Introduction To Generic Drug

S.Ganesan IPR Dept. , R&D Orchid Chemicals and Pharmaceuticals 4th September 2004

OBJECTIVES
To provide basic idea about the generic drugs , their approval and Marketing in US. Introduction to Hatch-Waxman Act and its role in developing US generic market Strategies used to delays generic drug entry by Brand Company Determining the expiry of US patents Patent term extensions under 35USC 156

What is a generic drug

Same active ingredient(s) Same route of administration Same dosage form Same strength Same conditions of use Compared to reference listed drug (RLD) (brand name product) in orange Book

U.S. Pharmaceutical Sales in $.

.
$150 $125 $101.7 $100 $87.9 $57.5 $61.7 $68.4 $77.9 $121.7 $138.5

$ in Billions

$75 $50 $25 $0

1993

1994

1995

1996

1997

1998

1999

2000

Source: IMS Health

Value of Generics:

Real Business is yet to come...

$50 $40 $30 $20 $7 $10 $0 Off-Patent w/o Competition Losing Patent Protection by 2010
$ in Billions

$41

Hatch-Waxman Act
The Drug Price Competition and Patent Term Restoration Act of 1984 Its a dual balancing act

Hatch-Waxman Act
Benefits to Innovator: Patent term extension Exclusivity provision Benefits to Generic :

Abbreviated New Drug Application (ANDA)

bioequivalence no clinical testing Patent challenges and generic exclusivity Exemption to infringement

NDA vs ANDA.
NDA ANDA

1. Chemistry
2. Manufacturing 3. Controls 4. Labeling 5. Testing 6. Animal studies 7. Clinical studies 8. Bioavailability

Chemistry
Manufacturing Controls Labeling Testing Bioequivalence

Cost of Drug Innovation Vs Imitation

Innovation Long Gestation Period --- 10 yrs (approx) Low Success Rate High R&D cost ~ 800 mn$/NCE Imitation Short Gestation Period -- 1.5 to 2 Yrs Low R&D cost ~1-2 mn$

Patent Term Extension

(PTE)
Provides (limited) patent term restoration to innovators to compensate for delay in FDA approval process One PTE per drug One PTE per patent Extension may not be more than 5 years Total term (as extended) may not exceed 14 years from approval

Patent term extension

Patent Must Claim:
Product
Drug Product

= Active Ingredient
Biologic, medical device, food and color additives

Method of using product

Patent term extension

Basic Conditions: Term of patent not expired Patent never extended Product subject to review before commercial marketing or use Application submitted by owner or agent First permitted marketing of product

Patent term extension

Term of Extension: 1/2 x [(Begin: IND Effective) (End:Initial NDA Submission)] + (Begin: Initial NDA Submission) (End: Date of Approval) Reduce if applicant did not act with due diligence To sum up;

Formula = 50% development time + 100% review time (less any non-diligent time) up to 5 years

PTE-Tacrine
N

HOECHST-ROUSSEL Vs LEHMAN 4,631,286 claims 1-hydroxy-tacrine and its use Requested extension on the basis of Tacrine Approval Rejected by USPTO Extension is given to Innovator (Warner-Lambert) Method of use patent.

Cefdinir Omnicef Tablet

Cefdinir Omnicef Oral Suspension

Adjustments in patent term extension..

1. 2. 3. The PTOs delay
(examining or processing an application)

interferences, and Application pending for more than 3 years.

Orange Book
Title of the Orange Book: Approved drug products with therapeutic equivalence evaluations Electronic Version: http://www.fda.gov/cder/ob/ All FDA approved drug products listed (NDAs, OTCs and ANDAs) Expiration dates: patent and exclusivity Reference Listed Drugs/ brand drugs identified by FDA for generic companies to compare with their proposed products FDAs Position: Administrative Function Only
Lists Patents that are Granted

Exclusivity & Patent Listings

NDA must notify about patents that claim the drug product that is the subject of the NDA. Patents that are notified by originators in NDAs are listed by the FDA in the publication Approved drug products with therapeutic equivalence evaluations Commonly recognized as the Orange Book. Patent listings 30 days of new approval 30 days of issuance if drug already approved Lists all current exclusivities and submitted patents

Creation of ANDA
Patent Certifications I no patent information filed in OB II filed patent has expired III will await patent expire IV wont infringe or patent invalid requires notice to patent holder with detailed statement of law and fact for why patent should not block ANDA

 Mesalamine (ENEMA; RECTAL )

Paragraph II

 Zaleplon 4,626,538 06.06.2008 (1,810 days)

PARA III

 Amlodipine Para IV or III

 Rosiglitazone Maleate Para IV or III

PARA IV

Statutory Exclusivities Under Hatch- Waxman..

Exclusivity is marketing protection Exclusivity is given & enforced by FDA Exclusivity prevents the marketing of an identical generic or 505(b)(2) product for a certain period of time Exclusivity prevents either the submission or approval of an ANDA application

New Chemical Entity (NCE) Exclusivity

Granted to a drug that contains no active moiety that has been approved by FDA in any other [NDA]. Five year exclusivity NCE exclusivity runs from time of NDA approval and bars FDA from accepting for review any ANDA or 505(b)(2) application for a drug containing the same active ingredient for. five years if ANDA or 505(b)(2) does not contain a paragraph IV certification to a listed patent four years if ANDA or 505(b)(2) contains a paragraph IV certification to a listed patent

 Fondaparinux Sodium Patent expired on August 19, 2003 NCE market exclusivity expires December 7, 2006

3-Year Exclusivity
Available for NDAs which contain: Reports of "new" "clinical trials" That were "essential to approval" of the NDA Conducted or sponsored by the applicant FDA may not approve an ANDA or 505(b)(2) NDA for 3 years after approval Applies for new indications, Rx OTC switch (Omeprazole ), new dosing regimen, and some other labeling changes, New esters, etc

