FDA- Patent Term Extension - Legal avenues for … Patent Term Extension - Legal avenues for Generic Player Pub. L. No. 98-417 Codified at 15 U.S.C. 68b-68c, 70b (1994); 21 U.S.C

HATCH-WAXMAN ACT SWAPNA SUNDAR CEO, IP DOME – IP STRATEGY ADVISORS

FDA- Patent Term Extension - Legal avenues for Generic Player

Pub. L. No. 98-417 Codified at 15 U.S.C. §§ 68b-68c, 70b (1994); 21 U.S.C. §§ 301 note, 355, 360cc (1994); 28 U.S.C. § 2201

(c) swapna sundar, IP Dome, 2012

DRUG PRICE COMPETITION AND PATENT TERM RESTORATION ACT OF 1984

IMPORTANT CONCEPTS Definitions and understanding


Pioneer/innovator drugs vs. Generic drugs • Brand name/ pioneer/

innovator drugs are drugs which are patent protected.

• Brand names are usually capitalised such as Lopressor

• copies of brand-name drugs that have exactly the same dosage, intended use, effects, side effects, route of administration, risks, safety, and strength as the original drug. In other words, their pharmacological effects are exactly the same as those of their brand-name counterparts.

• Names are not capitalised such as metoprolol

• Should not look identical to brand name drugs

• Can have different colours, flavours, or combinations of inactive ingredients, but active ingredients must be the same as brand name drug.


Drug pricing is controlled by Federal Trade Commission


Some important terms

• Formulation is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product.

• Dosage forms are a mixture of active drug components and nondrug components and include pill, tablet, or capsule, drink or syrup.

• An active ingredient (AI/API) An active ingredient is any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals.

• Drug Product is the finished dosage form that contains a drug substance, generally, but not necessarily in association with other active or inactive ingredients.


Contd.

• A Reference Listed Drug (RLD) is an approved drug product to which new generic versions are compared to show that they are bioequivalent.

• A New Molecular/chemical Entity is an active ingredient that has never before been approved for marketing in US by FDA.

• The strength of a drug product tells how much of the active ingredient is present in each dosage.

• Drug products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product.


The active ingredient of a new human/animal drug, antibiotic drug, or human/vet. biological product

- Any medical device, food additive or color additive subject to regulation under the Federal Food, Drug and Cosmetic Act

A patent is considered to claim the product if it a. claims the active ingredient per se, or b. claims a composition or formulation which contains the

active ingredient(s) and the claim covers the composition or formulation approved for commercial marketing or use

if any one active ingredient has not been previously approved, it can form the basis of an extension of patent term provided the patent claims that ingredient

(c) Swapna Sundar, IP Dome

Product

Types of FDA applications

• FDA: US Food and Drug Administration • IND: Investigational New Drug Application • NDA: New Drug Application • ANDA: Abbreviated New Drug Application • 505(b)(2) application


FDA Center for Drug Evaluation and Research (CDER) ensures that drugs marketed in US are safe and effective. CDER does not test drugs. Innovator Co. is responsible for testing and submitting evidence of safety and efficacy. Office of Testing and Research conducts limited research in the areas of drug quality, safety, and effectiveness. A team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists reviews the sponsor's NDA containing the data and proposed labelling.


DRUG APPROVAL Vs. DRUG PATENTING

Balancing Innovation with Affordability “ . . . the American people will save money, and yet receive the best medicine that pharmaceutical science can provide.”

- President Reagan, Sept.

24, 1984

We have now just enshrined, as soon as I sign this bill, the core principle that everybody should have some basic security when it comes to their healthcare.

- Barack Obama

Market share of generics


HATCH-WAXMAN ACT Basics


Why Hatch-Waxman Act?

• efficacy: 1962 amendments to FDCA in Response to the THALIDOMIDE issue, first introduced proof of Safety and efficacy requirements. • Counter the lengthy approval period for innovators Which resulted in de facto shortening of the patent term • Counter the onerous approval requirements for generics

which resulted in “off-patent” drugs with no generic competition

What products are included? • human drug products: active ingredient of a new drug or human biologic product

• medical devices

• food additives, or colour additives • and animal drug products (Generic Animal Drug and Patent Term Restoration Act (Public Law 100-670) 1988)


Key Features of the Hatch-Waxman Act • Streamlined generic approval process • “Safe Harbor” for pre-approval activities

• Patent term restoration to offset lengthy regulatory approval process

• Non-patent exclusivity for innovators and generics • Framework for patent notification and litigation

PATENT TERM ADJUSTMENT Patent Term Guarantee Act of 1999, a part of the American Inventors Protection Act.


