August 31, 2011

Intellectual Property Considerations During Nonclinical Drug Development

Mary Breen Smith

msmith@sbiplaw.com

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Business Goal: Marketing Exclusivity

• Cost of a new drug (NDA) through FDA approval: $800 million (estimate) o drug discovery, preclinical work, Phase I/II/III clinical trials

• Generics can “freeride” off of the work performed by innovator companies to gain market approval

• How best to recoup these expenses and maximize profitability?

• Regulatory statutes provide marketing exclusivity periods (e.g., exclude generic competition)

• Patent statutes also provide exclusivity periods

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Regulatory Exclusivity via Hatch-Waxman Act

Codified at 21 U.S.C. §355

• Section 505(b)(1) NDA or Supplemental NDA

o New Chemical Entity (NCE) : Five year data exclusivity from the date of first NDA

approval for all products containing chemical entities never previously approved by

FDA for any indication

o For a supplemental NDA: Three year marketing exclusivity for approved drug with

changes (combinations, new indications, dosage strength, route of administration,

amended patient population requiring new clinical investigations, etc.)

• Section 505(b)(2) NDA

o Generally used for approved drug with changes (like supplemental NDA). Differs

from supplemental NDA in that Applicant does not have to originate all data, can use

prior NDA data “without right of reference”

• Three year marketing exclusivity granted (note: five years exclusivity will apply if

NCE approved through the 505(b)(2) route)

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Regulatory Exclusivity (via Hatch-Waxman) cont’d.

• Additional exclusivities

o Orphan Drug: Seven year marketing exclusivity against same drug for the

same disease

• Only “rare diseases or conditions”; for a 505(b)(1) or 505(b)(2) application

o Pediatric

• Six month of additional term tacked onto end of other exclusivity term --

either patent or regulatory• 505(j) ANDA

o An abbreviated NDA (ANDA) is for a proposed drug that is identical to a

reference listed drug and must demonstrate its bioequivalence.

o 180 days granted for first applicant to file ANDA

o Must wait at least four years after NCE NDA approval to apply for ANDA

(Paragraph IV certification) or five years without certification

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Regulatory Exclusivity cont’d.

• Regulatory Exclusivityo Biologic License Application (BLA) (under Public Health Service Act, not

Hatch-Waxman)• 12 year market exclusivity• Four years for data exclusivity• “biosimilar” approval rules still in draft stage

• Deviceo Classes I, II, IIIo No clinical work if substantially identical to a predicate device (Class I and II)o PMA, premarket approval necessary for Class III or non predicate Class I or

II devices o No marketing exclusivity grantedo Data exclusivity: follow on Class 3 devices cannot use original PMA data for

six years but can use information from the published literatureo Patents important

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Patent Exclusivity

• An issued U.S. patent is a U.S. government grant of limited monopoly rights for inventions. Inventions are, by definition, both novel and non-obvious over what is already known (“the prior art"). o U.S. patent rights are limited to U.S. only; for patent rights in other

countries, must separately pursue rights in those countries

• The Constitutional basis for federal patent and copyright systems is to be found in the Constitution of the United States Article 1, Section 8, clause 8

• The patent laws pre-date the regulatory laws and are separate systems and rights, but do intersect at a few points (see next slides)

• The patent system has the potential to extend the marketing exclusivity for a new drug, indication, dosage, biologic, etc. significantly beyond those periods provided by Hatch-Waxman/Public Health Service Act

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Patent Exclusivity cont’d.• Basic patent term: 20 years from effective filing date of a patent

application. o Approval of a patent (issuance of patent) from the U.S. Patent and

Trademark Office may take several years. However, the relevant date is the filing date; term of patent depends only on filing date. Change occurred in 1995; prior to that term was 17 years from date of issuance of the patent (filing date didn’t matter).

• Types of patentable subject matter relevant for pharma/bio/device:o New composition of matter (e.g., NCE, monoclonal antibody, recombinant

protein, vaccine, DNA sequence, combinations of drugs)o Methods of use (e.g., to treat a disease, dosing methods, etc.)o Diagnostic methodso Deviceso Manufacturing methodso Analytical methodso Patient populations

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Intersection Between Patent Laws and Regulatory Laws

• An ANDA must have a certification regarding the patent status of the NDA approved drugo (I)that such patent information has not been filed, o (II)that such patent has expired, o (III) of the date on which such patent will expire, or o (IV)that such patent is invalid or will not be infringed by the

manufacture, use, or sale of the new drug for which the application is submitted

• INVALID: patent claims are not enforceable due to some legal deficiency

• NONINFRINGED: generic product is not within the scope of the patent’s claims

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Intersection Between Patent Laws and Regulatory Laws cont’d.

o Orange Book: 21 USC §355(b)(1)

• NDA holder must list with the FDA all patents they have

(and add patents as they issue) covering the approved

product (within 30 days)

• Electronic Orange Book (

http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm

o NDA holder then has 45 days to file patent infringement

lawsuit to take advantage of provision allowing up to 30

additional months of marketing exclusivity “Thirty month stay”

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Intersection Between Patent Laws and Regulatory Laws cont’d.

o Orange book “listable” patents (cont'd.)

• limited to "composition" or "method of use" patents

• Cannot list manufacturing methods (methods for making (chemically synthesizing) the drug compound)

• Patent Term Extension (PTE)o Up to five years additional patent life (beyond twenty year term) for

delays in the regulatory approval process (e.g., IND and NDA

process) under 35 U.S.C. 156o Applicable to a single patent chosen by the applicant upon

regulatory approval of product for first indication

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Intersection Between Patent Regime and Regulatory Regime cont’d.