Omeprazole Rx-OTC Switch NP (01.03.2007)

Lansoprazole (INJECTABLE; INTRAVENOUS

NDF: 27.05.2007

Orphan Drug Exclusivity

Granted to drugs designated and approved to treat diseases or conditions affecting fewer than 200,000 in the U.S. (or more than 200,0000 and no hope of recovering costs) Seven year exclusivity Orphan exclusivity bars FDA from approving any other application (ANDA, 505(b)(2) or full NDA or BLA) for the same drug for the same orphan disease or condition for seven years. Eg ; Zoledronic Acid

Product Patent Expiry : 24.07.2007

NCE Expiry : 20.08.2006 ODE Expiry : 20.08.2008

Anagrelide Hydrochloride Patent US RE 31,617 Expiry; January 13, 1993 Approval date Mar 14, 1997 ODE until March 14, 2004

Pediatric Exclusivity
Pediatric exclusivity is an incentive developed by Congress to encourage sponsors to conduct pediatric studies Six month exclusivity Pediatric exclusivity does not stand alone - it attaches only to existing exclusivity or patents Possible delay of generic approval by six month period

Sumatriptan Succinate

Patent Challenge Exclusivity

Granted to ANDA application containing PARA-IV certification Only to first filer

Moexipril
First generic to file paragraph IV certification Listed Patent only one US 4,743,450 relates pharmaceutical composition non-infringement of a US Patent by TEVA
180 day exclusivity

505 (b) 2 Applications

Not a completely New Product Not a me too Product Approval requires clinical data (Basic studies related to safety and Efficacy can be taken from others)

505(b)(2) applications
Like ANDAs Blocked by exclusivity Required to file patent certifications Unlike all ANDAs Able to earn exclusivity May differ from RLD in more ways

Patent Term Calculation

The Face of the Patent is not the Whole Story in Determining Effective Patent Life in the US Factors Affecting include: GATT Terminal Disclaimer Patent Term Adjustment Maintenance Fees Interference Invalidation

Patent Term
GATT
US Patents filed prior to June 8, 1995 receive the greater of 17 years from grant or 20 years from first filing. After June 8, 1995, 20 years from first filing.

Patent Term Calculation Illustrative example

US 5,856,336 expires Date of Filing Date of Effective Filing Date of Grant Date of Expiry Date of priority

: : : : :

May 25, 1992 FD Aug.19, 1988 FFD Jan. 5, 1999 GD Jan 5, 2016 Aug 3, 1988

Patent Term Calculation

US 5,565,447 expires Date of Filing Date of Effective Filing Date of Grant Date of Expiry Date of priority

: : : : :

May 9, 1995 Mar 28, 1994 Oct 15, 1996 Mar 28, 2014 Aug 3, 1988

But there is a Certificate of Correction for First filing

Patent Term Calculation

US 5,565,447 expires Date of Filing Date of Effective Filing Date of Grant Date of Expiry Date of priority

: : : : :

May 9, 1995 Mar 28, 1994 wrong date Jul. 19, 1993 Oct 15, 1996 Mar 28, 2014 wrong expiry Oct 15, 2013 Aug 3, 1988

There is a Certificate of Correction for First filing

Terminal Disclaimers

To Obviate a Provisional Double Patenting Rejection A Terminal Disclaimer can reduce the Patent term and will not increase the term of patent.

Maintenance Fees

Payment of maintenance fees is necessary to prevent patent expiration Must be paid on or before due date or within six months grace period. Can be paid after grace period if unintentional (within 24 months) or unavoidable (any time). 3 and , 7 and , 11 and month

Patent Term Calculation

Patent term extension (PTE) is 5 Year from actual Patent expiry or 14 years from product approval by FDA which ever is earlier

Patent Term Calculation

How to know if innovator has applied for Patent term extension (PTE) Apply 14 year rule Request for PTE has to be made within 60 days from approval date. Requested USPTO for the information on PTE applications No information is available for some of the products Federal Register- Search

Cefprozil
Product Patent : Date Of Grant : First filing Date : Before GATT Expiry : After GATT : Extensions Given : Date of Expiry : Date of Approval : Apply 14 year Rule Corrected Expiry : US 4,520,022 28.05.1985 28.01. 1983 28.05.2002 28.01.2003 1305 days 25.08.2006 23.12.2001 23.12.2005

Medicare Reform
Loopholes in Hatch Waxman Act Multiple and Improper patent Listing Brand Migration (Prilosec to Nexium) Tie up with first Generic company Cementing With Medicare Reform Only one 30 month Delay Clarify patent submission and listing requirements Generic drug entry

Drug Product Hytrin

Total Number of Stays 3

Total Length of Stays

Net Sales in Year the Second Stay was Issued Between $500 and $750 million

70 months
(The time from the beginning of the first stay until the end of the final stay lasted approximately 70 months, but the stays were not overlapping)

Paxil Taxol

5 2

65 months

Over $1 billion

BuSpar

Potentially 60 months Between $750 (The actual length of stays were million and $1 shorter because of court billion actions) Potentially 30 months Between $500 (The actual length of stays were and $750 million shorter because of court
actions)

Neurontin capsules Neurontin tablets Tiazac

53 months

Between $250 million and $500 million 37 months Between $250 million and $500 million Potentially 60 months Between $100 (The actual length of stays were and $250 million shorter because of court
actions)

2002 FTC Study at p. 49

To Sum Up
Knowledge of IP is essential for all Generic Business is awaited Know about when to enter. Early entry will be benefited Cost effective NIP is needed for Generic Drug Consult IPM for any IP related matters

THANKS