1994 amendment 35 U.S.C. § 154: extended patent

term to 20 years USPTO failure to take certain actions within specified time frames (35 U.S.C. § 154(b)(1)(A)) USPTO failure to issue a patent within three years of the actual filing date (35 U.S.C. § 154(b)(1)(B)) Delays due to interference, secrecy order, or successful appellate review (35 U.S.C. § 154(b)(1)(C)) Provides day-for-day adjustment for each failure or delay resulting in adjustment


3 bases for adjustment:

l on the application within fourteen (14) months of

filing/national stage entry

l on a reply or appeal within four (4) months of filing

l on an application within four (4) months after appeal if allowable claims remain in the application

• In some instances, a remand shall be considered a decision reversing an adverse patentability determination

l Failure to issue the patent within four (4) months of the date the issue fee was paid and all outstanding requirements were satisfied


Failure to act within specified time frames (14-4-4-4):

USPTO failure to issue a patent within three years of the

actual filing date:

In an international (PCT) application, “actual filing date” in 35 U.S.C. § 154(b)(1)(B) means the date national stage processing commences

The three-year period does not include time consumed by any of Continued examination, Secrecy order, interference, or any appellate review, or – Applicant-requested delays


Contd.

applicability


The PTA rules only apply to original applications filed on or after May 29, 2000. PCT applications are not eligible but US national stage applications are. Reissue patents are not eligible for PTA because their term is fixed by the term of the original patent. PTA cannot extend the term of a patent beyond the date established by a terminal disclaimer filed in that patent.

16 38

0 14 36 No adjustment beyond any date

specified in a terminal disclaimer No double counting of overlapping

delays. Days to be calculated as calendar days.


Limitations on adjustment

Reductions can occur when the applicant “failed to engage in reasonable efforts to conclude processing or examination of an application for the cumulative total of any periods of time in excess of 3 months that are take not respond to a notice from the Office beyond three months making any rejection, objection, argument or other request.” (35 U.S.C. § 154(b)(2)(C)). Regulations define failure to engage in reasonable efforts to conclude processing or examination of an application. 37 C.F.R. 1.311 Notice of Allowance for fee due within 3 months.


Applicant Adjustment Reductions

24

Impact

37 C.F.R. § 1.704(c)(1)-(11) provides for a reduction in the PTA accumulated because of Office delays, e.g., suspension of action or deferral of issuance of a patent an applicant’s request; (2) abandonment of an application or delay in filing a petition to withdraw abandonment holding; (3) converting a provisional to a non-provisional and (4) submission of papers after notice of allowance.

When is PTA determined

The USPTO sends a PTA calculation to the applicant twice during prosecution of an application. The first time is with the notice of allowance and issue fee due. The PTA calculation is performed shortly before the notice is mailed. The calculation includes an assumption that the patent will issue within four months of issue fee payment.

The USPTO performs a second PTA calculation when the

patent is about to issue for inclusion on the face of the patent. The second calculation includes consideration of the time period from payment of the issue fee to issuance of the patent.


Applicant (patentee) has 180 days from

patent grant to seek review of the USPTO’s adjustment determination by civil action at the US Distt. Court for DC

No third party challenge to USPTO determination prior to patent grant


Judicial review of USPTO determination

Formula Computation


PATENT TERM RESTORATION

28

Patent Term Restoration

• Who: submitted by patent owner or his agent (35 U.S.C. § 156(d)(1)).

• When: filed with the USPTO within the sixty-day period beginning on the date the product received permission for commercial marketing or use (35 U.S.C. § 156(d)(1)).

• What: contents of the application contain information as per 35 U.S.C. § 156(d)(1)(A)-(E).

