Patenting Repurposed Drugs: Overcoming Subject Matter

Patenting Repurposed Drugs: Overcoming

Subject Matter Eligibility, Prior Art, and

Obviousness Hurdles

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TUESDAY, APRIL 13, 2021

Presenting a live 90-minute webinar with interactive Q&A

John M. Covert, Director, Sterne Kessler Goldstein & Fox PLLC, Washington, D.C.

Marsha Rose Gillentine, Ph.D., Director, Sterne Kessler Goldstein & Fox PLLC, Washington, D.C.

Gaby L. Longsworth, Ph.D., Director, Sterne Kessler Goldstein Fox PLLC, Washington, D.C.

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FOR LIVE EVENT ONLYProgram Materials

Technical Minds. Legal Muscle.

Strafford

Sterne Kessler Goldstein & Fox PLLCApril 13, 2021

confidential © Sterne, Kessler, Goldstein & Fox P.L.L.C. 2021 66

• Why drug repurposing?

• Regulatory considerations for 505(b)(1) and 505(b)(2)

applications

• The Orange Book

• Relevant case studies: new drug formulation vs new use

• IP considerations for drug repurposing

Outline of today’s discussion:


• De novo drug development is costly ($1.3 billion) and time-consuming (10

– 17 years)

• Developing a new formulation or new indication for known drug

• Drug candidates that failed to meet a clinical endpoint but have shown

some positive attributes for possible new use

• Newly developed products can be reformulated or repositioned

− Reformulation: different formulation for the same pharmaceutical drug

− Repositioning: new therapeutic use for a known drug

• Typically target a new patient population, new indication, new dosage

form, dosing regimen or route of administration.

Repurposing drugs


Timeline: Traditional drug development

Flowchart of the traditional drug development process: Avg time at least 16

years

7-8 years

Discovery and preclinical

7-8 years

Safety, Efficacy and clinical studies (Phase 1-3)

> 2 years

FDA review

Post marketing monitoring


Timeline: drug repurposing

Flowchart of drug repurposing: avg time ~5 years

Identification and selection of compound

1-3 years

Licensing and acquisition of

rights

2-4 years

Clinical trials ( preclinical, phase 1, phase 2)

1-6 years

FDA review

Post marketing


• 505(b)(1) New Drug Application (NDA) - contains full reports of safety and efficacy studies conducted by

or for applicant or as to which it has right of reference

• 505(b)(2) Application (“Paper” NDA) - modification to an approved drug

− Relies upon one or more studies not conducted by or for applicant and for which applicant has no right of

reference

− Application must contain sufficient data to support the safety/efficacy of the drug modification

− May be marketed as “branded” or generic

• Abbreviated New Drug Application (ANDA) - duplicate of an approved NDA product:

− Relies on safety and efficacy studies from NDA

− Must have identical active ingredient, route of administration, dosage form, strength, labeling and intended use

− Must demonstrate bioequivalence

Drug Application Types


• Contains full reports of safety and efficacy studies conducted by

or for applicant

• Contains full reports of safety and efficacy studies as to which

applicant has right of reference

• This is the Reference Listed Drug (RLD)

505(b)(1) New Drug Application (NDA)


• Applicant relies on safety and effectiveness data of the

reference-listed-drug

• Applicant can modify the proposed product to deviate from the

RLD

− Salt form, dosage form, route of administration, strength, new

combination product, modified active ingredient, new indications for

previously approved drugs, or an over-the-counter switch

505(b)(2) Application (“Paper NDA”)


• ANDA is submitted based on 505(j) applications

• ANDAs are submitted for:

− Generic drugs;

− Based on an NDA that must be previously approved and listed, known

as the reference listed drug (RLD)

Abbreviated New Drug Application (ANDA)


• Patent Exclusivity is granted by the US Patent and Trademark Office

− Patentee lists the patents covering the drug in the FDA’s “Orange Book”

− Staggered periods of exclusivity based on issuance

• Exclusive marketing rights granted by the FDA upon approval of a drug:

− Orphan Drug (ODE) - 7 years

− New Chemical (NCE) - 5 years

− "Other" Exclusivity - 3 years for a "change" if criteria are met

− Pediatric Exclusivity (PED) - 6 months added

− **Hatch-Waxman Exclusivity - 180 days awarded to First-to-File ANDA containing a