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1 year 5 years

6 Mo.PedE

1st ANDA Submitted (Yr. 4)

Paragraph IVChallenge

(30-month stay)

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024

2025

US Patent A Patent Term A Patent Term Extension

7-Yr. OD Exclusivity

5-Yr. Data Exclusivity

NDA Filing

xx/xx/2009Marketing Approval

xx/xx/2017US patent A

(composition of matter)expires

xx/xx/2022A Patent Term Extension (if

granted) Expires

xx/xx/2025US Patent B (use for label indication) expires (patent

obtained later)

Regulatory Exclusivity Periods

- 6 Mo. pediatric exclusivity period attaches to the END of all existing marketing exclusivity and patent periods

- Additional 3-Yr. data exclusivity period available for new indications

6 Mo.PedE

6 Mo.

PedE

Case Study: Patent and Regulatory Exclusivity for Drug NDA approved xx/xx/2009 for Drug

Strategies for Maximizing Exclusivity • Maximize patent exclusivity periods

o Obtain multiple patents with a variety of types of patent claimso Aim for patents having later expiration dates than regulatory exclusivity

periodso Obtain multiple Orange book listable patents to require ANDA applications to

certify against each (requires obtaining legal opinions for each)o File for PTE for patent which best balances covering approved product, strong

patent, and provides longest patent life

• Maximize regulatory exclusivity periodso Obtain supplemental approvals thus new regulatory exclusivity periods

• Original NDA applicant can do supplemental approval applications immediately; all others must wait the five year data exclusivity period

o Supplemental—new indications, new dosage, new formulation (3 year) o Orphan indications (7 year)o Pediatric (6 months)

• Preclinical work can provide information/data to support new patent applications and new regulatory periods

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Publication of Preclinical/tox Studies

• Patents have a “Novelty” requirement: must be new, i.e., not previously known. TRAP FOR THE UNWARY

• “Known” includes publications in technical journals, poster sessions, submitted abstracts for meetings, seminars, slides, lectures, etc.o Disclosures to employees and to others (CROs) under a nondisclosure

agreement (signed) are not public

• In the U.S., there is a “one year” grace period to file a patent application dated from when a public disclosure occurso Most countries require patent filing PRIOR to the first public disclosure

• I have clients who have ONLY U.S. rights to new inventions and have lost worldwide rights o “oh, we already have a patent” o Best practice: run by IP counsel all abstract s/posters and manuscripts sent

by outside collaborators

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Potential New Patentable Subject Matter from Preclinical/tox Studies

• Typical patent position going into preclinical studies is minimalo A “composition of matter” patent may exist

• Often this is an older patent (close to expiration date)• Or there may be no patent (in public domain because either

unpatented or expired patent)• University technology transfer groups may have cost restraints

which may impact patent quality

o Preclinical work can provide new patentable subject matter• If the subject matter is “nonobvious” over previous

disclosures/patents, can obtain new patent with later expiration dates. GOOD NEWS!

• Even “obvious” subject matter can result in new patent claims, but may not have later expiration date.

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Potential New Patentable Subject Matter from Preclinical/tox Studies cont’d.

• Preclinical type of data supportive of new patent applicationo Generally, pharmacology/toxicology showing “expected” results not separately

patentable (also, may not be patentable subject matter) • e.g., pharmacology results (compartment, half life, efficacy, tox) generally not

patentable subject matter per se (although data confirming activity can be used to support existing patent application(s))

• “Mechanism of action” generally not patentable o Some types of data can be separately patentable

• Different indications (new activities)o Example: panel of tumor cell lines, where activity in additional cell

lines is observed (not predicted based on related compounds)o New Method of Use patento New Supplemental NDA (new regulatory period)o Orphan indication?o Orange book listable (if claims cover “label”)

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Potential New Patentable Subject Matter from Preclinical/tox Studies cont’d.

• Preclinical type of data which can subject of new patent application• Combination studies showing synergism between two compounds

o Potential new composition of matter patento Potential new method of use patento Potential new supplemental NDAo Potential NCE (if neither separately approved)o Orange book listable (if claims cover “label”)

• Biomarkers showing which patient populations are more responsiveo interest in these patents since biomarker can be included on labelo Potential new method of use patento Potential new supplemental NDAo Orange book listable (if claims cover “label”)

• Improved analytical techniques (CRO-derived)o Potential new method of use of patent

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Potential New Patentable Subject Matter from Preclinical/tox Studies cont’d.

o Separately patentable subject matter further includes:• Dosing regimens that provide unexpectedly better results

o Generally, finding optimum dosing regime is “routine” experimentation

o New method of use patento Supplemental NDAo Orange Book listable (if claims cover “label”)

o Other types of patentable subject matter (not generally derived from preclinical studies, though)

• New crystal forms/polymorphs (generally quite patentable) or new salt forms (often more difficult to patent without “unexpected” benefits)o New composition of matter patento New method of use patento Supplemental NDAo Orange book listable (if claims cover “label”)

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Potential New Patentable Subject Matter from Preclinical/tox Studies cont’d.

o Other types of patentable subject matter (not generally derived from preclinical studies, though)

• Separated enantiomer (often difficult to patent for being obvious without “unexpectedly” better properties)

o New composition of matter patento New method of use patento Orange book listableo Supplemental NDA

• New formulations (often difficult to patent without “unexpectedly” better properties)

o e.g., enteric coatings; orally active; extended releaseo New composition of matter patento New method of use patento Orange book listableo Supplemental NDA

• Improved manufacturing techniques• Improved storage and handling techniques

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