Patents and the Polymorph

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www.LicensingLaw.Netwww.LicensingLaw.Net Pharmaceutical Patent Attys, LLCPharmaceutical Patent Attys, LLC 11

Patents and the PolymorphPatents and the Polymorph

Washington, DCWashington, DC(Henry Stuart(Henry Stuart publpubl., Feb. 2004)., Feb. 2004)


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Economic ImportanceEconomic Importancenn Revenue loss to innovator firms:Revenue loss to innovator firms:

$51,508,000,000$51,508,000,000nn Revenue gain to generic firms:Revenue gain to generic firms:

$19,117,000,000$19,117,000,000(Figures are for upcoming ten years, discounted at 7%)(Figures are for upcoming ten years, discounted at 7%)

New rule is expected to increase (iv) patentNew rule is expected to increase (iv) patent

certifications by 50%certifications by 50%

nn How to succeed within this new framework?How to succeed within this new framework?


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= Overview == Overview =nn How to draft polymorph patents for theHow to draft polymorph patents for the Orange BookOrange Book

nn Expressly permitted patentsExpressly permitted patents

nn Drug Substance & Drug ProductDrug Substance & Drug Product

nn ProductProduct--byby--processprocess

nn Method of UseMethod of Use

nn Conditionally permitted patentsConditionally permitted patentsnn Polymorphic formsPolymorphic forms

nn Certain patents may need to be reCertain patents may need to be re--issued to qualifyissued to qualifynnManufacturing Intermediates, Packaging, MetabolitesManufacturing Intermediates, Packaging, Metabolites

nnWhat happens when a patent is listed?What happens when a patent is listed?nn 3030--month Stay, 180month Stay, 180--day exclusivityday exclusivitynnDeclaratory Judgment resolutionDeclaratory Judgment resolution

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Drug Substance & ProductDrug Substance & Product

nn DeclarationDeclaration 2.1: Does the patent claim 2.1: Does the patent claimthe drug substance that is the activethe drug substance that is the active

ingredient in the drug product described iningredient in the drug product described in

the approved NDA or supplement?the approved NDA or supplement?

nnthe final rule does not open the door tothe final rule does not open the door to

submission of any patents claimingsubmission of any patents claiming

formulations [not] described in theformulations [not] described in the

NDA.NDA.nn I f at least one patent claim isI f at least one patent claim islistablelistable, the entire, the entire

patent becomes so.patent becomes so.


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Drug Substance & ProductDrug Substance & Productnn CombinationsCombinations

nn FDA Office of Combination ProductsFDA Office of Combination Products

nnExclusion of a patent claiming a drugExclusion of a patent claiming a drug

substance in conjunction with another activesubstance in conjunction with another activeingredient or method of using theingredient or method of using the

combinationcombination

nn This was considered, but ultimately was notThis was considered, but ultimately was not

adopted.adopted.nn I f at least one patent claim isI f at least one patent claim islistablelistable, the entire, the entire

patent becomes so.patent becomes so.


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ProductProduct--byby--processprocessnn Example: eating hardExample: eating hard--cooked eggs to treatcooked eggs to treat

low serum albumin.low serum albumin.

nn N.BN.B.: Raw eggs may contain bacteria.: Raw eggs may contain bacteria

BOIL

ASSUMING THAT THIS HASBEEN KNOWN FOR A LONGTIME, NEITHER THE

BOILING PROCESS NORTHE EGG IS PATENTABLE


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ProductProduct--byby--processprocessnn New combination of process and productNew combination of process and product

nn BothBoth processprocess andand productproduct might be oldmight be old

BOIL MICRO-WAVE

Faster, cheaper


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Drug Substance & ProductDrug Substance & Productnnwhen the PTO issues a patent, the PTOwhen the PTO issues a patent, the PTO

necessarily determines thatnecessarily determines that some aspectsome aspectof the patent claims is novel. We want toof the patent claims is novel. We want tomake sure that the NDA applicant ismake sure that the NDA applicant is