The

New

Dru

g D

evel

opm

ent P

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ss:

Step

s fr

om T

est T

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ew D

rug

App

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ion

Rev

iew


Formula Under 35 USC §156

50% of the time spent in initial clinical trials (IND);

PLUS 100% of the time spent in new drug application (NDA) approval process Not the same as Patent Term Adjustment which is a USPTO process for adding day-for-day credits to patent term based on prosecution delay. This is offset by applicant delay. Extn can be in addition to adjustment

A new animal drug or veterinary biological product may be extended based on a second or subsequent approval of the active ingredient provided:

1) The patent claims the drug or product 2) The drug or product is not covered in another patent that

has been extended 3) The patent term was not extended on the basis of the

regulatory review period for use in non-food producing animals

4) The second or subsequent approval was the first permitted commercial marketing or use of the drug or product for administration to a food-producing animal


Second extn.

Patent Term Restoration under 35 USC §156

Maximum extn: No more than 5 years, or amounting to a total of 14 years from date of FDA approval (14 Y marketing time). If the product has 14 years to go from marketing, no extn. Can be granted. Other requirements: Patent should not have expired No previous extension under this provision First permitted commercial marketing or use

33

Statutory Requirements for Patent Extension The patent claims the product, or a method of using the product or a method of manufacturing the product (35 U.S.C. § 156(a)). The term of the patent has not expired before the application for PTE has been submitted (35 U.S.C. § 156(a)(1)). The term has never been extended under 156 before (35 U.S.C. § 156(a)(2)). The product has been subject to a regulatory review period before its commercial marketing or use (35 U.S.C. § 156(a)(4)).

Patent and Exclusivity Search Results from query on Appl No 021366 Product 002 in the OB_Rx list.

Patent Data

Appl No

Prod No

Patent No

Patent Expiration

Drug Substance

Claim

Drug Product Claim

Patent Use

Code

Delist Requested

021366 002 6316460 Aug 4, 2020 Y

021366 002 6858618 Dec 17, 2021 U-618

021366 002 RE37314 Jan 8, 2016 Y

Exclusivity Data Appl No Prod No Exclusivity Code Exclusivity Expiration

021366 002 NCE Aug 12, 2008

021366 002 I-573 Nov 6, 2011

021366 002 I-547 Nov 8, 2010

Example timeline: rosuvastatin 11/9/93

06/12/92

8/9/98

6/26/01

8/12/03

12/9/07

2/10/10

8/27/98

8/7/01

8/12/07

8/12/08

2/12/11

440 patent filing date

IND becomes effective

NDA filed

NDA approved - product marketing begins

infringement suits filed

trial scheduled

440 patent issues

reissue application

Re 314 patent issues

generic applicant first-to file date

NCE marketing exclusivity expires

30 month automatic stay expires

6/12/12

1/8/16

Original patent expiration date

patent expiration date following extension

Restoration and adjustment


CASE LAW

37

Cases deciding issues in Patent Term Extn

Limitations on amount of term extension: -Includes only time after patent issue date (35 U.S.C. § 156(c)). -Time where applicant failed to exercise due diligence is

subtracted (35 U.S.C. § 156(c)(1)). -Only one-half of the testing phase is counted (35 U.S.C. §

156(c)(2)). -The total market exclusivity time of a drug cannot exceed 14

years, regardless of how much time was lost to clinical testing and regulatory review. (35 U.S.C. § 156(c)(3)).

-The total time of extension is limited to no more than 5 years (35 U.S.C. § 156(g)(6)).

38

Case 01: Ortho-McNeil v. Lupin (603 F.3d 1377 (Fed. Cir. 2010))

Is a patent claiming a specific enantiomer eligible for patent term extension when a racemate of the enantiomer was previously approved? Yes, a patent claiming the specific enantiomer may be extended under 35 U.S.C. § 156 even though the racemate of the enantiomer was previously approved and a patent claiming the racemate received extension.

39

Case 02: Photocure v. Kappos (603 F.3d 1372 (Fed. Cir. 2010))

Is a patent claiming an ester of a previously approved active ingredient eligible for patent term extension? Yes, the statutory language recites, “active ingredient including any salt or ester of the active ingredient,” not active moiety. Glaxo II (894 F.2d 392 (Fed. Cir. 1990) is controlling in that the term “product” in 156(a)(5)(A) means “active ingredient,” that is, the substance physically present in the final dosage form.

40

Case 03: The Medicines Company v. Kappos (E.D. Va. 1:10CV286)

Patent Term Extension - Does the term “date” as used in section 156(d)(1) (“beginning on the date. . . .”) refer to a business day or calendar day? Medicines Company argues business day. Government argues calendar date. Case is pending.