“Paragraph IV certification”

Available Exclusivities


• Patents with claims that cover the

− drug substance (active ingredient)

− drug product (formulation and composition)

− approved method of use

• Not Orange Book listable:

− process or manufacture of the drug substance

− packaging of the drug product

− metabolites or intermediates of the drug substance

Patents eligible to be listed in the Orange Book


Available FDA Exclusivity Comparison


• Avoids much of the cost related to clinical safety and efficacy

testing

• No “sameness” requirement so easier to avoid Orange Book

patents

• Greater incentive if eligible for exclusivity

− FDA exclusivity of up to 7 years for orphan drugs

− Patent exclusivity can apply if applicant obtains its own patents

− Exclusivity is not shared with other generics

Advantages of 505(b)(2) Applications


505(b)(2) strategy – can be lucrative

505(b)(2) Reference Drug What Changed in 505(b)(2) Revenue

Bendeka Treanda Dosage Form 2 billion since 2016

Basaglar Lantus New Formulation 1.12 Billion in 2019

Avycaz Fortaz New Combination 61 million in 2017

Belbuca Buprenorphine Dosage Form 271.9 million (total over ’17, ’18, ’19)

Duopa Sinemet Dosage Form 118 million in 2020

Quick Orange Book Primer


• The Hatch-Waxman Act, also known as the Drug Price Competition and Patent Term

Restoration Act of 1984, required that the FDA make publicly available a list of approved

drug products with therapeutic equivalence evaluations. This list is commonly

abbreviated as the Orange Book (the hard copy had an orange cover).

• Inclusion in the Orange book: approved NDA, 505b2 or ANDA product and not withdrawn

for safety or efficacy reasons.

• Orange Book also includes patent information. NDA/505b2 holders are required to

submit information on patent that claims the approved drug or an approved method of

using such drug.

• Since 2005, the Orange Book is available electronically and via a Mobile App. The

database is easy to search by entering the proprietary name, active ingredient, dosage

form, route of administration, or application number.

What is the Orange Book?






• Paclitaxel was previously approved as Taxol

− Paclitaxel (Taxol) was formulated in 50% Cremophor™ EL

(CrEL)/absolute ethanol

− Cremophor™ EL is associated with a host of side effects, including

severe anaphylactoid hypersensitivity reactions

• Abraxane was filed as a 505b2

− Abraxane is a Cremophor EL-free nanoparticle albumin-bound

paclitaxel composition

Abraxane is a 505(b)(2)


• Without patent protection or FDA exclusivity, commercialization

of many drug products is unlikely

• Exclusivity is a factor in predicting future competition and

pricing options, and the expected value of a potential product

• LOE predictions are factored into financial models associated

with product development, investment and deals

• 3 years of data exclusivity based upon new clinical investigation

is often perceived as inadequate to recapture investment

Exclusivity / Loss of Exclusivity (LOE)


• In the context of ANDA filings, loss of exclusivity frequently

leads to a patent cliff where the revenue stream to the approval

holder quickly diminishes

• Thus, it is important to innovate and to capture resulting

intellectual property during product development

• In a repurposing context, basic composition of matter and first

method of use patents are frequently expired

• New patents may be based on new uses, formulations, dosage

regimens, possibly combinations

Loss of Exclusivity cont.

Relevant Case Studies


1. Drug reformulation example - Mesalazine

Mesalazine, also known as mesalamine or 5-aminosalicylic acid (5-ASA), is used to treat

inflammatory bowel disease, including ulcerative colitis and Crohn's disease.

TAKEDA PHARMACEUTICALS’s LIALDA employs multi-matrix release (MMX) technology

Reformulated as ASACOL HD® by ALLERGAN employing multi coat release technology

Brand name Active ingredient

Dose

Dosage form

FDA approval date

Approval holder

Sales in USD as of 2016

(approx. data)

Lialda® Mesalamine 1200 mg delayed-

release tablets

Jan 2007

Takeda Pharma/Shire

merged

$792 million

Asacol HD® Mesalamine 800 mg delayed-

release tablets

May 2008

Allergan Pharma Inc.

$550 million


The FDA’s Orange Book lists one patent for LIALDA: U.S. Patent No 6773720.