identifyingidentifying the product claimthe product claim asas thethe novelnovelaspect.aspect. CommentsComments at 18.at 18.nn CfCf.: It is illegal for PTO to determine that.: It is illegal for PTO to determine thatsome aspectsome aspect of the claim is or is not novel; of the claim is or is not novel;

the claim must be evaluated as a whole.the claim must be evaluated as a whole.nn CfCf.: Every.: Every product claimproduct claim is novel; it is illegalis novel; it is illegal

for PTO to issue any claim which is not.for PTO to issue any claim which is not.


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Method of UseMethod of Usenn Must claim a use that is described in the NDA;Must claim a use that is described in the NDA;

method of use that is in the labelingmethod of use that is in the labeling

nn CfCf. off. off--point patents need not be certifiedpoint patents need not be certified

nn DeclarationDeclaration 4: 4:

nn Does the patent claim one or more approved methodsDoes the patent claim one or more approved methods

of using the approved drug?of using the approved drug?

nn Identify the use with specific reference to theIdentify the use with specific reference to theapproved labeling for the drug productapproved labeling for the drug product

nn Issues: drafting and certification consequencesIssues: drafting and certification consequences


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Certification ConsequencesCertification ConsequencesnnI attest that this submission compliesI attest that this submission complies

with the requirements of the regulation. Iwith the requirements of the regulation. I

verify under penalty of perjuryverify under penalty of perjury

nn

No good faith belief qualifier, nor exceptionNo good faith belief qualifier, nor exceptionfor subsequent change infor subsequent change in lawlaw oror factfact..

nn If patent claim does not verbatim copy useIf patent claim does not verbatim copy use

codecodenn Where will Doctrine of Equivalents be in the future?Where will Doctrine of Equivalents be in the future?

nn If newlyIf newly--discovered prior art unexpectedlydiscovered prior art unexpectedly

limits claim scopelimits claim scope


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MethodsMethods -- Listing ImplicationsListing Implicationsnn Estoppel may be found in court.Estoppel may be found in court.

nnThe [] requirement to identify claims wasThe [] requirement to identify claims wasintended to help prevent arguments as tointended to help prevent arguments as towhether a particular claim claimed thewhether a particular claim claimed the

approved drug product.approved drug product.nn TensionTension

nnAvoid estoppel by comprehensive listing ofAvoid estoppel by comprehensive listing ofclaimsclaims and risk erroneous listingand risk erroneous listing

nnAvoid perjury potential with an overlyAvoid perjury potential with an overly--conservative listingconservative listing and be estopped fromand be estopped fromenforcing legal rights.enforcing legal rights.


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MethodsMethods Generic StrategyGeneric Strategynn Section (viii) CertificationSection (viii) Certification

nnwhen an ANDA applicant has sought towhen an ANDA applicant has sought to

duplicate the labeling for which the innovatorduplicate the labeling for which the innovator

has submitted the patent, and not tohas submitted the patent, and not to

specifically omit, or carve out labeling, wespecifically omit, or carve out labeling, we

require the ANDA applicant to submit arequire the ANDA applicant to submit a

certificationcertification

nn

PurepacPurepac v. Thompsonv. Thompsonnn Consider claiming the carvedConsider claiming the carved--up labelup label

nn Property & Infringement valueProperty & Infringement value

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= Overview == Overview =nn

How to draft patents for theHow to draft patents for the Orange BookOrange Booknn Expressly permitted patentsExpressly permitted patentsnnDrug Substance & Drug ProductDrug Substance & Drug Product


nnMethod of UseMethod of Use



nn

What happens when a patent is listed?What happens when a patent is listed?nn 3030--month Stay, 180month Stay, 180--day exclusivityday exclusivitynnDeclaratory Judgment resolutionDeclaratory Judgment resolution


