Constructingnarrativesofheroismandvillainy: - PDF document

OPENDEBATE OpenAccess Constructingnarrativesofheroismandvillainy: ’ sBRACAnalysis ® compared toGenentech ’ sHerceptin ® ALaneBaldwinandRobertCook-Deegan * Abstract Background: ThedevelopmentofHerceptin ® iswelcomedasamajoradvanceinbreastcancertreatment,while Myriad ’ sdevelopmentofBRACAnalysis ® isawidelyuseddiagnostic.Howeverusefulandsuccessfulthisproductis, itspresenceinthepubliceyeistaintedbypredominantlynegativepressaboutgenepatentingandbusiness practices. Discussion: WhileretrospectioninvitesasharpcontrastbetweenGenentech ’ striumphalnarrativeofscientific achievementandMyriad ’ spublicimageasacontroversialmonopolist,acomparativehistoryofthesecompanies ’ productsrevealstwostrikingconsistencies:patentsandpublicdiscontent.Despitethesesimilarities,timehas reducedthenarrativetothatofheroversusvillain:Genentechislauded-atleastforthefinaloutcomeofthe Herceptin ® story-asacorporategoodcitizen,Myriadasaruthlessmercenary.Sincepatentsundergirdboth productsyetthenarrativesaresodifferent,thestoriesraisethequestion:whyhavepatentstakenthefallasthe scapegoatincurrentbiotechnologypolicydebate? Summary: AwidelypublicizedlawsuitandaccompanyingbadpresshavecastMyriadasavillainintheevolving narrativeofbiotechnology.WhilethelawsuitsuggeststhatthisvillainyisattributabletoMyriad ’ sintellectual property,wesuggestthroughacomparativecasestudythat,atleastintheMyriadcase,itisnotsimplyaboutthe patentsbutalsootherbusinessstrategiesthecompanychosetopursue.Patentswereanecessarybutnot sufficientcauseofcontroversy. Background Introduction On29March2010,JudgeRobertSweetoftheUnited StatesDistrictCourtfortheSouthernDistrictofNew Yorkshockedtheworldofintellectualpropertylawwith hisrulingin AssociationforMolecularPathologyv.US PatentandTrademarkOffice (the ‘ Myriad ’ case).He ruledthatMyriadGenetics patentsonthe BRCA1 and BRCA2 genesclaimednon-patentableDNAmolecules andmethods[1].AttorneysDanVorhausandJohnCon- leywrylyobserved, ‘ pigsfly, ’ [2]atleastforawhileinthe DistrictCourt.Meetingthesamefateasthemythical Icarus,thewingsconstructedbyJudgeSweetmelted underthescrutinyoftheCourtofAppealsforthe FederalCircuit(CAFC)on29July2011[3],andwere arguedagainbeforeCAFCon20July2012byorderof theUnitedStatesSupremeCourt.Thecasewas appealedagaintotheUSSupremeCourton25Septem- ber2012,andcertiorariwasgrantedon30November 2012[4-6]].ThecasewillbeheardbytheSupreme CourtonApril15,2013withadecisionbeforeJuly. Throughtheeyesofpatentpractitioners,Judge Sweet ’ sdecisionwasananomaly,butitisjustanother episodeinshiftingjurisprudence,withasuccessionof casesbetweenCAFCandtheSupremeCourt.Thiscase ofpatentprotection.Indeed,italreadyhas,withMyr- iad ’ sbroadmethodclaimsbeinginvalidatedbyboththe districtcourtandCAFC.Backedbyadecadeofprece- dentpatentinggenes,thepatentsthatMyriadGenetics holdson BRCA1 and BRCA2 genescontinuealong- standingpatternofgrantingsimilarpatentsintheUni- tedStates[7].Accountsofthegenediscoverieswidely *Correspondence:bob.cd@duke.edu GenomeEthics,Law&Policy,InstituteforGenomeSciences&Policy,Duke University,Box90141,304ResearchDrive,Durham,NC27708-0141,USA BaldwinandCook-Deegan GenomeMedicine 2013, 5 :8 http://genomemedicine.com/content/5/1/8 ©2013BaldwinandCook-Deegan;licenseeBioMedCentralLtd.Thisisanopenaccessarticledistributedunderthetermsofthe CreativeCommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited. acknowledgethatasidefromcontributiontoscienceandsociety,patentsandpublicationwerethebrassringstobegrabbedbycontendersinthegreatraceof1990to1995toidentify,clone,andsequenceandBRCA2[8-11]].Whiletherehavebeengenepatentcon-troversiesovertheyears,nonehasapproachedtheintensityofpublicconflictoverBRCApatents[5].Evenbeforethecurrentlitigationbegan,policyreportsaroundtheworldcitedfarmoreoftenthananyothergenepatents[12],andpublicnewsmediacoverageisfarmoreextensiveforthanothergenepatentscases(mostofitstronglynegativecoverage)[13].Whyhavetheseparticularpatentsarousedsuchintensecontroversy?AspatentscholarRebeccaEisen-bergnoted,SignificantoppositiontogenepatentingwithinthemedicalandscientificcommunitiesdidnotariseuntilthepatentabilityofDNAhadlongbeenestablished[7,14].Itmaybehelpfultoassesswhetherthecontroversyshouldproperlybeattributedtopatentsthemselves,ortounpopularbusinesspracticesthatMyr-iadcouldputinplacebecauseofpatentexclusivitythatmadeittheonlyUScommercialtestingservice.ShouldthefocusbeonwhetherMyriadshouldhavegottenpatentsatall,oralsoonwhatMyriaddidwithToassesstheextentthatthepatentsplayedaroleinthemalcontentamassedagainstMyriad,weselectedacomparablestoryofproductevolutionasapointofcomparison:GenentechsHerceptin.WhilenotdirectlycomparablebecauseHerceptinisatherapeuticandBRACAnalysisisadiagnostic,thedevelopmentofHer-nonethelessresemblesthatofBRACAnalysisinseveralrespects.Botharenovelbreakthroughsinmanagingbreastcancer.Bothwerebroughttomarketbybiotechnologycompanies.Bothproductsweremainlydevelopedinthe1990s.Mostimportantly,forthepur-posesofthisanalysis,bothinventionswerepatented.Amongthedifferingelementsofthesetwostoriesisprofoundlydifferentpublicreception.Insteadofapubicoutcryintheformofaverypubliclawsuit,GenentechwascelebratedwithacorporateleadershipawardfromtheNationalBreastCancerCoalition[14].Thus,toanswerthequestionofwhatrolepatentshaveplayedinpublicperceptionsofMyriad,wehavesoughttocom-pareMyriadscorporatehistorywithGenentechsdevel-opmentofHerceptinwithsignificantpatentprotectiononanovelproduct,whichencounteredaverydifferentreceptionfromasimilarconstituencyatmoreorlessthesametime.Toassessthequestionposedinourthesis,wecomparedsdevelopmentofBRACAnalysistoGenentech,inordertoassesstheroleofpatentsrelativetootherfactors,suchasengagementoftheconstituen-ciesmostdirectlyaffected(peopleatriskofdevelopingbreastandovariancancer)andcompliancewithhealthprofessionalstandardsandnorms.Weconstructedthishistorybysurveyingtherelevantliterature,USSecuritiesandExchangeCommission(SEC)reports,corporatestatements,mediareports,patentdatabases,andoff-the-recordinterviewswithrelevantactors.Inthisanalysis,weattempttoisolatepatentandnon-patentfactors,describinghowMyriadandGenentechdevelopedtheirrespectiveproducts.Thisincludesdifferencesbetweentherapeuticsanddiagnostics,howprofessionalguidelinesweretreated,andmostimportantlyhowthecompaniesdealtwithintensecontroversyamongbreastcancercon-stituencies.Onecrucialdifferenceishowthecompaniesdealtwiththenationallyrecognizedandwell-organizedadvocacyorganizationswhenconflictwiththoseorgani-zationserupted.WewillfirstprovideabasichistoricaloverviewofhowBRACAnalysisandHerceptindeveloped,lookingforfactorsthatmightexplainthedivergentnarratives.DiscussionCorporatehistoriesMyriadGeneticsOn17October1990,geneticistMary-ClaireKing,thenattheUniversityofCalifornia,Berkeley,madeaground-breakingannouncementtotheAmericanSocietyofHumanGenetics:herteamhaddiscoveredageneticlinkagetobreastandovariancanceronchromosome17[10].Thisfollowedastrategyoflocatingageneonthechromosomesbystudyingfamilieswithaninheritancepatternsuggestingmutationsinasinglegene.Shefoundthelinkagebycomparingmultipleaffectedandunaf-fectedmembersinsuchfamilies.Thestrategywaspio-neeredbyfindingageneticlocusassociatedwithriskofsdiseaseonthetipofchromosome4in1983[15].Thereafter,severalgenesforcysticfibrosis,Alzheimersdisease,neurofibromatosis,andothercondi-tionswereidentifiedbycloningandsequencingDNAfromtheregionandidentifyingdisease-associatedmuta-tions[15-17]].Kingextendedthestrategytobreastcan-cer,notthencommonlyconsideredageneticcondition.Shefocusedonfamiliesthathadmanymem-bersaffectedbybreastcanceratayoungage,suggestingabrokengenemightbefound.Itturnedoutthatovar-ianandsomeothercancersalsotraveledinthesefamilies,inapatternconsistentwithinheritanceofasinglemutatedgeneincreasingriskofbothovarianandbreastcancers.Kingandhercolleaguesthuslocatedbutdidnotcloneandsequencethegene.sdiscoverywasliketracingthecorrectaddresstotheconfinesofNewYorkCity,thestartingflareforanintenseracetocloneandsequencethegenebyfindingdisease-causingBaldwinandCook-DeeganGenomeMedicinehttp://genomemedicine.com/content/5/1/8Page2of14 mutations[10].Itwasoftencharacterizedasahuntforbreastcancergene,butitwasnotquitethat.Rather,itwasahuntformutationsthatalteredagenewhosebiologicalfunctionwasentirelyunknown,buttheconsequenceofitsmutationwaspredispositiontocer-taincancers.Theracelastedfouryears,fluctuatingbetweenintenseinternationalcompetitionandperiodsofteamcollaboration.Asthesearchdraggedon,theincentivesofpride,patents,andpublicationwereleavenedbydiagnostichope-beingabletounmaskthesilenthereditarypreda-torthathaddevastatedandstigmatizedgenerationsofwomen.Thecontenderswereamongthebiggestnamesworldwideinhumangeneticsresearchand,intheend,itwastheteamworkingwithMarkSkolnickofMyriadGeneticsthatuncoveredthesequencebyfindingcancer-associatedmutations.InAugust1994,SkolnickannouncedthathehaduncoveredtheBRCA1gene[10].Earlierthatmonth,anothercontributortohereditarycancerhadbeenunmaskedwhenaputativegenewastentativelylocatedonchromosome13,byMichaelStrattonandhisteamofUKscientists[18].sresultsidentifyingthissequenceastheBRCA2sequencewerepublishedinin1995[19].In1996,Myriadsteam,arguingthatStrattonspublishedsequencewasincomplete,followedthispublicationwiththecompletesequenceandamoreextensivemutationalanalysis[20].Thatresultedfromanotherracethatcul-minatedincloningandsequencingmutationsinBRCA2in1995[10].TheraceendedinadeadheatbetweenagroupledbyMichaelStrattonintheUKandtheMyriad/UtahteaminUtah[21,22].MyriadsworkwaspartiallyfundedbygovernmentgrantstotheUniversityofUtah.SomeworkwasdonebygovernmentscientistsattheNationalInstituteforEnvir-onmentalHealthSciences,andsomewasdonebyMyriaditself,usingfundsfromitsinvestorsandunderanagree-mentwithEliLilly&Co.Myriadthusco-fundedthework,anditwasnosecretthatpatentswouldbesought.AndpatentingwasnotconfinedtoMyriad,Mary-ClaireKingslinkagemethodwaspatentedandlicensedtoOncorMedbytheUniversityofCalifornia,andOncorMeditselfhadaUSpatentonBRCA1(seebelow).MyriadfileditsfirstpatentapplicationsinAugust1994,andthisinitialapplicationripenedintoseveralpatents,startingwiththegrantofitsfirstpatent,5,693,472in1997[10,23]OncorMedalreadyhadapatentcoveringtheconsensuswild-typesequence[24].In1998,OncorMedsuedMyr-iadandthenMyriadcounter-suedforpatentinfringe-ment.Thiscaseultimatelysettled,withrightsgoingtoMyriadunderaconfidentialagreement[9].ThepatentsoriginallyassignedtoOncorMedandGeneLogichavesincebeenre-assignedtoMyriad.Usingthesepatentrights,MyriadGeneticsbecamethesolecommercialtestingserviceformutationsinBRCA1andBRCA2intheUnitedStates.Apatientcarryingamutationinthesegenescanhaveuptoan87%riskfordevelopingbreastcanceranda44%chanceofdevelop-ingovariancancerinalifetime[25].Studieshaveshownthatpatientswithdeleteriousmutationscanreducetheirriskofcancerthroughprophylacticmeasuressuchastakingtamoxifenorotherchemopreventiveagents,orsurgicalremovalofbreastsandovaries[26,27].Armedwithintellectualpropertyprotectiononbothcompositionsofmatter(claimsonisolatedDNAmole-cules)anddiagnosticmethods,MyriaddevelopeditsBRACAnalysistest[28].Itisthefirst-linediagnosticinhigh-riskfamilieswithearly-onsetbreastandovariancancer,withsecond-linetestingformajorrearrange-ments(MyriadsBARTtest)orsequencing20othergenesformutationsinothergenesthataremuchlesscommonbutcanalsoconferinheritedcancerrisk(testsavailablefromAmbryGeneticsandacademiclabora-tories).BRACAnalysisisMyriadsflagshipproduct,accountingforover$400millioninrevenueand80%ofMyriadsrevenuesin2011,withBARTandothertestsforinheritedriskofpancreaticcancer,colorectalcancer,melanomaandothertestsaccountingformostoftherestofMyriadsrevenues[29].CliniciansandpatientsalikereadilyacknowledgethatMyriadperformsverywellindoingtests,reportingresults,marketing,andobtainingreimbursementfromthird-partypayers.Myriadisquiteproficientandcom-petitivewithothergeneticdiagnosticcompanies[24].However,intheyearssinceSkolnicksimpressivedis-covery,thecorporateimageofMyriadGeneticshascon-sistentlybeenunpopular.Caulfield,Bubela,andMurdochreviewedEnglish-languagenewspaperarticlesonMyriadGeneticsandthegenepatentsinmanycountries[13].NotonlydidMyriadsgenepatentsgarnermoreinternationalnewsattentionthanothergenepatentingcontroversies,butalso77.6%ofthesearticleshadanegativetone.Thispresentsananomaly:acompanythatiswidelyregardedasbeinganefficientlaboratory,wasastartupthathelpeddiscoverthegeneticcauseoftwodreadcan-cersandprovidesaservicethatallowspeopleatrisktomitigatetheriskisnonethelessreviled.Thisshouldbeaherostorybutisinsteadadarknarrative.Why?ThecontrastwithGenentechandHerceptin,aproductthatdevelopedatmoreorlessthesametimeandforanextensivelyoverlappingcustomerbase,isstriking.ThebeginningoftheHerceptinstorybeginsnotatGenentech,butattheMassachusettsInstituteofTech-sWhiteheadInstitute,whereRobertWeinbergdiscoveredthegenethatledtooneofthemostBaldwinandCook-DeeganGenomeMedicinehttp://genomemedicine.com/content/5/1/8Page3of14 significantdiscoveriesinbreastcancertherapeutics[30].