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IP IP IP IP IP IP IP IP StrategiesStrategiesStrategiesStrategiesStrategiesStrategiesStrategiesStrategies forforforforforforforfor Crystalline Crystalline Crystalline Crystalline Crystalline Crystalline Crystalline Crystalline FormsFormsFormsFormsFormsFormsFormsForms 20102010201020102010201020102010

London, London, London, London, London, London, London, London, DecemberDecemberDecemberDecemberDecemberDecemberDecemberDecember 7 7 7 7 7 7 7 7 thththththththth 20102010201020102010201020102010

OverviewOverview•• A A couplecouple ofof key key pointspoints whenwhen dealingdealing withwith noveltynovelty ofof

crystalline crystalline formsforms : : priorprior art art documentsdocuments and and differencedifferencefromfrom priorprior art art practicepractice

•• The first key The first key pointpoint . . StructuralStructural studiesstudies via single via single crystalcrystal XX--raysrays diffractiondiffraction in in priorprior art art documentsdocuments . . –– Case Case studiesstudies on API 1 and API 2on API 1 and API 2

•• The The secondsecond key key pointpoint . . ExactExact reproductionreproduction ofof priorprior art art practicepractice ..–– Case Case studystudy on API 3.on API 3.

•• Take home Take home lessonslessons toto help the help the assessmentassessment ofofnoveltynovelty ofof a a newlynewly foundfound crystalline crystalline formform

A A basicbasic featurefeature forfor a a patentablepatentable crystalline crystalline formform ::

WeWe willwill bebe concentratingconcentrating on NOVELTY, on NOVELTY,

under under twotwo particularparticular aspectsaspects::

––PriorPrior art art documentsdocuments

––DifferenceDifference fromfrom priorprior art art practicepractice

NOVELTYNOVELTY

The first key The first key conceptconcept forforthe the assessmentassessment ofof the the noveltynovelty ofof a crystalline a crystalline

formform

DemonstrationDemonstration thatthat no no priorpriorart art existsexists regardingregarding thatthat

particularparticular crystalline crystalline formform ..

ThisThis assessmentassessment isis usuallyusually donedone bybyreviewingreviewing

•• DatabasesDatabases•• LiteratureLiterature•• PatentsPatents•• ActsActs ofof congressescongresses

Do crystalline Do crystalline formsforms havehave

peculiarpeculiar literatureliterature sourcessources ??

ApartApart fromfrom the the traditionaltraditional OrganicOrganic

ChemistryChemistry JournalsJournals, , PublicationsPublications ofof studiesstudies

generatinggenerating and and usingusing single single crystalcrystal XX--raysrays

diffractiondiffraction are a are a veryvery wide and wide and powerfulpowerful

source source ofof information information forfor crystalline crystalline formsforms..

TheyThey are are anan oftenoftenoverlookedoverlooked source source ofof priorpriorart art forfor crystalline crystalline formsforms

UsuallyUsually theythey do do notnot containcontain the the

typicaltypical data data usedused forfor Crystalline Crystalline

formsforms characterizationcharacterization ((nono PXRDsPXRDs, ,

DSCsDSCs TGAsTGAs, , ssNMRsssNMRs, , RamansRamans).).

MostMost oftenoften theythey report the report the

resultsresults ofof single single crystalcrystal

diffractiondiffraction studiesstudies

WhatWhat kindkind ofof information do information do

thesethese documentsdocuments containcontain ??

The The skilledskilled in the crystalline in the crystalline

formform science science knowsknows thatthat

•• ItIt isis straightforwardstraightforward toto calculatecalculatethe PXRD the PXRD fromfrom single single crystalcrystal datadata

•• SoftwaresSoftwares are are availableavailable on the on the web web thatthat can can makemake thisthis job. job. ForForexampleexample ……

The Cambridge The Cambridge CrystallographicCrystallographic

Data Data CentreCentre (CCDC) (CCDC) offersoffers a a

webweb--basedbased searchsearch interface interface toto

the Cambridge the Cambridge StructuralStructural

Database (CSD)Database (CSD)

ThisThis interface interface allowsallows toto retrieveretrieve

data data suchsuch asas bibliographicbibliographic sourcessources

ofof itsits storedstored data and the data and the

calculatedcalculated PowderPowder XX--RayRay

diffractiondiffraction profilesprofiles

CASE STUDY 1CASE STUDY 1

API 1API 1

A A priorprior art art documentdocument

Journal Journal ofof MedicinalMedicinal ChemistryChemistry 19921992

ReportsReports data data ofof X X rayray diffractiondiffraction on on

single single crystalcrystal ofof the APIthe API 11

A 2003 Patent Claims:

Calculated PXRD in CSD for API 1(reporting as source J. Med. Chem. 1992)

Experimental PXRD claimed in 2003 Patent

CCDC software allows also to retrieve the peakpositions (2Theta) and Miller indexes for eachcalculated PXRD peak position

RecognizingRecognizing the the relevancerelevance ofof

priorprior art on single art on single crystalcrystal XX--rayray

diffractiondiffraction helpshelps the the discovererdiscoverer

ofof a a supposedsupposed newnew crystalline crystalline

formform toto determinedetermine ifif itit isis reallyreally

newnew or or notnot..