41

Case 04: Wyeth v. Sebelius (603 F.3d 1291 (Fed. Cir. 2010))

When does the approval phase begin for a new animal drug application when the parts of the application are submitted on a rolling basis? • The approval phase begins when the

Administrative New Animal Drug Application is submitted to FDA referencing all the previously submitted and approved application components.

Wyeth V. Kappos

• Where periods of delay overlap, the net adjustment is limited to ‘the actual number of days the issuance of the patent was delayed,’ to prevent double counting.

• Thus according to PTO, a patentee was due only the greater of one delay not both.

• Federal Circuit held that though double counting should be avoided, the language of the statute was unambiguous that both delays must be counted unless they fall on the same calendar day.


Presenter

Presentation Notes

Here

1. Patented drugs 2. Generics


NEW DRUG PRODUCT EXCLUSIVITY

505(b)(1) or New Drug Applications • Contains full reports of investigations of safety and effectiveness • Five year exclusivity

505(b)(2) Application • At least some of the information required for

approval comes from studies not conducted by or for the applicant


New chemical entities (NCE)

Continued Orphan Drug: 7 years If FDA approval is for disease affecting less than

200,000 U.S. citizens & tropical diseases eg. Myeloma/glioma in adults & muscular dystrophy in kids

Pediatric use: 6 months in addition to existing exclusivity

or patent term: Must have written request from FDA Must report studies to FDA Must fulfill request conditions Esomeprezole Montelukast Pancrelipase

Presenter

Presentation Notes

FDA can’t approve a generic product regardless of patent protection

New Drug Product Exclusivity Exclusivity Regardless of Existence of Patent NCE (New Chemical Entity): 5 years New active ingredient, new molecules, new salts FDA cannot accept a generic application for 5 years (4

years if a Para IV challenge) Effectively 7 ½ years if there is a Para IV challenge after

4 years New product/new use /supplemental exclusivity: 3 years (new clinical studies to support a new indication,

formulation, salt, dosage regimen, etc.; enantiomers)

Presenter

Presentation Notes

FDA can’t approve a generic product regardless of patent protection

♦ Not a generic and not totally new ♦ Similar, but with limited differences, to previously approved drug ♦ Variation of previously approved drug(s) containing the same active Moiety Changes such as Dosage form, Strength, Delivery mechanism, Different formulation (e.g., different salt, complex, enantiomer, new combination of previously approved drugs) Hatch-Waxman: ♦ 505(b)(2) - Streamlined approval process for new products with same active moiety as previously approved drug – Reference listed drug (RLD) Must provide safety and effectiveness studies but can rely on published scientific data


505 (b)(2) Drug

New Delivery Mechanism – Canasa® (mesalamine) suppositories – Axcan – ClobexTM (clobetasol proprionate) lotion – Galderma – LuxiqTM (betamethasone valerate) foam - Connetics – TestimTM (testosterone) gel – Auxilium ♦ New Dosage Form – AltoprevTM (lovastatin) extended release tablets - Andrx – DepoDurTM (morphine Sulfate) liposomal injection – Skye Pharma – Doxil® (doxorubacin HCl) liposomal injection


Examples 1


Examples 2

♦ New Formulation – PexevaTM (paroxetine mesylate) tablets – Synthon – Stalevo® (carbidopa/levodopa/entacapone) tablets – Orion – Xopenex® (levabuterol HCl) inhalation – Sepracor ♦ New Indication – Avodart® (dutasteride) capsules – GlaxoSmithKline: urinary condition –benign prostatic hyperplasia /male pattern baldness – Thalomid® (thalidomide) capsules – Celgene: for cancer

Orange Book


FRAMEWORK FOR NOTIFICATION AND LITIGATION


In Roche Prods., Inc. v. Bolar Pharm. Co.(1984) held that scientific inquiry that has "definite, cognizable, and not insubstantial commercial purposes" did not qualify as experimental use. Bolar used ‘valium’ to test bioequivalence of its generic version. In Embrex, Inc. v. Service Engineering Corp. (2002)that the experimental use defense applied only to actions performed "for amusement, to satisfy idle curiosity, or strictly for philosophical inquiry."