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Polymorphic FormsPolymorphic Formsnn Different physical form, yet equivalent toDifferent physical form, yet equivalent to

NDA active ingredientNDA active ingredient

nn crystalline structures, waters of hydration,crystalline structures, waters of hydration,

solvates, amorphous formssolvates, amorphous formsnn Example : hardExample : hard--cooked eggscooked eggs

CHICKEN

OSTRICH

BIG BIRD

STORK


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Polymorphic FormsPolymorphic Formsnn Listed if bioequivalence data existsListed if bioequivalence data existsnn Issues:Issues:

nn Having dataHaving data

nn Timing of dataTiming of data

nn Effect of dataEffect of data

nn Having dataHaving data

nn Manufacturing and packaging process controls,Manufacturing and packaging process controls,product specifications, analytical methods areproduct specifications, analytical methods are

requiredrequired

nn What if Holder doesnt manufacture / sell theWhat if Holder doesnt manufacture / sell thepolymorph?polymorph?


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PolymorphsPolymorphsnn The test data must exist when aThe test data must exist when a

polymorph patent Declaration is submittedpolymorph patent Declaration is submitted

to FDA.to FDA.

nn

CfCf. Patent must be submitted to FDA w/in 30. Patent must be submitted to FDA w/in 30

days after PTO issues it.days after PTO issues it.


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PolymorphsPolymorphsnn Potential Solution: severalPotential Solution: several--month delaymonth delay

between Notice of Allowance and patentbetween Not ice of Allowance and patent

Issue dateIssue date

nn

Cf. PTO can revoke a Notice of AllowanceCf. PTO can revoke a Notice of Allowance


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nn Bioequivalence data mayBioequivalence data may

show that the polymorph isshow that the polymorph is

legally an obvious (read:legally an obvious (read:minor or inconsequential)minor or inconsequential)

variant of the innovatorvariant of the innovator

nn Can make it difficult to obtainCan make it difficult to obtain/ retain a patent claim/ retain a patent claimcovering the polymorphcovering the polymorph

nn Patent attorneyPatent attorney mustmust bebegiven this bioequivalence datagiven this bioequivalence data

SubmitEquivalence

data

ObviousnessRejection

ChangeTarget

Compound

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How to draft patents for theHow to draft patents for the Orange BookOrange Booknn Expressly permitted patentsExpressly permitted patentsnnDrug Substance & Drug ProductDrug Substance & Drug Product





nn



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PackagingPackaging

nn patents must notpatents must not

be submitted forbe submitted for

bottles or containersbottles or containers

and otherand other

packaging, as thesepackaging, as these

are not dosageare not dosage

forms.forms.


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Business MethodsBusiness Methodsnn Patient registries, titration / dosagePatient registries, titration / dosage

schedulesschedules

nn CelgenesCelgenes thalidomidethalidomide

nn Roches 13Roches 13--ciscisretinoic acidretinoic acid

nn Relate claim verbiage to matter withRelate claim verbiage to matter withwhich FDA is comfortablewhich FDA is comfortable


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Manufacturing IntermediateManufacturing Intermediate

We consider reagents to be inWe consider reagents to be in--processprocessmaterials rather than drugmaterials rather than drugHow does one list a softHow does one list a soft--cooked egg patent?cooked egg patent?

SOFT-COOKED HARD-COOKEDRAW


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MetabolitesMetabolitesnn

The final rule prohibits submission ofThe final rule prohibits submission ofpatents claiming metabolitespatents claiming metabolites

nn DeclarationDeclaration 2.5: Does the patent claim a 2.5: Does the patent claim a

metabolite of the approved active ingredient?metabolite of the approved active ingredient?


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MetabolitesMetabolites

nn If a patent claims an approved use of anIf a patent claims an approved use of anapproved drug to administer a metabolite,approved drug to administer a metabolite,

the patent may bethe patent may be listablelistable -- yet invalid.yet invalid.

nn Schering Corp. v. GenevaSchering Corp. v. Geneva PharmaPharma., Inc.., Inc. (Fed.(Fed.