CASE STUDY 2CASE STUDY 2

API 2API 2

A key A key priorprior art art documentdocument

Journal Journal ofof MedicinalMedicinal ChemistryChemistry 19931993

ReportsReports the the resultsresults ofof experimentsexperiments ofof

X X rayray diffractiondiffraction on single on single crystalcrystal ofof

the API 2the API 2

A WO2008 A WO2008 patentpatent

applicationapplication claimsclaims

Calculated PXRD in CSD for API 2(reporting as reference J. Med. Chem. 1993)

Experimental PXRD claimed in WO2008

The calculated PXRD peak positions

look look forfor literatureliterature dealingdealing withwithsingle single crystalcrystal XX--raysrays diffractiondiffractiondatadata relative relative toto thatthat API.API.ThenThen work out the work out the simulatedsimulated or or calculatedcalculated PXRD and compare PXRD and compare ititwithwith youryour experimentalexperimental data.data.

So So anan importantimportant actionaction toto do do

in in orderorder toto knowknow ifif a a newlynewly

foundfound crystalline crystalline formform ofof anan

API API isis novelnovel isis::

DemonstrationDemonstration thatthat PracticePractice ofof the the priorprior art art teachingsteachings do do notnot end up in end up in yieldingyielding the the supposedsupposed newnewcrystalline crystalline formform

The The secondsecond key key conceptconceptforfor assessingassessing the the noveltynovelty

ofof a crystalline a crystalline formform

CASE STUDY 3CASE STUDY 3

API 3API 3

Three key Three key priorprior art art

documentsdocuments

•• US US ‘‘932932

•• US US ‘‘211211

•• OrgOrg. Proc. . Proc. ResRes. Dev. 1999. Dev. 1999

PriorPrior artart US US ‘‘932 932 teachingsteachings

PriorPrior art US art US ‘‘211 211 teachingsteachings

PriorPrior art art OrgOrg. Proc. . Proc. ResRes. .

Dev. 1999 Dev. 1999 teachingsteachings

The key The key pointpoint isis the pH at the pH at

whichwhich API 3 API 3 isis precipitatedprecipitated

•• US US ‘‘932932: : ““neutralizedneutralized withwith HClHCl””

•• US US ‘‘211211: : ““neutralizedneutralized at pH 5 at pH 5 withwith 6 N 6 N HClHCl””

•• OrgOrg. Proc. . Proc. ResRes. Dev. 1999. Dev. 1999: : ““adjustadjust at at pH 3 pH 3 withwith aqueousaqueous hydrochlorichydrochloric acidacid””

WhatWhat happenshappens whenwhen the the priorprior art art teachingsteachings

are are appliedapplied toto prepareprepare API 3 ?API 3 ?

•• US US ‘‘932 932 ““ neutralizedneutralizedwithwith HClHCl””

•• US US ‘‘211 211 ““ neutralizedneutralized at at pH 5 pH 5 withwith 6 N 6 N HClHCl””

•• OrgOrg . Proc. . Proc. ResRes. Dev. . Dev. 1999 1999 ““ adjustadjust at pH 3 at pH 3 withwith aqueousaqueoushydrochlorichydrochloric acidacid ””

The The teachingteaching ofof OPRD OPRD yieldsyields a a

crystalline API 3crystalline API 3.

In the first In the first twotwo casescases therethere isis

no complete no complete conversionconversion intointo

the acid the acid formform and the and the productproduct

precipitatesprecipitates asas amorphousamorphous, ,

whilewhile in the in the thirdthird case the case the

productproduct precipitatesprecipitates asas pure pure

acid acid formform and and itit isis crystalline.crystalline.

PXRD PXRD describeddescribed

in a WO2008in a WO2008

ExperimentalExperimental PXRDPXRD

on material on material obtainedobtained

byby applicationapplication ofof

OPRD OPRD

A A carefulcareful investigationinvestigation and and

reproductionreproduction ofof the the priorprior

art art methodologiesmethodologies

describeddescribed toto obtainobtain API 3 API 3

allowsallows toto understandunderstand ifif ourour

newlynewly foundfound crystalline crystalline

formform isis novelnovel..

ToTo summarizesummarize1.1. Single Single crystalcrystal XX--raysrays studiesstudies are are

a a mainmain source source ofof priorprior art art forfor

crystalline crystalline formsforms. Care . Care shouldshould

bebe takentaken withwith newlynewly foundfound

crystalline crystalline formsforms toto compare compare

calculatedcalculated PXRD PXRD fromfrom single single

crystalcrystal data, data, withwith experimentalexperimental

PXRD. PXRD. IfIf experimentalexperimental PXRD PXRD

and and calculatedcalculated PXRD are PXRD are

differentdifferent, , therethere isis a strong case a strong case

in in favourfavour ofof noveltynovelty ofof the the formform..

2.2. PracticePractice ofof priorprior art art teachingsteachings

can can bebe a strong a strong tooltool in in favourfavour ofof

noveltynovelty, , whenwhen itit isis possiblepossible toto

demonstratedemonstrate thatthat a a supposedsupposed

newnew crystalline crystalline formform isis notnot

producedproduced whenwhen followingfollowing thosethose

teachingsteachings..

ToTo summarizesummarize

ThankThank youyou

forfor youryour kindkind attentionattention !!