Representative formulation patent claim for Lialda (Takeda):

Controlled-release oral pharmaceutical compositions containing as an active ingredient 5-amino-salicylic acid,

comprising:

a) an inner lipophilic matrix consisting of substances selected from the group consisting of unsaturated and/or

hydrogenated fatty acid, salts, esters or amides thereof, fatty acid mono-, di- or triglycerids, waxes, ceramides,

and cholesterol derivatives with melting points below 90° C., and wherein the active ingredient is dispersed both in

said the lipophilic matrix and in the hydrophilic matrix;

b) an outer hydrophilic matrix wherein the lipophilic matrix is dispersed, and said outer hydrophilic matrix consists

of compounds selected from the group consisting of polymers or copolymers of acrylic or methacrylic acid,

alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins, starches

and derivatives, alginic acid, and natural or synthetic gums;

c) optionally other excipients;

wherein the active ingredient is present in an amount of 80 to 95% by weight of the total composition, and wherein

the active ingredient is dispersed both in the lipophilic matrix and in the hydrophilic matrix.

Drug reformulation example - Mesalazine


Drug reformulation example - MesalazineFDA’s Orange Book lists three patents for Asacol HD: U.S. Patent Nos. 6,893,662; 8,580,302 and

9089492.

Representative formulation patent claim for Asacol HD (Allergan):

1. A pharmaceutical composition in a solid unit dosage form for oral administration in a human or

lower animal comprising:

a. a safe and effective amount of a therapeutically active agent;

b. an inner coating layer selected from the group consisting of poly(methacrylic acid, methyl

methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate) 1:1, and mixtures thereof; and

c. an outer coating layer comprising an enteric polymer or film coating material; wherein the inner

coating layer is not the same as the outer coating layer;

wherein if the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:1 then the outer

coating layer is not poly(methacrylic acid, methyl methacrylate) 1:2 or is not a mixture of

poly(methacrylic acid, methyl methacrylate) 1:1 and poly(methacrylic acid, methyl methacrylate) 1:2;

and wherein the inner coating layer and the outer coating layer contain no therapeutically active

agent.


• Asacol: Warner Chilcott Company LLC v. Zydus

Pharmaceuticals (USA) Inc. et al

− District of Delaware; Settled – US 6,893,662

− Under the terms of the settlement, Zydus can launch its ANDA product

in Nov 2015, or an authorized generic in July 2016 if it fails to obtain

FDA approval of its ANDA by such time

• Asacol: Allergan Pharmaceuticals International Ltd. et al v. Sun

Pharmaceutical Industries Limited et al

− District of New Jersey; Settled – US 9,089,492

Mesalazine - Litigation outcome


2. Drug reformulation example - Venlafaxine

Cases of reformulation are particularly frequent in the realm of psychiatry because non-adherence to treatment is

a key issue in the treatment of mental illnesses. Venlafaxine, sold under the brand name Effexor among others, is

an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat

major depressive disorder (MDD), generalized anxiety disorder (GAD).

WYETH’s Effexor® immediate release tablets

WYETH reformulated as Effexor® XR ER capsules using encapsulated spheroid technology


Dose

Dosage form

FDA approval date

Approval holder

Sales in USD

(approx. data)

Effexor Venlafaxine hydrochloride 12.5-100mg

immediate release tablets

Dec 28, 1993

Wyeth pharmaceuticals Inc

$2 billion over 2001

Effexor XR Venlafaxine hydrochloride 37.5-100mg

extended release capsules

Oct 20, 1997

Upjohn LLC

$2.75 billion as of 2004


Wyeth’s marketing exclusivity for the original venlafaxine compound patent lapsed on June 13, 2008. The ER

formulation lengthened Wyeth’s monopoly on venlafaxine hydrochloride by nine years, until March 20, 2017.

US6274171B1

An extended release formulation of venlafaxine hydrochloride comprising a pharmaceutically acceptable capsule

containing spheroids comprised of from about 6% to about 40% venlafaxine hydrochloride by weight, about 50% to

about 94% microcrystalline cellulose, NF, by weight, and optionally from about 0.25% to about 1% by weight of

hydroxypropyl-methylcellulose, USP, wherein the spheroids are coated with a film coating composition comprised

of ethyl cellulose and hydroxypropylmethylcellulose.