Roche v. Bolar

Bolar exception • Roche Products V. Bolar Pharmaceutical Co. (Fed. Cir.

1984). Roche was the assignee of the rights, expiring in 1984 in prescription sleeping pill "Dalmane”.

• In early 1983, Bolar decided to market a generic drug equivalent to Dalmane after patent expiry. Bolar immediately began its effort to obtain federal approval and to prove bio-availability. Took steps to acquire flurezepam HCl for studies on stability etc. required for ANDA filing.

• Roche complained before Distt. Ct. that testing 6 m before expiry constituted infringement. Held: Tests, demonstrations, and experiments which are in keeping with the legitimate business of the alleged infringer are infringements for which experimental use is not a defense


Framework for patent notification and litigation

NDA holder must notify FDA of any patent that claims

a drug or method of using a drug and with respect to which a claim of infringement can reasonably be asserted FDA publishes in “Orange Book”

“Safe Harbor” for pre-approval activities Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193

(2005) statutory text “provides a wide berth for the use of patented

drugs in activities related to the federal regulatory process” use of patented compounds in preclinical studies is protected .

. . as long as there is a reasonable basis for believing that the experiments will produce “the types of information that are relevant to an IND or NDA.”

“Safe Harbor” for pre-approval activities

Before the Act, a generic manufacturer who used a patented drug during the patent term for the purpose of conducting tests to submit information to the FDA committed patent infringement

Roche Products v. Bolar, 733 F.2d 858 (Fed. Cir. 1984)

Safe Harbour Provision 35 USC § 271:

(a) direct infringement (b) induced infringement (c) contributory infringement

(e)(1) It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention 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 or veterinary biological products.

Requirements for generic approval

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

ANDA 1. Chemistry 2. Manufacturing 3. Controls 4. Labeling 5. Testing 6. Bioequivalence

Notice Letter

Generic applicant who files a paragraph IV certification must notify the patent and NDA holder with a detailed statement

Patent/NDA holder has 45 days to sue Generic applicant can file a declaratory judgment action if not sued

Submitting an ANDA with a PIV certification is infringement

35 USC § 271 (e)(2): It shall be an act of infringement to submit - (A) an application under section 505(j) of the Federal Food,

Drug, and Cosmetic Act or described in section 505(b)(2) of such Act for a drug claimed in a patent or the use of which is claimed in a patent, or

(B) … if the purpose of such submission is to obtain approval under such Act to engage in the commercial manufacture, use, or sale of a drug or veterinary biological product claimed in a patent or the use of which is claimed in a patent before the expiration of such patent.

Automatic Stay of FDA Approval

“somewhat artificial” act of infringement that vests district courts with jurisdiction - Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661 (1990)

Initiation of Lawsuit means FDA cannot approve an ANDA

until: Final court ruling; Patent expires; or 30 months from notification

Remedies for infringement § 271(e) (4) For an act of infringement described in paragraph (2) (A) the court shall order the effective date of any approval of the drug involved in the infringement to be a date which is not earlier than the date of the expiration of the patent which has been infringed,

(B) injunctive relief may be granted against an infringer to prevent

the commercial manufacture, use, offer to sell, or sale within the United States or importation into the United States of an approved drug or veterinary biological product, and

grant injunctive relief;

(C) no damages unless there has been commercial manufacture, use, or sale .

…except that a court may award attorney fees under section 285.

http://www.bitlaw.com/source/35usc/285.html

MARKET AND LINKAGE What is linkage? How does it operate?


• Generic Marketing Approval is “Linked” to

the Expiration of the Pioneer Drug Patent • If a patent exists, marketing approval will

not be granted to a generic until the patent has expired or is found to be invalid.

• Orange Book patent listings: New Drug Application (NDA) must include patent information and the FDA considers the existence of patents as part of the approval process for certain drug applications


Patent linkage

1) Lists:

1) Approved Drugs, 2) Discontinued Drugs 3) Provides Patent and Exclusivity Information

2) Published annually with monthly cumulative supplements

• Electronic Orange Book also available. • When generic drug companies inform FDA that it does not

believe a particular listed patent does covers the FDA-approved drug product - FDA requests evaluation of complaint by innovator company

• Innovator company can request de-listing or respond with good-faith belief that listing is proper


Orange book

Active Ingredient Search Results from "OB_Rx" table for query on "rosuvastatin."