(christenedforitsoriginaldiscoveryinratbraintumors)wasfoundwhenlookingforcancer-asso-ciatedgenes,whenstudyingbasicmolecularandcellulareventsassociatedwithcancer;itsclinicalsignificancebeyondadvancingbasiccancerbiologywasnotimmedi-atelyapparent.Itwasnotuntil1989thatAxelUllrich,DennisSlamonandcolleaguespublishedtherelevanceofthegene(re-christenedindeferencetoSla-mon,Ullrich,andWeinbergswork)[31].Over-expres-wasassociatedwithaparticularlynastyformofbreastcancer.Onestrategytoaddressthiswastofindanantibodythatwouldbindtotheproteininhopesofinhibitingitseffects,thuscounteringitsoverexpression.Thepromiseofpotentiallycuringwomenwithanaggressivelyrecurringtypeofbreastcancerwithoutthekill,burn,andslashcombinationofchemotherapy,radiation,andsurgerywaseventuallyrea-lizedinHerceptin,theresultingtherapeutic.ThemonoclonalantibodyinhibitingHer-2neuwaspatentedandmanufacturedbyGenentech,whichhascontinuedtoproduceitasHerceptinsmanagementofHerceptindidnotalwaysgarnergoodwillamongnationalbreastcanceradvocates.Indeed,Genentechgotofftoarockystart,asitwasreluctanttoplowresourcesintoamonoclonalantibodyproduct,giventhemanydisappointmentsfrommonoclonalantibodytherapeuticsoverthepreviousdecade[30].Andatthetime,cancerwasnotwidelyregardedasapromisingtargetforblockbusterespeciallywhenthisproposedproductwouldbefortheminorityofthosewithbreastcancerwhoshowedover-expression.Slamonwasaconstantclinicalchampion,andapparentlyalsosometimesregardedasathorninthesideofGenentechseniormanagement[30].WomenfromBreastCancerAction(BCA)inSanFranciscodemonstratedactivelyoutsideGenentechheadquarterstopressurethecompanyintoprovidingaccesstothethen-experimentaltreatment.GenentechcontactedFranViscofromtheNationalBreastCancerCoalition(NBCC),anationalumbrellaadvocacyorgani-zation.Sheagreedtohelpdeveloptheclinicalstudiesneededtoshowclinicalsafetyandefficacy,solongasNBCCandotherauthenticpatientrepresentativeswerefullyengagedandatthetableinhelpingdesignandcarryoutthetrials[30].Innosmallpartbecauseofsstandingasahighlycrediblenationaladvocacyorganization,thetrialsneededtogeneratedataforFoodandDrugAdministration(FDA)approvalproceededTheinitialclinicaltrialswerequitepromising,anddespiteseveralfitsandstartsbyGenentechanditsthen-partialownerRoche,HerceptinreceivedFDAapprovalin1998.Asaspecifictherapy,Herceptinwasonlyeffectiveonthe25%oftumorsthatexpressedhighlevelsofHer-2[32].Whileitwasnoteffectiveformostbreastcancers,manypatientswhorespondedtoitimproveddramatically.Inearlyclinicaltrials,patientswithadvanceddiseaselived5monthslongerwhentrea-tedwithHerceptinandchemotherapy[32].A2005NewEnglandJournalofMedicinearticlereportedthatreducedrelapsesbyhalfinwomenwhostartedtreatmentearly[33].HerceptinssuccesswassowidelycelebratedduringitsearlyclinicaltrialstagethatGenentechwasdelugedwithdemandsforacompassio-nateaccessprogramtoprovidethedrugforterminalpatientslookingforalastchanceattherapy[30].In2009,RochespartialownershipofGenentechbecamefullacquisition,combiningGenentechsopera-tionsintoRoches[34].Inthelastfullyearbeforethisacquisition,aJanuary2009SECfilingreportedthatGenentechgenerated$9.5billionprofitfromUSpro-ductsalesoutofoperatingrevenueof$13.4billion.Her-ceptinsalesaccountedfor$336millionofthoserevenuesin2008[34,35].In2011,globalHerceptinsalesreached$5.728billion[35].BRCAtestingandHerceptinhadparalleltrajectories:bothcontributednovelinsightsintobreastcancerandhadclinicalimplicationsthatdemonstrablyimprovedsurvival;bothwerebroughttomarketbystart-upbio-technologyfirms;bothstakedpatentrightsaspartofthebusinessmodel;andbothproductsbecamesignifi-cantprofitcenters.Thesecommonfactorsbeliedra-maticdifferencesinthepublicreceptionaccordedthesetwoproducts.Thecontributingdifferenceslieineachscorporatepracticeandinthenatureoftheproductstheyweredeveloping.InthecaseofMyriadreputation,illwillisarguablyduelesstothepatentsMyriadacquiredthanthewayitdeployedthem.AssertionofpatentprotectionThestrengthandextentofintellectualpropertyprotec-tionislargelydeterminedbytheenforcementofgrantedrights.HerceptinandBRACAnalysisdemonstratethebroadspectrumofpatentuse,illustratinghowthepro-tectionofintellectualpropertyplaysoutinpublicdebate.Onceitsecuredpatents,MyriadwasquicktopursueaggressiveenforcementactionsagainstpublicandacademicinstitutionsbothintheUnitedStatesandinternationally.TwoparticularlysalientexampleswereconflictswiththeUniversityofPennsylvaniaandtheCanadianProvinceofOntario.Inher2009declarationbeforetheUnitedStatesDis-trictCourtfortheSouthernDistrictofNewYork,Uni-versityofPennsylvaniaresearcherDr.ArupaGangulyrecalledhowinMayof1998,sheandhercolleagueDr.HaigKazazianreceivedanotificationletterfromtheMyriadGeneticsDirectorofCorporateCommunicationsBaldwinandCook-DeeganGenomeMedicinehttp://genomemedicine.com/content/5/1/8Page4of14 acknowledgingMyriadsfiveexistingBRCA1someofwhichwereinfringedbyGangulyandKaza-ziansongoingBRCA1research(whichincludedtesting)[36].PerGangulysrecollection,thisletterofferedacollaborationlicensethatwasofverylimitedscope,asitwouldnotallowustocompletediagnostictestingservicesfor,orcomprehensiveresearchonthegenewhichwehadbeendoingatthelab[36].Afterthisoriginalnotificationletter,aflurryofescalatingcommunicationcontinuedamongMyriadGenetics,Ganguly,Kazazian,andthelegalcounselforbothparties.DespiteresearcherattemptstocomplywithMyriadsoriginalrequest,increasinglyaggressivelettersarrivedatPenn,demandingwrittenassuranceBRCAtestinghadstopped.AsGangulyrecounted,IwascompelledtoceaseallwhetherforclinicalorresearchpurposespurposesInthisdeclaration,GangulyalsorecalledanotherinstanceofaggressiveenforcementletterswhenworkingonaresearchprojectsponsoredbytheNationalCancerInstitute.Asaninvestigatoronthisproject,sheprovidedBRCA2screeningtoparticipants.InSep-tember1998,theNationalCancerInstitute(NCI)receivedaletterfromMyriadGeneticsconcerningpatentinfringementbyclinicalresearchthatinvolvedBRCA1andBRCA2testing.Pennwastoserveasatest-ingcoreforseveralNCI-fundedtrialsthatincludedtestingandreporting.Gangulystoppedperform-ingBRCAtestingfortheprojectaftertheMyriadletter.NCIsigneda1999MemorandumofUnderstandingthatgaveMyriadrightstodoBRCAtestingforNCI-spon-soredresearchunlessitdidnotentailreturningresultstothosetested,oritwasdoneonlybylaboratoriesatthesameinstitutionaswasprovidingpatientsclinicalcare[37].Inreturn,MyriaddeeplydiscountedthepricetoNCIanditsgrantees.ThePennsylvaniaresearchersassumedsanctuaryfrompatentinfringementunderaresearchexemption[9].TheUSresearchexemption,however,doesnotincluderesearchusinganinvention,asopposedtoaverynar-rowjudge-madecaselawexemptionforphilosophicalinquiryorresearchonhowtheinventionworks[38,39].MyriadclearlydisagreedthatPennsworkwar-rantedaninformalresearchexemption,andPennsusealmostcertainlydidnotqualifyfortheformallegalexemption.Myriadsentthreateningletterstotheoffendingparties.Thoughthecompanyconfirmedithadnointentionofenforcingthepatentsagainstresearchers,thescopeoftheirvoluntaryforbearancefromenforcementwasapparentlyrestrictedtobasicresearch,notclinicalresearchthatentailedtestingandreportingresultsaspartofaclinicalstudy,evenafeder-allyfundedone.Myriaddidnotmakeapublicpolicystatement,butinsteadconductedtheprocessthroughlegalnegotiationandprivatecorrespondence.Thisiscommoninbusi-ness-to-businesspatentconflicts,butitwasstartlingtoclinicalresearcherswhoviewedtheirworkusingtestingasanaturaloutgrowthoftheirclinicalresearch.Inshort,thisstyleofoperatingthroughlawyerswithPennandotheracademicinstitutionsthatreceivedMyr-sletterswasregardedaslegalisticbullying.Insteadofcounteringitspoorpublicimage,Myriadletthefearersist[9].GoldandCarbonescasestudyofMyriadnoted,tothelargemajorityofresearcherswhohadnotbeenfollowingcloselyMyriadspublicstatements,itseemedthatMyriadwaswillingtoblockscientificresearchtoturnaprofit[9].Itwasashortstepfromthislegalmaneuveringtoanarrativeofdarkvillainy.WhenMyriadworkedtoexpanditsbusinessabroad,itencounteredtheCanadianProvinceofOntario.InanattempttotaketheBRACAnalysistestabroad,MyriadlicensedCanadiantestrightstoMDS,aCanadianfirm.TheintentionwasforMyriadtofocusonitspracticeintheUnitedStateswhileMDSactedasanambassadortotheCanadianprovincialgovernments.MDSandMyriadencounteredstrongresistanceintheOntarioMinistryofHealth.IntheCanadianpublichealthcaresystem,Myriadscommercializationmodelandthesheerexpenseofthetestweredeemedincom-patiblewithOntariosgeneticservicesmodel.Provincialhealthprogramsalreadyadministeredgenetictestsandhadtheinformationneededtodotesting,basedonthepublishedsequencesandothermedicalliterature.(SuchpublicationsincludedMyriadandUtahpapers,butalsodatafrommanyothergroups.)Whilethegov-ernmentalpolicyarmworkedtodeviseasystemthatcouldpreventtheincorporationproblemsexperiencedinMyriadsotherinternationalventures(includingtheUKandAustralia),Myriadgrewincreasinglysuspiciousandsentoutcease-and-desistlettersinMay2001.ThelackofcommunicationbetweenMyriadandOntariowasamissteponbothsides.Therisingstormappearedtohavequelledinfall2001,whenOntarioMinisterofHealthandthePresidentofMyriadGeneticsagreedtomeet.Myriadsnextstepseriouslyescalatedtheconflict.Myriadpresentedapackageoflettersfromcur-rentandformerUSgovernmentrepresentativesandtheBiotechnologyIndustryOrganization,threateningactionsasaggressiveastradesanctionsandcancellationoftheBiotechnologyIndustryOrganizationsannualconventioninToronto[9](theauthorsofthispapercitetheselet-ters,whichtheyhaveonfile).Thiscontretempsresultedinastormofnegativemediaaccounts,marringMyriadalreadyunattractivepublicface.ItalsoputanyCanadianpoliticianinanimpossiblebind-pushbackagainstBaldwinandCook-DeeganGenomeMedicinehttp://genomemedicine.com/content/5/1/8Page5of14 MyriadorbowbeforeanAmericancorporationwhosedemandsperturbedpracticesinthehighlypopularCana-dianprovincialhealthsystems.Themediaoutcryoverlysimplifiedtheconflictandreducedittopatenting,thusconflatingMyriadspoorpoliticalstrategicdecisionsanditsparticularservice-monopolybusinessmodelwiththegrantingofgenepatents.ThoughMyriadspatentprotectiondidgiveittheexclusiverightsitusedthisdispute,thethrea-teningbehaviorsexhibitedbyMyriadwerenotinherenttothepatents.Indeed,itishardnottoregardMyriadCanadiangambitascounterproductive,giventhatMyr-iadfailedtosecuretheCanadianmarket(QuebecandsomeotherprovincesdorefersometeststoMyriad,butmosttestingisnotthroughMyriad)andalsoneverfol-loweduponthethreats.Itlostbusinessanddestroyeditspublicimage.Thepatentstrong-armingfailed.Myr-sdecisionnottosueorotherwiseenforceitsCana-dianpatentsfurthermayhavebeeninpartbecauseevenifitwonthepatentbattle,itwouldstillhavehadtogetcoverageandreimbursementdecisionsfromtheveryprovincialhealthplansitwouldhavetosueforpatentinfringement.ByfightingtheOntarioHealthMinistry,itwasengagingitslargestpotentialCanadiancustomer.Evenanuncertainvictoryoverpatentswouldstillfaceapotentialbattleovercoverageandpayment.Anaggressivepatentenforcementstrategyisnotnovelasabusinessuseofpatents.Patents,afterall,areexclu-siverightsfullyintendedtoforestallcompetition,andenforcementlettersarecommonamongcompetitors.Thedistinctiveelementherewasnottheactbutprac-ticesstandardinbusinessbeingappliedtoresearchersandlaboratoriesatnonprofit,government,andacademicinstitutions,andthenagainstaprovincialhealthservice.Inonesense,thiswasastandardwaytoclearthemar-ofcompetitors,butthenonstandardfeaturewasthatthecompetitorswerenotcompetitorfirms,andsomeoftheusesweretightlylinkedtoclinicalresearch.ThisbehaviorliesattheheartofillwilltowardsMyriad,especiallyinthescientificcommunity.AsJimWatsonstatedin2010attheGenomesEnvironmentsandTraitsIhateMyriadthewaysomepeoplehateGoldmanSachs[40].Howeverstandarditmighthavebeentoenforcepatentsaggressively,theresentmentgeneratedbythisinitialpatentenforcementplantedtheseedforapublicinterestlawsuitadecadelater.StandardsofcorporatepracticeAfterMyriadpublisheditsdiscoveryofthethelogicalnextstepwastodevelopadiagnostictest.Naturally,justastherewasaracetofindthegene,therewascompetitiontodevelopthetestforthatgene.TheprimarycompanycontenderswereOncorMedandMyriadGenetics,duetoduallyissuedpatentsonpropertiesoftheBRCA1gene.ThelicensesultimatelyendedupinthepossessionofMyriad,butforabriefperiodbothfirmshadintellectualpropertyandofferedcommercialBRCAtesting,givingustheopportunitytoretrospectivelyanalyzethedivergentcorporatepracticemodels,clarifyingtheelementsofMyriadsbusinessmodelthatdifferedfromOncorMedsandthattarnishedspublicimage.InMarch1996,theFederalTaskForceonGeneticTestingpublishedareportmakingrecommendationsontheregulationofgenetictesting[41].Amongthemostcontroversialelementsofthisreportwasthepositionthatregulationoftestingcentersdidnotsufficetoassesstheclinicalvalidityofutilityofgenetictests[41].Thereportrecommendedexpandingtheregulatorycri-teriaundertheClinicalLaboratoryImprovementAmendmentsof1988(CLIA),thestatutethatgovernslaboratories.Approvalbyaregulatoryagencywasrecommendedtoensurequalityofinformedconsent,geneticcounseling,andtestutility,notjustwhetherthetestmeasuredwhatitclaimed,buthowandwhetheritaffectedclinicaldecisionsandimprovedoutcomes.Thetwocompanies,MyriadandOncorMed,tookoppositeapproachestorespectingtheserecommendationsintest-marketingstrategies.OncorMedwasthefirsttomarkettheBRCAtestcommerciallyin1996[41].Itscommercializationstrat-egycompliedwiththeTaskForcesrecommendations,includingtestingonlyinresearchprotocolsapprovedbyinstitutionalreviewboards.Toensureminimalconsu-merrisk,testingwasaccompaniedbyconsumereduca-tionandinformedconsent.Pre-andpost-testgeneticcounselingwasrequired,andmarketingwasdirectedtophysiciansparticipatinginresearch.OncorMedalsohadverystrictfamilyriskcriteriathatwomeninpursuitoftestingwouldneedtomeetinordertoavoidunduepsy-chological,emotional,orfinancialrisk,andavoidover-utilizationofanexpensivetestthatlow-riskwomendidnotnecessarilyneed[41].OncorMedwaspubliclycom-mittedtointroducingBRCAtestingthroughapathwaythatcompliedwithhealthprofessionalstandardsandonlyinthecontextofclinicalresearchtodemonstratesafetyandclinicalutility.Myriadtookadifferentapproach.Myriadmarketeditstestoutsideresearchprotocols,eventuallyincludingdirect-to-consumeradvertising.MyriadhadguidelinesratherthanstrictrequirementsaboutwhowaseligibleBRCAtesting,unlikeOncorMedsstrictprotocols.Finally,Myriad,didnotrefusetotestbasedoninap-propriatepatientselection,didnotrequireacopyofsignedconsent,anddidnotrequireverificationoftheavailabilityofqualifiedcounselorstoassistthepatientorthatcounselinghadtakenplace[41].Thus,unlikeOncorMed,MyriaddidnotpledgetointroduceBaldwinandCook-DeeganGenomeMedicinehttp://genomemedicine.com/content/5/1/8Page6of14 testingonlythrougharesearchpathwaythatwouldpro-duceevidenceofclinicalutilitythroughcollaborationswithpublicresearchinstitutions.Clearlythetwocompaniesapproachedtheintroduc-tionofBRCAtestingfromdifferentperspectives.WhileOncorMeddrovetheirmarketingstrategytomeettherequirementsofhealthprofessionalrecommendations,Myriadclearlyhadthedesiretoreachabroaderpopula-tion.TherewasaclearbenefittoMyriadsapproach:themorewomenwhoaretested,moredatacouldbecol-lectedtobetterrefineandinterpretthetest,andmorewomencouldpotentiallylearnaboutpredispositiontoalife-threateningdisease.Whilethereisnothinginher-entlyreprehensibleaboutthisapproach,itwaswidelyinterpretedasMyriadsemphasisonprofitandlessercommitmenttocreatinganevidencebasebeforewidelyReturningtotheHerceptinstory,GenentechabidedbystandardsofprofessionalpracticebyfollowingastrictFDA-approvedprotocolwhenintroducingitsnewtreatment.However,Genentechhadlittlechoice.ThisisbecauseGenentechwasdevelopingatherapeuticpro-duct,notadiagnosticservice.Asthedeveloperofatherapeutic,Genentechhadnochoicebuttoconductpremarket-approvalstudiesunderstrictFDA-approvedprotocols.MyriadandOncorMedhadachoice,becauselaboratory-developedtestswerenotsubjecttoFDApre-marketapproval.Whetherrightorwrong,ignoringthepublicstatementsofadvocacyorganizations,recommen-dationsofafederaltaskforce,andBRCAtestingguide-linesofseveralhealthprofessionalgroupsdidlittletoameliorateMyriadsimageasaprofit-maximizingIndevelopingadiagnosticforriskassessmentratherthanatreatmentforcancer,Myriadwasarguablyalreadyatadisadvantageinthequestforpublicopinion.AscrucialasBRACAnalysishasbeentotheadvance-mentofbreastcancermanagement,itsimplyprovidesinformationasopposedtotreatingadisease.Wherehasthepowertoridawomanofhercancer,BRACAnalysishasthepowertoaffirmtheprobableoccurrenceofawomanscancer,oridentifythegeneticcauseofanexistingcancer.Thisfavorsamorewelcom-ingreceptionforHerceptin,becauseatherapeuticismoredirectlyconnectedtosavingalife.IntheUShealthcaresystem,theissueofaccesstoexpensivedrugswaswidelyunderstoodtobeaproblem,butacommononefortherapeuticsandmedicaldevices.However,BRACAnalysiswassimilartoaroutinebloodtestdiagnosingthepresenceorabsenceofacondition.Infact,MarkSkolnickcommentedthat,theresnodif-ferenceinmymindorinthegovernmentsmindbetweenalipidassay,aproteinassay,animmunoassay,oraDNAassay[41].Theprofitmarginsweregenerallylowerfordiagnostics,andaccessproblemsandcostwereunusual,althoughtherewerealsodebatesaboutexpensiveimagingtechnologies.Butapplyingtheblockbusterfinancialmodel-charginghighpricesforapatentedproduct-wasnovelforadiagnostic.Whilethistestisunderthesamefunctionaltaxonomyasaroutineclinicaltest,patientsfoundthemselvesconfront-ingbarrierssuchascostandaccessmoreoftenasso-ciatedwithapharmaceuticaldrugorexpensivedevice.Theeconomicsofproductdevelopmentarealsoquitedifferentbetweendiagnosticsandtherapeutics.Genen-techhadtoconductcomplexandveryexpensiveclinicaltrialstoproveclinicalsafetyandefficacybeforemarket-ingHerceptin,buttheexpenseofdevelopingatestwasconsiderablylower.Myriadalsoinvestedinatestinglaboratory,certificationofitsprocedures,andincurredexpensesindevelopingBRACAnalysis.Muchofthisinvestmentwas,however,attributabletoitsparti-cularsole-sourceservicemodel,notnecessarilytodevel-opingtesting.Itcould,forexample,haveout-licensedthetest.TherewerealreadyninelaboratoriesofferingBRCAtestingthatwithdrewfromthemarketwhenMyriadenforceditspatents[42].Someofthesewereuniversityornonprofittestinglaboratories(suchasPennorMayo).Thatis,whilenouniversitycoulddevelop,testandmanufactureHerceptinexceptthroughanindustrypartner,manylaboratoriescouldandactuallydidintroduceBRCAtestingbeforeMyriadclearedthemfromthemarkettoestablishdominanceforBRACAnalysis.TheyclearedthesamebarrierstoentrythatMyriadfaced.Thus,althoughBRACAnalysisandHerceptinmighthavebeencomparableinsomeways,theyoccupytwoverydifferentnichesinhealth-careservices,contributingtodifferentpublicacceptance.ComparativerelationshipswithpatientandpractitioneradvocacygroupsAnothercontrastbetweenGenentech(andOncorMed)andMyriadGeneticswasoutreachtoandcollaborationwithadvocacygroupsrepresentingtheirpotentialcusto-mers.Whilecollaborationandcommunicationbetweenprovidersandpatientpopulationsisessentialtoclinicalresearchandmedicalcare,successfulcorporatebehaviorisnotalwaysdeterminedbythestrengthofarelation-shipwithrepresentativegroupsoftargetconsumers.Whenabusinessmonopolyiscreated,thenecessityforpositivecorporaterelationshipswithconsumersisdiminished,asthereisnocompetition.AcomparativeanalysisofadvocacygroupinteractionbetweenGenen-techandtheNationalBreastCancerCoalitionduringHerceptindevelopment,andbetweenMyriadGeneticsandmanypatientandpractitioneradvocacyorganiza-tionsintheintroductionandmarketingofBRACAnaly-revealsacrucialdiscrepancyinhowthecompaniesBaldwinandCook-DeeganGenomeMedicinehttp://genomemedicine.com/content/5/1/8Page7of14 managedconstituencyrelationships,especiallyafterinitialoppositionwasencountered.MyriadGeneticsGivenMyriadsfocusonhereditarybreastcancerdiag-nostics,anaturalallywouldbetheprominentadvocacygroupFORCE(FacingourRiskofCancerEmpowered).FORCEwasspecificallyorganizedtoaddresstheneedsofpeoplefacinginheritedriskofcancersofvarioustypes,andbreast/ovariancanceraccountsformostofitsmembership.ThoughFORCEislistedasareferenceorganizationonMyriadsBRACAnalysisinformationsite,therelationshipbetweenMyriadandFORCEhasbecomestrainedovertime[25].TworepresentativeinstancesofMyriadshandlingofadvocacyorganizationsare:(1)inpubliccommentariescondemningMyriadsuseofitspatents;and(2)concernaboutMyriadsmarketingoftestsdirecttoconsumersandtoprimaryphysicianswithouttheprofessionalstan-dardofgeneticcounseling.InastatementtotheUnitedStatesPatentandTrademarkOffice,FORCEDirectorSueFriedmanwrotethat,WebelievethattheexclusivegenepatentsoftheBRCA1andBRCA2genesheldbyMyriadLaboratorieshavehadadetrimentalimpactonthecommunityweserve[43].Thisstatementcontinuedtoelaborateonthreeprimaryissueswiththepatents:thestiflingofresearch,anegativeimpactontestinter-pretation,andhighcost.FORCEiscorrectinassertingthatthesecorporateissuesarerelatedtoMyriadsgenepatents,butanimportantpointtomakeisthatpatentsdonotinherentlyproducethesekindsofbehaviors.IftestinghadevolvedfromdiscoveriesandpatentsheldbyMary-ClaireKing,MichaelStrattonorsomeoftheothercompetitorsintheracetofindBRCAgenes,itispossiblethatlicensingandbusinessplanswouldhavegeneratedfarlessintenseopposition,possiblyeveniflicensedexclusivelytoafirmthatallieditselfwithbreastcancerorganizationsandfollowedthecoursethatOncorMedinitiallypursued[41].CollaboratingwithadvocacygroupslikeFORCEorNBCCorBCAwhenmakingdecisionsabouttestingpolicymighthavechan-gedtheunderlyingstorybychangingtheperceptionsandbehaviorofkeyconstituencyorganizations.AnotherexampleofcontroversialbehaviorisMyriaddecisiontostopcontributingtotheBreastCancerInfor-mationCore(BIC)databaseinlate2004.TheBICdata-baseisapublicdatabaseofbreastcancersusceptibilityvariantsencounteredinclinicalpracticeandresearch.Thisinformationismadeavailabletoqualifiedinvestiga-torstoimproveclinicalunderstandingandenablemoreeffectiveclinicalinterpretationofBRCAvariants[44].MyriadcontributedtoBICinto2004,butthenstoppeddoingso,initiallybecauseoftechnicalissues,butby2006,itwasadeliberatestrategytobuildadatabasethatwouldleveragethecompanyslargetestingexperienceintoaproprietarydatabasethatwouldnotexpirewithMyriadspatents.Bywithholdingthesevar-iantsfromthepublicdatabase,Myriadgainedacompe-titivetradesecretadvantageoverothercompanies.Thetradesecretdatabasewillpersistwhentheirpatentsrunout,andwillremainanadvantageuntilpublicdatasourcessupplythesameinformation[45].FORCEnotesina2010GenomicsLawReportarticle:Amongotherthings,suchastrategywouldruncontrary,atleastinsprit,toapolicyagainstextendingpatentmonopoliesbeyondtheirtermstermsTheproprietarydatabaseistradesecrecyleveragedonpatentmonopoly,anditisperfectlylegal.Bybecomingtheworldslargesttestingservice,Myriadalsodiscoversnewvariantsandincorporatesthoseintoitsdatabase.ThedataaregeneratedatMyriadsexpense(albeitfrompaymentsforclinicalservicesonsamplessentforgenetictesting).Forothergeneticconditions,clinicalinterpretationislargelybasedonpublicdata;fortesting,Myriadhasadistinctadvantage,evenoverthebestacademiccenters,becauseofitsuniquedataset.Again,thisisneitherillegalnorillogical;butitisanovelpracticeinclinicalgenetics,andsonewforthisconstituency.Leveragingaproprietarydatabasefromapatent-basedmonopolyseemslikelytogeneratecontro-versyasawarenessofthispracticegrows.Onasimilarnote,FORCEhascriticizedMyriadsfail-uretodevelopapromisingtherapeutic.Inher2012statementtotheUSPatentandTrademarkOffice(USPTO),FriedmanaddressedproblemsindealingwithMyriadwhendevelopingdrugstotreatbreastcancer.Poly-ADPribosepolymerase(PARP)inhibitorsareapromisingclassofdrugsforcancertreatment.CancerswithmutationsinBRCA1maybeparticularlypromis-ingtostudy.Inordertodevelopthisclassofdrugs,thecompanionlaboratorythatdevelopsthedrugneedstoalsogainFDAapprovalforadiagnostic[43].ThoughthemostrecentpolicystatementfromFORCE[46]doesnotbringupthispointabouttherapeuticdevelopmentandMyriadhasannounceditisindeedworkingoncompaniondiagnosticsforatleastonePARPinhibitormanufacturer,fromitspriortestimonyitisclearthatsCLIA-certifiedtestwascrucialfordevel-opmentofthetherapeutic,andyetlicensingfordrugvelopmentwasproblematicforatleastsomemanu-facturers,andaconcerntoFORCE[47].