Stefano Turchetta Stefano Turchetta - - R&D R&D Manager Manager ITALFARMACO Group ITALFARMACO Group IP IP IP IP IP IP IP IP Strategies Strategies Strategies Strategies Strategies Strategies Strategies Strategies for for for for for for for for Crystalline Crystalline Crystalline Crystalline Crystalline Crystalline Crystalline Crystalline Forms Forms Forms Forms Forms Forms Forms Forms 2010 2010 2010 2010 2010 2010 2010 2010 London, London, London, London, London, London, London, London, December December December December December December December December 7 7 7 7 7 7 7 7 th th th th th th th th 2010 2010 2010 2010 2010 2010 2010 2010
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Ip strategies for crystaline forms london dec. 2010
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IP IP IP IP IP IP IP IP StrategiesStrategiesStrategiesStrategiesStrategiesStrategiesStrategiesStrategies forforforforforforforfor Crystalline Crystalline Crystalline Crystalline Crystalline Crystalline Crystalline Crystalline FormsFormsFormsFormsFormsFormsFormsForms 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
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
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