Appl No TE Code RL

D Active Ingredient Dosage Form; Route Strength Proprietary

Name Applicant

021366 No ROSUVASTATIN CALCIUM TABLET; ORAL 10MG CRESTOR IPR


021366 Yes ROSUVASTATIN CALCIUM TABLET; ORAL 40MG CRESTOR IPR


Listing example

Lists Product Name Patent Number Patent Expiration Date Exclusivity

Information


Listing example 2

Presenter

Presentation Notes

FDA relies on innovator drug company’s assertion Patent information published in Orange Book

• Under 505 (b) and (c) of the FDAC Act, patent

information covering the drug must be submitted within 30 days of approval of NDA / supplement or within 30 days of grant of patent – US FDA Requires Applicant to list patents that

cover the drug as part of NDA filing – Applicant Must submit signed declaration – FDA relies on innovator drug company’s assertion – Patent information published in Orange Book


Listing procedure

• Listing irrelevant patents • The '84 Act does not prevent an NDA

holder from listing a newly acquired patent

• This further delays generic competition • Only one thirty month stay proposed • Shared Exclusivity


Abuse of listing provision

Patent challenges and generic exclusivity

Overview of the legal process- ANDA Requirements: • Information to show that that the listed drug is

approved; • That the listed drug has the same active ingredient as

the new drug; • That the route of administration, the dosage forms,

the strength of new drug etc are the same as the listed drug;

• That the new drug is bio-equivalent to the listed drug.


Generic applicant patent certifications

ANDA Certification

Paragraph I:

Paragraph II:

Paragraph III:

Paragraph IV:

Patent status

No Patent info in Orange Book

Patent expired

No product launch until patent expires

Patent is invalid,

unenforceable, or will not be infringed by the manufacture, use, or sale of the drug product for which the ANDA is submitted


eight major parts to the FDA's review of generic drug: There should be RLD listed brand-name drug. Generic must have the same active ingredient and the same labeled strength. It must have the same dosage form-tablets, patches and liquids are examples of dosage forms. It must be administered the same way, for example, swallowed as a pill or given as an injection. The manufacturer must show the generic drug is "bioequivalent" to RLD drug The generic drug's labeling must be essentially the same RLD drug. Fully documented chemistry, manufacturing steps, and quality control measures. Each step of the process must be detailed for FDA review.


The raw materials and the finished product meet USP specifications. U.S. Pharmacopoeia is the non-profit, scientific body chartered by Congress to set standards for drug purity in US. Generic drug maintains stability as labelled before it can be sold. Once on the market, the firm must continue to monitor the drug's stability. The firm must show that the container and its closure system won't interact with the drug. Firms making sterile drugs must submit sterility assurance data showing microbiologic integrity of these products. Full description of the facilities to manufacture, process, test, package, label and control the drug. It must certify that it complies with federal regulations about current good manufacturing practices and undergo FDA inspection of the manufacturing facility to assure compliance. Before FDA approves a generic drug, it usually conducts an inspection at the proposed manufacturing site to make sure the firm is capable of meeting its application commitments and to ensure the firm can manufacture the product consistently.


BIO-EQUIVALENCE generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner) to the pioneer drug. measure the time it takes the generic drug to reach the bloodstream and its concentration in the bloodstream in 24 to 36 healthy, normal volunteers. This gives them the rate and extent of absorption-or bioavailability-of the generic drug, which they then compare to that of the pioneer drug. The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the pioneer drug. Brand-name drugs are subject to the same bioequivalency tests as generics when their manufacturers reformulate them.

• Generic Drug Company must certify when

filing Abbreviated New Drug Application (ANDA)

1) That the drug has not been patented; 2) That the patent has already expired; 3) The date on which the patent will expire, and the generic drug

will not go on the market until that date passes; or 4) That the patent is not infringed or is invalid

Referred to as paragraphs I, II, III and IV certifications

Section 505(j)(2)(A)(vii)


Para I to IV • If the applicant makes a certification under paragraphs

I or II, the statute provides that the FDA may approve the ANDA effective immediately

• If the applicant makes a certification under paragraph

III, the FDA may approve the ANDA effective on the date that the applicant certifies that the patent will expire