Cir., Aug. 1 2003) (Cir., Aug. 1 2003) (loratadineloratadine metabolite ismetabolite is

inherently createdinherently created in vivoin vivo; the metabolite is; the metabolite is

therefore not new; the metabolite patenttherefore not new; the metabolite patent

claim is thus invalid).claim is thus invalid).

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How to draft patents for theHow to draft patents for the

Orange BookOrange Book

nn Expressly permitted patentsExpressly permitted patentsnnDrug Substance & Drug ProductDrug Substance & Drug Product





nn



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3030--Month StayMonth Staynn

One full opportunity per ANDA or 505(b)(2)One full opportunity per ANDA or 505(b)(2)nn OneOne -- Change from prior practiceChange from prior practice

nn CfCf.. In re OmeprazoleIn re Omeprazole: the statute does not limit the number of: the statute does not limit the number ofstays availablestays available

nn CfCf. Continuation with a terminal disclaimer (. Continuation with a terminal disclaimer (cfcf.. PaxilPaxil,,FosamaxFosamax))

nn Only oneOnly one -- subsequent (iv) certifications need not be noticedsubsequent (iv) certifications need not be noticed

nn full opportunityfull opportunitynn 45 day response period45 day response period

nn Amending a (iv) to a (iii) certification before 45 day perioAmending a (iv) to a (iii) certification before 45 day period runs,d runs,before suit commences.before suit commences.

nn NoticeNoticenn (ii), (iii) certifications and 505(j)(2)(A)(viii) flings d (ii), (iii) certifications and 505(j)(2)(A)(viii) flings do noto not

require notice, thus may fail to provide a full opportunity forrequire notice, thus may fail to provide a full opportunity for a staya staynn ? What if notice is given in fact ?? What if notice is given in fact ?


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180180--Day ExclusivityDay ExclusivitynnEach patent listed in the Orange BookEach patent listed in the Orange Book

may form the basis for a claim to 180may form the basis for a claim to 180--dayday

exclusivity. Thus an increase or decreaseexclusivity. Thus an increase or decrease

in listed patents as a result of this finalin listed patents as a result of this finalrule could affect the number of exclusivityrule could affect the number of exclusivity

periods.periods.

nn With only one stay, there is less incentive toWith only one stay, there is less incentive to

list patentslist patents -- and each listed patent is an aidand each listed patent is an aidto a potential generic company.to a potential generic company.

nn Consider drafting patents toConsider drafting patents to precludepreclude listinglisting


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Declaratory JudgmentsDeclaratory Judgmentsnn

Holder need not sue on ANDA filing.Holder need not sue on ANDA filing.nn If Holder waits to sue until after genericIf Holder waits to sue until after generic

is launched, infringement may beis launched, infringement may bewillfulwillfulnn treble damages, attorneys fees, permanenttreble damages, attorneys fees, permanent

injunction, personal liabilityinjunction, personal liability

nn Declaratory judgmentDeclaratory judgment

nn

Jurisdiction requires:Jurisdiction requires:1)1) Current infringing activity 271(e)(2)Current infringing activity 271(e)(2)

2)2) Reasonable apprehension of being suedReasonable apprehension of being sued


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Declaratory JudgmentsDeclaratory Judgments

nn Dr. Reddys v. PfizerDr. Reddys v. Pfizer (New Jersey)(New Jersey)nn SertralineSertraline declaratory judgment petition dismisseddeclaratory judgment petition dismissed

on 11 July 03on 11 July 03

1)1) Pfizer alleged that it needed more time to assessPfizer alleged that it needed more time to assess

whether infringement exists.whether infringement exists.2)2) Dr. Reddys failed to show reasonable apprehensionDr. Reddys failed to show reasonable apprehension

of suitof suit

nn AnanthAnanth IyerIyer ofofExpressExpress PharmaPharma PulsePulse (Bombay)(Bombay)predicted this in an article published in the spring.predicted this in an article published in the spring.