US6419958B2

A method for providing a therapeutic blood plasma concentration of venlafaxine over a twenty-four hour period with

diminished incidence of nausea and emesis which comprises administering orally to a patient in need thereof, an

extended release formulation that a peak blood plasma level of venlafaxine in from about 4 to about 8 hours, said

formulation containing venlafaxine hydrochloride as the active ingredient.

US6403120B1

A method for providing a therapeutic blood plasma concentration of venlafaxine over a twenty four hour period with


extended release formulation that provides peak blood plasma levels of venlafaxine of no more than about 150

ng/ml, said formulation containing venlafaxine hydrochloride as the active ingredient.

Drug reformulation example- Venlafaxine cont.


Wyeth’s marketing exclusivity for the original venlafaxine compound patent lapsed on June 13, 2008. The ER

formulation lengthened Wyeth’s monopoly on venlafaxine hydrochloride by nine years, until March 20, 2017.

US6274171B1

An extended release formulation of venlafaxine hydrochloride comprising a pharmaceutically acceptable capsule

containing spheroids comprised of from about 6% to about 40% venlafaxine hydrochloride by weight, about 50% to

about 94% microcrystalline cellulose, NF, by weight, and optionally from about 0.25% to about 1% by weight of

hydroxypropyl-methylcellulose, USP, wherein the spheroids are coated with a film coating composition comprised

of ethyl cellulose and hydroxypropylmethylcellulose.

US6419958B2

A method for providing a therapeutic blood plasma concentration of venlafaxine over a twenty-four hour period with


extended release formulation that a peak blood plasma level of venlafaxine in from about 4 to about 8 hours, said

formulation containing venlafaxine hydrochloride as the active ingredient.

US6403120B1

A method for providing a therapeutic blood plasma concentration of venlafaxine over a twenty four hour period with


extended release formulation that provides peak blood plasma levels of venlafaxine of no more than about 150

ng/ml, said formulation containing venlafaxine hydrochloride as the active ingredient.

Drug reformulation example- Venlafaxine cont.


• Wyeth LLC v. Nostrum Pharmaceuticals, LLC et al.

− District New Jersey – settled – US 6,274,171, US 6,419,958, US 6,403,120

• Wyeth LLC v. Dr. Reddy's Laboratories, Ltd. et al.


• Wyeth, LLC v. Intellipharmaceutics International Inc. et al

− S. District New York – settled – US 6,274,171, US 6,419,958, US 6,403,120

• Wyeth LLC v. Intellipharmaceutics International Inc. et al

− District Delaware – voluntary dismissal – US 6,274,171, US 6,419,958, US 6,403,120

• Wyeth LLC v. Aurobindo Pharma Limited et al.


Venlafaxine - Litigation outcome


• Wyeth v. Orgenus Pharma Inc. et al.


• Wyeth v. Cadila Healthcare Limited et al

− District Delaware – dismissed – US 6,274,171, US 6,419,958, US 6,403,120

• Wyeth v. Torrent Pharmaceuticals Limited et al

− District Delaware – dismissed – US 6,274,171, US 6,419,958, US 6,403,120

• Wyeth v. Apotex Inc et al

− S. District Florida – US 6,274,171, US 6,419,958, US 6,403,120 – not unenforceable, not

invalid- case closed

• Wyeth v. Biovail Corporation et al

− District Delaware – terminated – US 6,274,171, US 6,419,958, US 6,403,120



• Wyeth v. Wockhardt Limited

− C. District California – terminated – US 6,274,171, US 6,419,958, US 6,403,120 – sealed orders

• Wyeth v. Mylan Pharmaceuticals Inc.

− N. District West Virginia – settled – US 6,274,171, US 6,419,958, US 6,403,120

• Wyeth v. Sandoz, Inc.

− E. District North Carolina – settlement by Sandoz – US 6,274,171, US 6,419,958, US 6,403,120

• Wyeth v. Osmotica Pharmaceutical Corporation

− E. District North Carolina – settled (joint by Wyeth) – US 6,274,171, US 6,419,958, US

6,403,120

• Wyeth v. Lupin Ltd. et al

− District Maryland – patents ruled infringed, not invalid, not unenforceable, permanent injunction

against Lupin - US 6,274,171, US 6,419,958, US 6,403,120



• Wyeth v. Anchen Pharmaceuticals et al

− C. District California – patents ruled infringed, not invalid, not unenforceable, permanent

injunction against Anchen - US 6,274,171, US 6,419,958, US 6,403,120

• Wyeth v. Anchen Pharmaceuticals et al

− C. District California – patents ruled infringed, not invalid, not unenforceable, sealed joint

stipulation to enter consent judgement - US 6,274,171, US 6,419,958, US 6,403,120

• Wyeth v. Impax Laboratories Inc.