• Paragraph I, II, III certifications relatively straightforward – Existence of ANDA normally a secret until

approval date

• Paragraph IV certification more complicated to administer – ANDA applicant must notify innovator

company of its filing; must describe reasons patent will not be infringed, is invalid, or unenforceable


• Paragraph IV Certification

– Innovator has 45-days after receipt of notice to

file an infringement suit; the submission to FDA of paragraph IV certification in an ANDA creates infringement for purposes of federal court jurisdiction

– If lawsuit filed FDA approval is stayed for 30-months; at end of period FDA issues tentative approval


• Provision that is intended to allow the patent-holder time to vindicate its patent in court

• If the court finds that the patent is invalid or is not infringed, the FDA's approval becomes effective as of the date of that ruling


Most ANDA applicants await resolution of the litigation before going to market to avoid liability for damages

Basis for invalidity • Anticipation • Obviousness • Prior art date to be kept in mind • Combining two references-motivation to combine • When a reference cannot be used as prior art against the challenged patent

• Species and genus situations • Obviousness type double patenting


180 days Market Exclusivity • Section 505(j)(5)(B)(IV) • First to file • When does it start • Judgment trigger • Commercial marketing trigger


Successful defence invalidated In 1997, Mova v. Shalala decision the D.C. District Court Mova was the first generic to file a paragraph IV certification ANDA for

a patent owned by Upjohn. Upjohn sued Mova within 45 days but when Mylan filed para IV ANDA, Upjohn did not sue.

FDA approved Mylan’s ANDA. Mova filed suit to compel the FDA to delay the approval of Mylan’s ANDA and preserve Mova’s right to exercise exclusivity.

FDA argued that the statute was ambiguous, therefore, FDA reasoned that “successful defense” requirement was necessary. Because Mova had not yet successfully defended the lawsuit, the FDA reasoned, it was not entitled to exclusivity. Citing its earlier decision in Inwood, the court held successful defense requirement was not essential.

Court granted Mova the relief it sought. Statute might produce unintended results:

1. elimination of the requirement could encourage frivolous ANDA 2. could delay market entry of generic drugs because it required later

filers that were ready to go to market to wait for the conclusion of what is often lengthy litigation (as was the situation in the


• FDA’s interpretation was that the first Paragraph IV applicant

was required to have “successfully defended against a suit for patent infringement” before the applicant is eligible for the 180-day marketing exclusivity period. Court refused to accept FDA reading.

If the first applicant is never sued, the FDA claims, then the court-decision trigger will never be satisfied. Later ANDA applicants will be unable to market their products until the first applicant decides to put its product on the market.

• Court’s “wait and see” approach: grants exclusivity to the generic that is first in-time to file an ANDA, and then requires

• the FDA to stay any subsequent ANDA until the first-filer resolves its suit


First applicant loses its suit • If the first applicant loses its infringement suit, the first

applicant would then be able to satisfy neither the court-decision trigger nor the commercial-marketing trigger

• Thus, the FDA claims, no generic drugs could enter the

market until after the pioneer company's patent expired


First applicants who enter into an agreement with the NDA holder • First ANDA applicant to file a patent challenge may never trigger the start of the 180-day period, thereby blocking the FDA from granting approval to any generic product.

• First generic challenger will enter into a lucrative cash settlement with the patent owner that results in a judgment in favor of the patent


Hoechst-Roussel v Andrx : H-R, the patentee reached a settled with Andrx in respect of once-daily diltiazem product developed by Andrx allegedly infringing upon a formulation patent for Hoechst Marion Roussel's Cardizem CD a once-daily medication for the treatment of hypertension and angina. Andrx developed a second formulation that did not infringe on the Hoechst Marion Roussel patent. Andrx has agreed to market this second formulation and to not market the first. Andrx delayed marketing the formulation until the suit was settled. Hoechst Marion Roussel agreed to compensate Andrx for that delay and will make a final lost-profit payment of approximately $50 million to Andrx. (June 1999) Pfizer V. Apotex (TorPharm): In respect of Amlodipine Besylate ‘Norvasc’, for hypertension and angina, the patent was held invalid as court held that it was found during ‘routine…testing’ to optimise selection of known pharma compounds.