nn Resolving patent disputes prior to ANDAResolving patent disputes prior to ANDA

product launch not always possibleproduct launch not always possible


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Declaratory JudgmentsDeclaratory Judgmentsnn CfCf.: a firms inability to predict whether it will.: a firms inability to predict whether it will

or will not be sued for patent infringement is aor will not be sued for patent infringement is amatter outside the scope of this final rule. * * *matter outside the scope of this final rule. * * *some patent infringement suits may be initiatedsome patent infringement suits may be initiatedafter the 45 day period available to obtain a 30after the 45 day period available to obtain a 30--month stay has expired. * * * the NDA holdermonth stay has expired. * * * the NDA holderor patent owner can bring suit at a later time,or patent owner can bring suit at a later time,but loses the opportunity to obtain a 30but loses the opportunity to obtain a 30--monthmonthstaystay

nn

CfCf.: an NDA holder who defers filing a lawsuit.: an NDA holder who defers filing a lawsuiton a lateron a later--filed patent until a 30filed patent until a 30--month stay hasmonth stay haselapsed may feel that the subsequent litigationelapsed may feel that the subsequent litigationis still timelyis still timely

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ToTo--DoDonn

CurrentlyCurrently--Listed method patentsListed method patentsnn Use of new declaration form is particularlyUse of new declaration form is particularly

advisable for methodadvisable for method--ofof--use patentsuse patents

nnvoluntary submission of new patentvoluntary submission of new patent

declarations will not bring patents within thedeclarations will not bring patents within thescope of the final rule with respect to noticescope of the final rule with respect to notice

and 30and 30--month stays.month stays.

nn But with respect to perjury and estoppelBut with respect to perjury and estoppel


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ToTo--DoDonn

=> Review existing method patents and=> Review existing method patents andconsider filing claimconsider filing claim--identifying Declarationsidentifying Declarations

nn Patents listed in the Orange Book as of August 17,Patents listed in the Orange Book as of August 17,

2003 are grandfathered in and enjoy benefits of2003 are grandfathered in and enjoy benefits ofthe old rule (e.g., multiple 30the old rule (e.g., multiple 30--month stays, etc)month stays, etc)

nn CfCf. in. in Glaxo v.Glaxo v.ApotexApotex, Glaxo asked the FDA (on 1, Glaxo asked the FDA (on 1

July 2003) to deJuly 2003) to de--list 3 patents from the Orangelist 3 patents from the OrangeBook.Book.


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ToTo--DoDo

Our long experience with administering theOur long experience with administering theHatchHatch--Waxman Amendments convinces usWaxman Amendments convinces us

that any advantage a party can find inthat any advantage a party can find in

manipulating the regulatory program willmanipulating the regulatory program will

be pursued. Despite our conviction thatbe pursued. Despite our conviction thatthe final rule will substantially reduce suchthe final rule will substantially reduce such

manipulation, we do not believe we canmanipulation, we do not believe we can

completely prevent attempts at creativecompletely prevent attempts at creativecompliance by the parties.compliance by the parties.

CommentsComments at 52.at 52.

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for further researchfor further research

nn

available onavailable on--line atline atwww.LicensingLaw.Netwww.LicensingLaw.Net//LibraryLibrary::

nn A color copy of this presentation together withA color copy of this presentation together with

the Federal cases cited; andthe Federal cases cited; and

nn

A paper on antitrust implications of patent listing,A paper on antitrust implications of patent listing,together with the Federal cases citedtogether with the Federal cases cited

Mark Pohl, Esq., Patent AttorneyPharmaceutical Patent Attorneys, LLCMorristown, New [email protected] Dial +1 (973) 984-0076

Patents and the Polymorph

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