− District Delaware – patents ruled infringed, not invalid, not unenforceable - US 6,274,171, US

6,419,958, US 6,403,120

• Wyeth v. Teva Pharmaceuticals




Finasteride, a synthetic 4-azasteroid compound, is an inhibitor of steroid Type II 5α-reductase, an enzyme that

converts testosterone into 5α-dihydrotestosterone (DHT).

Merck’s Proscar: 5 mg tablet for benign prostatic hyperplasia (BPH) in men with an enlarged prostate

Merck’s Propecia: 1 mg tablet for male pattern hair loss (androgenetic alopecia)

3. Drug repositioning example - Finasteride

Brand name Active ingredient / Dose

Dosage form

FDA approval date

Approval holder

Sales in USD

(approx. data)

Proscar Finasteride/ 5 mg

Film coated tablets

June 19, 1992

Merck Research Laboratories

$323 million as of 2008

Propecia Finasteride/ 1 mg

Film coated tablets

Dec 19, 1997

Merck Research Laboratories

$447 million as of 2010


Merck also holds several patents that relate to its finasteride product.

Representative method of use claim - Proscar®: US 5942519

A method for reducing the risk of precipitated acute urinary retention in a male subject at risk therefor,

comprising administration of an effective amount of an inhibitor of 5α-reductase to the subject.

Representative method of use claim - Propecia®:US 5547957

1. A method of treating male pattern baldness comprising orally administering to a male person

having a balding area 17β-(N-tert-butylcarbamoyl)-4-aza-5α- androst-1-ene-3-one in a dosage

amount from 0.05 to 3.0 mgs/day at least until growth of hair can be detected in the balding area by

haircount analysis of the balding area.

Representative method of use claim - Propecia®: US 5571817

1. A method of treating androgenic alopecia which comprises orally administering to a human in need

of such treatment a therapeutically effective amount of 17β-(N-tert-butylcarbamoyl)-4-aza-5α-androst-

1-en-3-one.

Drug repositioning example – Finasteride cont.


Proscar

• Mylan Pharmaceuticals Inc. v. Merck & Co., Inc.

− Middle District Pennsylvania; Dismissed – US 5,942,519, US 5,886,184, US 6,046,183

Propecia

• Merck Sharp & Dohme Corp. v. Watson Laboratories, Inc.

− District New Jersey; Voluntary Dismissal – US 5,547,957, US 5,571,817

• Merck & Co., Inc. et al. v. Hetero Drugs Ltd., et al.

− District New Jersey; Voluntary Dismissal – US 5,547,957, US 5,571,817, US 5,886,184

• Merck & Co., Inc. et al v. Hetero Drugs Ltd., et al

− E. District New York; Voluntary Dismissal – US 5,547,957, US 5,571,817, US 5,886,184

Proscar and Propecia - Litigation outcome


4. Drug reformulation example –Amantadine hydrochlorideAmantadine is a medication used to treat dyskinesia associated with parkinsonism

Symmetrel® marketed by Endo pharmaceuticals is available as immediate release tablets and syrup.

Indications: antiviral (Influenza virus) and Parkinson’s disease. Symmetrel is an NDA.

Gocovri® marketed by Adamas Pharmaceuticals is formulated as an extended-release oral capsule

formulation. Gocovri® is indicated for the treatment of dyskinesia in patients with Parkinson’s disease receiving

levodopa-based therapy. Gocovri® received Orphan drug exclusivity until August 2024. 505(b)(2)

approval letter

Osmolex® ER marketed by Osmotica Pharmaceuticals is formulated as amantadine extended-release tablets

with an immediate-release component. Osmolex® is indicated for treatment of drug-induced extrapyramidal

reactions in adult patients with Parkinson’s disease. 505(b)(2) approval letter

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/016023_S037_SYMMETREL%20SYRUP%20AND%20TABLETS_APPROV.pdf

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208944Orig1s000TOC.cfm

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209410Orig1s000TOC.cfm



Dose

Dosage form

FDA approval date

Approval holder

Sales in USD as of 2019

(approx. data)

Symmetrel® Amantadine hydrochloride

100mg and 50mg

Tablets, soft gelatin

capsules and syrup

November 1980

Endo pharmaceuticals

NDA withdrawn by Endo for

reasons not related to safety

or effectiveness.