[48]Again,thisisaperfectlylegalandunderstandablebusinessbeha-vior,andacompletelyforeseeableconsequenceofexclu-siverights,butitdoesgeneratecontroversyandcouldimpedeadvanceofatherapeuticapproach[47].Testcostandefficacyarealsoasourceofconcerntoadvocacygroups.InitsstatementtotheUSPTO,FORCEcitedlimitedfinancialassistanceandanincreaseintestcostovertime,despitedramaticdropsinthecostBaldwinandCook-DeeganGenomeMedicinehttp://genomemedicine.com/content/5/1/8Page8of14 ofDNAsequencing.TheMyriadtestpriceout-of-pocketisintherangeof$3,300,somewhathigherthanitspriceadecadeago,withanadditional$700forexpandedBARTtestingifneeded(pricingquotedbyaMyriadcustomerservicerepresentativetooneoftheauthors[ALB]on7August2012),whichsomedefineasstandardofcare[49].InheramicusbrieftotheUnitedStatesDistrictCourtfortheSouthernDistrictofNewYork,DrElizabethSwisher,anoncologist,noted,approximatelyone-thirdtoone-halfofmypatientsforwhomIrequestgenetictestingdonotmeetMyriadcriteria;yet,Ithinkmostshouldreceivethisadditionalal®]genetictesting[49].ShealsopointedtoanarticleinCancerResearchrecommendingBARTrangementtestingasstandardofcareforhigh-riskwomen,includingthoseoutsideofMyriadsscreeningcriteria[50].TheYaleSocietyofGeneticCounselors,anadvocacygroupofphysicians,nurses,andgeneticcounselorsasso-ciatedwithYale,hasbeenparticularlyoutragedbytheadditionalcostassociatedwithBART.ThisgrouppostedapublicopenletterimploringthecompanytoincorporatetheBARTre-arrangementscreeningintoitscomprehensiveBRACAnalysistest,insteadoftreatingitasanextra-costtestconductedonlywhenBRACAna-lysisisnegativeandyetsuspicionofaBRCAmutationpersists[51].CNNcoveredtheletterinanOctober2011newsstory[52].YalegeneticcounselorEllenMatl-offstated,WhatMyriadsdoing-chargingextraforthistest-isreallysleazy.Theyrecollectingbloodmoneyoffmypatients.ThisinflammatoryquoteisrepresentativeoftheextenttowhichsomehavebeenalienatedbyMyriadsbusinesspractices.Manybusi-nessesencounterstridentlanguagequestioningtheirpractices(forexample,manygroupshavequestionedGenentechspricingofAvastin,andNBCCapplaudedFDAsJuly2010withdrawalofapprovalforitsuseinbreastcancer,anindicationGenentechfoughthardtokeep)[53].TheintensityandregularityofpublicconflictwithMyriad,however,appeartobepartofitsDNA.ThispoorcommunicationwithrelevantadvocacygroupsoverBRACAnalysisstartedinthewakeofthesdiscovery,beforethetesthadevenbeenfullydeveloped.In1996,theAmericanSocietyofClinicalOncologyreleasedasetofguidingprinciplesregardingthemanagementofBRCAtesting[54].Inresponsetotheserecommendations,FrancesViscoofNBCClaudedtheexcitingscientificdiscovery,butexpressedconcernthatpublicpolicyandmedicalknowledgehadnotkeptpacewiththescience,andtestingshouldbebasedonevidenceofclinicalutility[55].BRCAtestingshould,therefore,takeplaceatleastinitiallyonlyinthecontextofresearch,alongthelinesofOncorMedspolicy.Viscoadvocatedadirectresearchprogramtoexaminetreatmentoptionsforwomenwhotestpositivefordele-mutations,tostudywhatcounselingisnecessaryandhowtoavoiddiscriminationinhealthinsuranceandemployment.Sheoptimisticallyrecog-nizedthat:Thisisatimewhenwe,asbreastcanceractivists,needthemedicalcommunitytostandwithusandrecognizetheneedtodoless,ratherthanmore...Wehaveawonderfulopportunityhere:wecanformapartnershipbetweenpatientandphysicianandthoughtfullyrespondtothisdiscovery...Weaskthatyoutakeadvantageofthisstandardofcare,onethatrecognizeshowlittleweknowandisdesignedtogettheanswers.FrancesVisco,onbehalfoftheNationalBreastCancerCoalition[55].Inthisstatement,NBCC,asthepre-eminentorganiza-tionforbreastcanceractivism,asserteditsrighttoaplaceatthetablewiththescientists,policymakers,andcorporateheadschargedwithimplementingMarkSkolnickofferedconflictingcommentaryinthesameissueoftheJournalofClinicalOncology.Hisargu-mentsdirectlycounteredViscos,statingthattowith-holdthelaunchofthetest,eventomaketimeforthestudyrecommendedbyVisco,wouldbeto,turnbacktheclockandignoretheabilitytoprovideknowledgetowomenwhoseekit;tomethisisunethical.directlyopposedthesentimentsofNBCCandannouncedareleaseplanfortestingthatflauntedNBCCssuggestions(confirmedinaninterviewbetweentheauthorsandFrancesVisco).InthewakeofMyriadlawsuit,NBCChasgoneonrecordinoppositiontoMyriadspatents,althoughneitherNBCCnorFORCEisadirectpartyintheongoinglawsuit(however,BCAisapartytothelawsuitagainstMyriad).Theroleofthepatentsinthesestoriesisambiguous:themonopolygaveMyriadstrongexclusiverightsthatbolstereditslegalauthority,andmayhaveemboldenedit.Orperhapsthepatentshadlittletodowiththedegreetowhichthecompanyabidedbyprofessionalrecommendationsandrelatedtodiseaseadvocacyorga-nizations.ByheedingViscosrecommendationsinthebeginning,Myriadmighthavemitigatedsomeofthepublicoutcrybyforgingalliancesinsteadoffosteringenmity.OncorMed,thefirmthathadlicensedMary-ClaireKingsgeneticlinkagepatentandMichaelStrat-patents,hadcommittedtoaresearchpro-gramtobuildevidencefortheutilityofBRCAtesting;Myriadmadeadifferentstrategicchoice.Sincebothfirmshadpatents,itisclearpatentsdidnotdrivethedifferingchoices,althoughMyriadsbusinessmodelwasenabledbyitspatentsandsubsequentemergenceasBaldwinandCook-DeeganGenomeMedicinehttp://genomemedicine.com/content/5/1/8Page9of14 soleproviderof BRCA testingwithOncorMed ’ sdemise. ItishardtoimagineMyriadcouldhavebeenassuccess- fulinbecomingthedominantUStestingservice,even inclinicalresearch,withoutitspatentrights,sopatent exclusivityisacontributingcause.Butthefactthat othermodelsfordeployingpatentedgeneticdiagnostics canavoidthecontroversiesassociatedwithBRACAnaly- sis ® showsthatbusinessdecisionsabouthowtouse exclusivityrequireseparateattentioninthecausalnet- work.Patentswerenecessarybutnotsufficienttocon- structthenarrativeofvillainyassociatedwithMyriad. Myriademergedfromitspatentbattleswith OncorMedwithpatentrightsto BRCA1 / 2 andwenton toturnaprofit,whileOncorMeddidnotsurvive. OncorMed ’ sstrategymayhavebredlesscontroversy, butMyriadisthefirmthatwentontosurviveasabusi- ness.Figure1demonstratesthisbyshowingMyriad ’ s revenuestreamfrom1993to2012. Thesettlementbetweenthecompaniesmaywellhave beendrivenbytheperceivedlikelyoutcomesofpatent litigationortheoutcomeofapatentinterferencepro- ceeding.Outcomesfromthep rivatesettlementsuggest Myriadhadtheupperhand.OncorMedfailedinits BRCA testingservicedespiteitsbetterrelationswith healthprofessionalorganizationsandadvocacyorganiza- tionsasa ‘ goodcitizen ’ vowingcompliancewithhealth professionalstandards;Myriademergedwithpatent rightsbutpoorrelationswithorganizationsrepresenting itscustomerbaseofphysiciansandfamiliesatriskof breastandovariancancer.Itisclearthatfrom2001to 2012,Myriad ’ swasthemoresuccessfulbusinessstrat- egy,mainlybecauseofitspatentposition. Myriad ’ sstrategynowfacesatransitioninwhichill willcouldhaverealbusinessconsequences.Itfacesfour challenges:newtechnology,expirationofpatents,possi- bleinvalidationofpatentclaims,anderosionofitspro- prietarydatabase.AsDNAsequencingcostsdrop, whole-genomeandall-exomesequencingiscominginto thecostrangeforsequencingjust BRCA1 / 2 .Newcom- petitorsmightsequencenotonlythetwo BRCA genes