TOTAL No. OF LAW SUITS AGAINST INNOVATORS: 749 INVOLVING :243 brand-name drugs. 72% of Para IV challenges result in litigation Generic challenger wins: 42% Average loss for innovator companies: 12% Average life of patents shortened by: 4 years Between 2008-2009, after 58 ANDA filings, Indian generic maker Orchid Chemicals & Pharmaceuticals Ltd has received approvals from the US Food and Drug Administration (US FDA) for its antibiotic combination piperacillin and tazobactam for injection, with 180-day exclusivity to market the products in US. Dr. Reddy’s marketed generic versions of Omeprazole, and Prozac with 180 day exclusivity. With 27 pending ANDAs, Ranbaxy won this month to sell generic Lipitor, and will share the exclusivity with Israeli generic Teva.



2000 -June 2008: 200 Originator – generic settlement agreements to resolve patent disputes or opposition procedures covering 49 medicines, of which 63% were best-selling medicines that lost exclusivity between 2000 and 2007. In 48% of cases, the generic company's ability to market its medicine was restricted. In addition to the restriction in many cases - a value transfer from the originator to the generic company in the form of a direct payment, a license, a distribution agreement or a "side-deal".

http://ec.europa.eu/competition/sectors/pharmaceuticals/inquiry/2_Originator_Generic_competition.pdf

Direct payments to generic companies in more than 20 settlement agreements for a total amount exceeding € 200 million


1.Teva 2.Mylan 3.Sandoz 4.Watson 5.Greenstone 6.Pan Pharma 7.Hospira 8.Apotex 9.Mallincrodt (covidien) 10. Dr. Reddy’s

Most generics interact closely with originator drug manufacturers – sometimes with respect to specific drugs, and at others on more general drug development


ANDAs are filed by generics that have an agreement with originator not to be sued, but to be supplied with generic copy of drug

Both generic and originator benefit without competition or fear of litigation

a long term relationship develops between originator and generic

Pfizer licensed the product to its own Greenstone subsidiary for generic Gabapentin (Neurontin). Examples of this relationship include: Paxil (Paroxetine) - licensed by GSK to Par Prozac (Fluoxetine) - licensed by Lilly to Barr Augmentin (Co-Amoxiclav) licensed by GSK to IVAX In February this year Dr. Reddy's announced a similar deal with Merck & Co. for two products Proscar (Finasteride) and Zocor (Simvastatin).

COUNTER GENERIC STRATEGY

AstraZeneca received FDA approval to market Omeprazole (exp. In 2001) in US in 1989, as Prilosec®. By 1999, AstraZeneca’s product became one of the most widely prescribed drugs of any kind in the world, with sales of some $6.1 billion annually. In 1999 AstraZeneca commenced suit against four generic pharmaceutical manufacturers after ANDA filing and in 2000 against 4 more. In 1995, the company decided to create a strategy to overcome losses due to patent expiry. What would the outcome be? How can this strategy work?


US Patent 4255431 on omeprazole - racemic mixture

WO patent 94/27988 on esomeprazole – s-enantiomer

Evergreening Purple as symbolics of dependable magic Distress resolution, fear reduction

“the purple pill”


Counter generic strategies • the most popular strategy is the launch of new product

formulations (82%) • defensive pricing (70%) lowering prices or renegotiating

purchasing contracts to fight generics • dependence on overall franchise strength and increased

marketing and promotion • ATORVASTATIN: Ranbaxy has 180 days of exclusivity on

the market due to a settlement with Pfizer - launched generic atorvastatin; competition Lipitor, and an offering from Watson Pharmaceuticals, which is selling an authorized generic version on behalf of Pfizer.

(c) swapna sundar, IP Dome, 2012 the most popular strategy used to defend brands against generic competition is the launch of new product formulations

Pfizer strategy • special contracts and increased product promotion, to

ensure consumers will find it easy and affordable to remain with Lipitor for six months.

• deals to ensure benefits for links in the pharmaceutical value chain. Pharmacy benefit managers have received discounts on Lipitor

• customers co-pays have dropped to $4 through a Pfizer program that provides a discount card.

• Pfizer has assured Congress that insurance companies are also seeing these discounts though no numbers have been given


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Documents

FDA- Patent Term Extension - Legal avenues for … Patent Term Extension - Legal avenues for Generic Player Pub. L. No. 98-417 Codified at 15 U.S.C. 68b-68c, 70b (1994); 21 U.S.C