Gocovri® Amantadine hydrochloride

129 mg, 193 mg, or 258 mg

Once daily

Extended-release capsules

August 2017

Adamas Pharmaceuticals

505(b)(2) submission based

on Symmetrel

$54.6 million in sales

Osmolex® Amantadine hydrochloride

68.5 mg and 137 mg

Once daily

Extended release tablets

(tablet consists of an

immediate-release outer

layer and an extended-

release inner core)

February 2018

Osmotica Pharmaceuticals

505(b)(2) submission based

on Symmetrel

Launched in 2019 (sales

data not yet available)

4. Drug reformulation example –Amantadine hydrochloride


Tablet formulation Syrup formulation

Each oral tablet contains 100 mg amantadine

hydrochloride

Each 5 ml of syrup contains 50 mg of amantadine

hydrochloride

Inactive ingredients: hydroxypropyl

methylcellulose, magnesium stearate,

microcrystalline cellulose, sodium starch

glycolate.

Inactive ingredients: artificial raspberry flavor,

citric acid, methylparaben, propylparaben, and

sorbitol solution.

Symmetrel®


The FDA’s Orange Book lists 15 patents for Gocovri® U.S. Patent Nos 8389578, 8741343, 8796337,

8889740, 8895614, 8895615, 8895616, 8895617, 8895618, 9867791, 9867792, 9867793, 9877933,

10154971, 10646456.

Representative formulation patent claim for Gocovri® US8796337 (expiry 2025)

1. A method of treating a human subject in need of amantadine therapy, comprising orally administering to the

subject a pharmaceutical composition comprising amantadine, or a pharmaceutically acceptable salt thereof, and

one or more excipients, wherein at least one of the excipients modifies release of the amantadine, or

pharmaceutically acceptable salt thereof, from the pharmaceutical composition,

• wherein a dose of the composition provides a mean change in amantadine plasma concentration as a

function of time (dC/dT) that is less than 40% of the dC/dT provided by a dose of the same quantity of

an immediate release form of amantadine, wherein dC/dT is measured in a single dose human

pharmacokinetic study in a defined time period of 0 to 4 hours after administration,

• and wherein the amantadine, or pharmaceutically acceptable salt thereof, is administered once daily at a dose

of 300 to 500 mg per day.

4. Drug reformulation example- AdamantineExtended release capsules- Adamas pharmaceuticals


• Representative formulation patent claim for Gocovri® US 8889740 (expiry 2025)

1. A dosage form suitable for once-daily administration to a human subject consisting of

(i) 50 mg to 500 mg of a drug selected from the group consisting of amantadine and

pharmaceutically acceptable salts thereof, and

(ii) at least one excipient, wherein at least 50% of the drug in the dosage form is in an

extended release form, and wherein the dosage form provides a mean change in

amantadine plasma concentration as a function of time (dC/dT) as measured in a single

dose human pharmacokinetic study over the time period between 2 hours and 4 hours after

administration that is less than 30% of the dC/dT provided by the same quantity of the

drug in an immediate release form as measured in a single dose human pharmacokinetic

study over the time period between 0 and 2 hours after administration.

4. Drug reformulation example- AdamantineExtended release capsules- Adamas pharmaceuticals


Drug reformulation example –AdamantineExtended release tablets - Osmotica Pharmaceuticals

FDA’s Orange Book lists nine patents for Osmolex ER: U.S. Patent Nos. 8252331; 8574626;

10213393, 10213394, 10500170, 10500171, 10500172, 10512617

Representative formulation patent claim for Osmolex ER® US10213393B1 (Expiry 2038)

