate listed patents
Ranbaxy v. Leavitt, 469 F.3d 120 (D.C. Cir. 2006)
Patent Term Extension Basics
• One PTE per drug
• One PTE per patent (even if it covers multiple
products)
• Calculation:
1/2 x [IND Effective Date → NDA Submission]
+ [NDA Submission → NDA Approval]_______
Regulatory Review Period
• Extension may not be more than 5 years
• Total term (as extended) may not exceed 14
years from approval
PTE Case study (Norvasc®)
• Norvasc® is amlodipine besylate
• Dr. Reddys sought approval to market
amlodipine maleate, contending PTE
only covered the approved besylate salt
• Is the “approved drug product” which is
the subject of the PTE the API
(amlodipine) or the particular salt form
that is marketed?
PTE Case study (Norvasc®)
• District Court agreed with Dr. Reddys:
– Since amlodipine besylate was subject to
regulatory review, only besylate salt was
covered by PTE
• Federal Circuit reversed:
– Amlodipine was the “drug product” subject to
regulatory review, so PTE covers amlodipine
and all salts
• If PTE covers active moiety + esters and salts,
can any products be marketed during the PTE at
all?
Products Not Covered by PTE
• Active moiety forms other than salts and
esters
– Polymorphs, polymorph salts, hydrates, etc.
• Usually not covered by NCE patent
• Can be filed in ANDA, eligible for AB-rating
and are directly substitutable
• Different salts and other nonequivalent
forms must be approved through a
505(b)(2) application or even an NDA
Bracketing the IP space of
Important Compounds
How?
•
•
•
•
Polymorphs, salts, esters, cocrystals
Enantiomers (Nexium®)
Formulation, administration
Extended release (Cardizem-XL®), longacting, immediate release, absorption,
pKa, pKd (Procardia-XL®)
• Combination, co-administration, drug
delivery
LCM Approach
© 2004 John Lucas
Bracketing the IP space of
Important Compounds
At what stage in the product lifecycle?
• NCE expiration
• Blockbuster sales
• FDA approval/commercial launch
• Phase III clinicals
• NDA submission
• IND submission
• 18-month publication of patent
When to begin?
PCT National Stage - $$$
FDA Approval
EP Validation Phase - $$$
Years
0
1
2.5
6
11
21
Patent Expiration
Preclinical
1
2
Phase
3
FDA Review
NCE Exclusivity
• Applies to any NDA (including 505(b)(2)) for a
drug no “active ingredient” (including ester or
salt) of which has been approved in any other
NDA
• Prohibits a generic from submitting an ANDA for
5 years from date of NDA approval
• If an ANDA includes a P-IV Certification it can be
filed after 4 years, but any 30-month stay is
extended by up to 1 year (to expire 7-1/2 years
after NDA approval)
Pediatric Exclusivity
• Extends any applicable patent or
regulatory exclusivity by an additional 6
months
• Sponsor must conduct FDA-requested
pediatric studies
• Two separate 6-month extensions are
possible
• Pediatric studies can also support a 3-year
NCI exclusivity
Sunset: October 1, 2007 [Best Pharmaceuticals for Children Act 2002]
Pediatric Exclusivity
• BUT, a provision in the act allows generic
companies to carve pediatric indications out of
their label and thus avoid the patent-term
extension in most cases.
– Statute does not say 505(b)(2) applications
can avoid NCI exclusivity by carve out
Pediatric Exclusivity
• Runs from expiration (including any extensions)
of each Orange Book listed patent
• Bars approval of ANDA or 505(b)(2) for 6
months
• Not a patent term extension so commercial
activities after patent expiration are not subject
to damages or injunction
• In case of Para II and Para III (patent
expiration), any exclusivity automatically begins
at patent expiration
Orphan Drug Exclusivity
• First NDA or BLA approved for a “rare” disease
or condition, i.e., one that
• affects less than 200,000 persons in US,
or
• affects more than 200,000 persons in US
but there is no “reasonable” expectation
that development costs for drug will be
recovered from US sales
Orphan Drug Exclusivity
• Exclusivity bars approval of another NDA,
ANDA, 505(b)(2) or BLA for same drug for
same disease or condition
• “Same drug” means:
– For small molecules, a drug that
contains same active moiety
– For large molecules, a drug that
contains the same principal molecular
structural features
Orphan Drug Exclusivity
Exceptions (allowing the FDA to approve a second drug
during 7-year period):
• If innovator cannot supply enough drug to meet the
needs of persons with the disease
• If the innovator consents
• If the new drug is shown to be different from the
approved orphan drug because the new drug is
“clinically superior”
•Greater effectiveness
•Greater safety (Avonex®)
•Major contribution to patient care
Three-Year NCI Exclusivity
• New clinical indications for approved products
• Supplements adding new conditions of use to
existing product:
– Formulations, indications, dosing regimens,
patient populations, OTC Switch, other
aspects of labeling
• Requires:
– New clinical studies that were conducted or
sponsored by the applicant, and were
"essential to the approval"
Three-Year NCI Exclusivity
• Prohibits FDA approval (but not submission) of
the ANDA for 3 years after NDA/sNDA approval.
Thus, ANDA approval can come exactly 3 years
later
• But, generics can "carve out" exclusive
conditions of use, and pharmacies will still
substitute for the exclusive uses
• Key brand strategy: "discontinued labeling."
Generic "Carve Out" Strategy
• Generic (ANDA) product must have the "same
labeling" as the innovator; but
• Generic labeling may omit (or "carve out")
labeling that is protected by patent or
exclusivity; except
• Carve out not permitted if to do so would
render the generic less safe for remaining
labeled uses
Discontinued Labeling Strategies
• Obtain new, patented or exclusive conditions of
use:
– New dosing schedule (tramadol, famotidine)
– New pK data (metaxalone)
– Combination use (ribavirin/peginterferon)
• Revise labeling to prevent "carve out“ by
generics
• FDA will not permit generic use of old labeling
Summary
 Use DJ action early to establish patent certainty
 Oppose Orange Book delisting after P IV filing
 PIV early to at least one listed patent to gain first
applicant status
 Investigate alternate forms of active moiety and
seek IP protection where possible
 Investigate forms not covered by NCE but still
AB rated
Summary (cont.)
 Investigate and protect formulations, methods
of administration or methods of manufacture
that offer an advantage
 Consider alternative salt forms through a
505(b)(2) application
 Search for drug products with gaps in IP
protection
 Consider pediatric carve-out to avoid 6-month
exclusivity
 Patented use carve-out before NDA holder
discontinues label
Thank You
Michael R. Dzwonczyk
mdzwonczyk@sughrue.com