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)

3 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”)

4 180-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

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

6 180-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

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/non- infringement 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.five patents listed in Orange Book 2.suit brought on 1 of 5 listed patents 3.Novartis refused to grant a covenant not to sue 4.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

14 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

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®), long- acting, 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? Years PCT National Stage - $$$ FDA Approval Patent Expiration EP Validation Phase - $$$ Phase Preclinical23FDA Review1

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