A method of treating Parkinson's disease in a patient, comprising:

i) administering to the patient once daily in the morning a pharmaceutical composition comprising about 129 mg of amantadine

free base equivalent for one week;

ii) increasing the dose of amantadine by administering to the patient once daily in the morning a pharmaceutical composition

comprising about 193 mg of amantadine free base equivalent;

wherein each of the pharmaceutical compositions comprises i) an extended release component comprising amantadine free

base equivalent; and ii) an immediate release component comprising about 48 mg of amantadine free base equivalent, wherein

each of the pharmaceutical compositions is an osmotic device comprising an osmotic agent and an osmotic coating,

wherein the maximum daily dose of amantadine is about 322 mg of amantadine free base equivalent,

wherein each of the pharmaceutical compositions provides a mean change in amantadine plasma concentration as a

function of time (dC/dT) that is between about 40% and about 70% of the dC/dT provided by the same quantity of

amantadine or a pharmaceutically acceptable salt thereof in an immediate release form, and

wherein the dC/dT values are measured in a single dose human pharmacokinetic study over the time period between 0 and 4

hours after administration.


• Adamas and Osmotica settled their patent litigation

• As part of the agreement, Adamas acquired the global rights to

Osmolex ER®

Gocovri® – Litigation Outcome


Belrapzo ® marketed by Eagle Pharmaceuticals is available as an injection or IV infusion. Belrapzo ®

is an NDA. 100MG/4ML dosage available

Bendeka ® marketed by Teva Pharmaceutical (Teva licenses the 505(b)(2) from Eagle as part of a

settlement agreement) is available as an injection or IV infusion. Bendeka is a 505(b)(2) approval ;

100MG/4ML dosage available.

Representative method of use claim - Bendeka®: US 8609707

A long term storage stable non-aqueous liquid bendamustine-containing composition, comprising:

bendamustine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable fluid

comprising about 90% polyethylene glycol and about 10% propylene glycol; and a stabilizing amount

of an antioxidant

5. Drug Reformulation Example – BENDAMUSTINE

HYDROCHLORIDEBendamustine hydrochloride is an alkylating drug indicated for treatment of patients with chronic

lymphocytic leukemia (CLL), and indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed

during or within six months of treatment with rituximab or a rituximab-containing regimen.

https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/208194Orig1s000ltr.pdf

https://www.rxlist.com/chronic_lymphocytic_leukemia/definition.htm

https://www.rxlist.com/cll/definition.htm

https://www.rxlist.com/lymphoma/definition.htm


Bendeka – currently ongoing

Bendeka - Litigation outcome


BUPRENORPHINE is approved for treating chronic pain and management of opioid dependence.

Bunavail ® marketed by Biodelivery Sciences is available as a buccal film. Bunavail contains

buprenorphine hydrochloride and naloxone hydrochloride. It was approved as a 505(b)(2) and discontinued

in 2020.

Suboxone marketed by Indivior, Inc. is available as a buccal film. Suboxone contains buprenorphine

hydrochloride and naloxone hydrochloride. Suboxone tablets were approved in 2002 as an NDA (now

discontinued). A sublingual film was approved as an NDA in 2010. This product is still on the market.

Belbuca ® marketed by BDSI is available as a buccal film. Belbuca is a 505(b)(2).

Representative method of use claim - Belbuca®: US 8147866

A mucoadhesive bioerodable drug delivery device suitable for direct transmucosal administration of

buprenorphine to a subject, the mucoadhesive bioerodable drug delivery device comprising: a bioerodable

mucoadhesive layer comprising an effective amount of buprenorphine disposed in a polymeric diffusion

environment.

6. Drug Reformulation Example – BUPRENORPHINE

HYDROCHLORIDE



A method for delivering buprenorphine to a human comprising: administering a mucoadhesive biodegradable

drug delivery device for transmucosal delivery.


A method of treating chronic pain, the method comprising: administering to a subject in need thereof a

mucoadhesive bioerodable drug delivery device, wherein the device is administered once or twice daily.

6. Drug Reformulation Example – BUPRENORPHINE

HYDROCHLORIDE


Belbuca

• BioDelivery Sciences International, Inc. et al v. Chemo Research, SL et al

− District of Delaware; Ongoing – US 8,147,866, US 9,655,843, US 9,901,539

• BioDelivery Sciences International, Incorporated et al v. Alvogen PB

Research & Development LLC et al

− District of Delaware; Ongoing – US 8,147,866, US 9,655,843, US 9,901,539

• BioDelivery Sciences International, Inc. et al v. Teva Pharmaceuticals

USA, Inc. et al

− District of Delaware; Settled – US 8,147,866, US 7,579,019, US 8,703,177, US 9,522,188

Belbuca - Litigation outcome


Belbuca

• BioDelivery Sciences International, Inc. et al v. Teva Pharmaceuticals

USA, Inc. et al

− District of Delaware; Settled – US 8,147,866, US 7,579,019

• BioDelivery Sciences International, Inc. et al v. Actavis Laboratories UT,

Inc.

− District of Delaware; Settled – US 8,147,866, US 7,579,019, US 8,703,177, US 9,522,188

Belbuca - Litigation outcome

IP Considerations


• Drug “reformulation“ or “repositioning” can be cost-effective

• No need to start from scratch

• Obtaining patent protection on previously-known drugs can be challenging

− Novel

− Non-obvious

− Subject matter eligibility

• Freedom to Operate

• Prior art searches

• FTO and prior art should direct IP and R&D strategy

IP Considerations


• Generally, repurposed drugs are subject matter eligible, but the

claims should be carefully written to minimize the likelihood of

Section 101 issues

• The Section 102 requirement that the repurposed drug be novel

can be challenging as there may be a lot of prior art.

• Obviousness under Section 103 may pose the most significant

challenge as Section 103 rejections can be difficult to overcome

without at least some evidence of secondary indicia

IP Considerations


• Diagnostic claims – Vanda (887 F.3d 1117 (Fed. Cir. 2018)) is a roadmap

to treatment of subpopulations of patients

− The claims recite a method of treating a patient having schizophrenia with

iloperidone, a drug known to cause QTc prolongation (a disruption of the heart's

normal rhythm that can lead to serious health problems) in patients having a

particular genotype associated with poor drug metabolism.

• In Vanda, the Federal Circuit held that: “claims that are directed to

particular methods of treatment are patent eligible”

• Further: “[t]he [Vanda] claims cover using a natural product in unnatural

quantities to alter a patient’s natural state, to treat a patient with specific

dosages outlined in the patents. We hold, therefore, that the method

claims are not directed to ineligible subject matter.”

IP Considerations – Subject Matter Eligibility


• Practically speaking, composition of matter claims reciting only the repurposed drug are

not patentable

• Drug previously known and thus its earlier public disclosure would be prior art to any

subsequent patent filing

• Crystal forms, however, are patentable

• Claims to novel pharmaceutical dosage forms/formulations are patentable

• Formulations may have to be narrowly claimed

• Combinations can also provide protection

IP Considerations – Composition of Matter/Dosage

Forms


• Repurposing a drug for a new indication is typically a novel use of the drug

• Use claim reciting a repurposed drug for treating a subject with the new indication should

be patentable

• Subpopulation claims

• Pharmacokinetic claims

• Dosing/dosing regimen claims

• Use claims may be more difficult for competitors to design around (compared to

formulation claims)

• Use claims can also be obtained in many foreign jurisdictions (though with potentially

different claim format)

IP Considerations – Method of Use claims


• Arguments against obviousness of claims for a repurposed drug include a showing of

unexpected results, or long felt need

• Scientific data showing a surprising, unexpected effect of a drug that would not have

been expected based on what was known at the time

• Examples of unexpected results can include that:

− a drug surprisingly works as intended for a new indication, or

− a drug works at the dose used (e.g., a surprisingly low dose), or

− a combination of drugs demonstrates synergy when used together (their combined

effect being greater than each drug acting alone)

− the drug acts via a different target or has a different mechanism of action for the new

use than for its previous use

IP Considerations – Secondary Indicia


• Such examples of unexpected results, or long felt need, can overcome

obviousness rejections for claims directed to method of use, or

pharmaceutical dosage forms

• Evidentiary support

• Careful patent application planning and drafting can avoid or overcome

potential § 103 and other rejections

IP Considerations – Secondary Indicia cont.


Contact Information

Gaby L. Longsworth, Ph.D.

Director

202-772-8824

[email protected]

John M. Covert

Director

202-772-8673

[email protected]

Marsha Rose Gillentine, Ph.D.

Director

202-772-8692

[email protected]

Thank you

Documents

Patenting Repurposed Drugs: Overcoming Subject Matter