butalsofindmutationsinothergenesassociatedwith breastandovariancancer[56]-orallgenes-formore orlessthesamecostatMyriad ’ stwo-genetest.Myriad ’ s broadestpatentswillbegintoexpirein2014.The ongoingpatentlitigationhasalreadyinvalidatedMyr- iad ’ sbroadestpatentclaims-tomethodsfordetecting mutationsin BRCA genes.ItsclaimsonshortDNA fragments(forexample,claims5and6ofUS5,747, 282)arelikelyalsoinvalid[57],andtheseareamongthe onlyclaimsthatwouldprecludediagnostictesting,other thanthroughPCRmethods,whichfallunderclaim16 ofUSPatent5,747,282.SincePCRamplificationisunli- kelytobeanecessarystepinfuturemulti-genesequen- cingstrategies,Myriad ’ sexclusivityin BRCA genetic testingcouldbeunderminedbytheplummetingcostof multi-genedeepsequencing,all-exomesequencing,and whole-genomesequencing.Dependingontheoutcome ofthependingcase,Myriadcouldendupwithonly Figure1 MyriadGeneticsrevenuestreamfrom1993to2011 .Dataderivedfrom[66]. BaldwinandCook-Deegan GenomeMedicine 2013, 5 :8 http://genomemedicine.com/content/5/1/8 Page10of14 patentsonspecificmutationsassociatedwithcancerrisk,orwithnopatentsonnaturallyoccurringsequencesatall.(Myriadhaspatentsonseveralspecificmutationsandmethodsfordetectingthem,someextendingintoatleast2028[58].)EvenifMyriadpatentsarenotvalid,Myriaddoeshaveitsproprietarydatabase,butthevalueofthatdatabasewilldiminishaspubliclyfundedresearchidentifiesdisease-associatedandneutralmutations.Moreover,ifpayersorhealthprofessionalsdemandedaccesstodatatoverifyMyriaddeterminationsofcancerriskasaconditionofpayment,thenMyriadstradesecretmightnolongerremainsecret[59].Myriaddiagnosticblockbustermodelhasproventobea$400millionperyearbusinesssuccess.Itdoesnotfollow,however,thatitwillwithstandtechnologicalcompetition,patentexpirationandlitigationordeter-minedpubliceffortstoimproveinterpretationofBRCAmutations.Inthisway,likepatentedbrand-namedrugs,Myriadsblockbustermodelisvulnerabletointroduc-tionofcompetitionwithpatentexpiryortechnologicalcompetition.OncorMedsstrategymighthaveproducedaloyalcustomerbaseofthoseorderingandseekingtesting;ifMyriadscustomersareonlyusingitsservicesgrudgingly,andjumptocompetitorsassoonastheycan,thenMyriadsbusinesssuccesscouldbeeva-nescent.WhetherMyriadslong-termbusinesssuccessdependsonitsexclusivepatentrightswillbecomemoreapparentoverthenextfewyears.IncontrasttothepublicimageofMyriadscorporaterelationswithprominentadvocacygroups,Genentechhashistoricallybeenhailedasastrongcommunitypart-ner,andanallywiththeNBCCindevelopingHercep-(thisalliancehasnotsurviveddifferingpositionsonAvastinanddrugpricing[60],however,sothealliancewasstrategicandcontingent).Genentechsoutreachtoadvocatesafterfacingdeterminedoppositionisparticu-larlyinstructive.On16August1995,theSanFranciscoWeeklyrananarticleonGenentech,entitledAstheylaydying:canceradvocatesrageatGenentechforwithholdinganexperi-mentaldrug[61].Thisisnotthekindofpressabio-technologyfirmwantsinthemorningpaper.ThearticletoldofMartiNelson,abreastcancerpatientandadvo-catewithBCA.UponsuspectingthatshemightbeaidedbytreatmentwithHerceptin,thenintheearlyclinicaltrialstages,shepressedGenentechtoprovideherthemedicationonacompassionateuseGenentechrefusedtogiveNelsonHER-2/neu[sic].ShediedonNov.9,1994.Afellowadvocatewasquotedinthisarticle,declaring,HowmanywomenhavetodieonGenentechsdoorstepbeforetheydoevenonecom-passionateuseforHER-2/neu[sic]...Wearenotgoingtoletthisrest.WhatGenentechisdoingisreallyugly.Inthemonthsleadinguptothepublicationofthatarti-cle,BCAhaddoneanythingbutletitrest.On5December1994,advocatesmarchedontheGen-entechcampus,demandingHerceptinaccessforcom-passionateuse[30].ThisgottheattentionofJohnCurd,GenentechsImmunologyandOncologyClinicalTrialsdirector(page122in[30]).Recognizingthathewascaughtbetweenadvocacythatwasnotmisguidedandthepragmaticcorporateneedtodenytheirwishes,hesoughtthehelpofWashington-basedadvocateFrancesVisco[30].AstoldinRobertBazellsbook,Her-2,CurdrecallsViscosadvicetohim:FranViscosaidtome,John.Iagreewithyouintellectuallyandscientifically.Compassionateusedoesnotmakealotofsense.Idliketoseethedata.Butthisisnotanintellectualissue.Thisisanemotionalandpoliticalissue.Andpolitically,youhavetohaveacompassionateuseprogram[30].Withthiscollaborationwasbornanewapproachtopharma-ceuticaldevelopmentatGenentech:advocateswerebroughttothetable.InApril1995,advocatesfrommanygroups,includingNBCC,wereinvitedtohelpdesignthephaseIIItrials.Thisnewmodelofcollaborationresultedinamarkedlysuccessfultrial.VisconotedinretrospectthatGenen-techwasthefirstpharmaceuticalcompanythatagreedtopartnerwithbreastcanceradvocates,commentingGenentechworkedwithusonallaspectsofthetrial,fromprotocoldesign,tooutreach,tooversight.Inparticular,thecompanysagreeingtoourrequestthatinvestigatorsinspecificcommunitiespartnerwithtrainedactivistsinfacilitatingaccrualtothetrialhelpedleadtorecordaccrual[62].InOctoberof1999,Genen-techwasawardedtheCorporateLeadershipAwardfortheircollaborationwithNBCC,holdingupthiscolla-borationbetweenadvocatesandindustryasthestandardanewmodelofcancerresearchresearchDifferentcorporateresponsestoconflictwithadvocatesAcriticaldifferencebetweenGenentechandMyriadwassopenandsystematiccultivationofcolla-borativeandamicablerelationshipswithadvocacygroupsrepresentingtheirclientbaseinresponsetoearlyconflict.Bothcompaniesencounteredconflict;GenentechmadeitproductivewhileMyriadpersistedwithitsinitialbusinessplan.ThepopulationsservedbyGenentechandMyriadoverlappedtoasignificantextent.Mediacoverageofbothconflictsincludesverysimilarnegativelanguagealludingtocompaniesfavoringprofitoverpatientaccess.Thenarrativesdifferatthepointofresolution:GenentechmadeadeliberateefforttorepairapoorrelationshipwithBCAandturnedtoNBCCasanactivepartner,whereasMyriaddidlittletoreconcilewithFORCEorNBCC.Myriadhasmadeeffortstocreateitsownadvocacyorganizations,butBaldwinandCook-DeeganGenomeMedicinehttp://genomemedicine.com/content/5/1/8Page11of14 theselackcredibilitypreciselybecausetheyarecorpo-rate-affiliated,ratherthancollaborationswithestab-lished,credible,nationalorganizations.Amicableandmeaningfulrelationshipswithadvocacyorganizationsdedicatedtobothpatientsandclinicianscanmattertoacompanyssuccess.Thisisnotasimplematter;NBCCisnotatallhappywithGenentechspur-suitofthebreastcancerindicationforthehighlyexpen-siveAvastin.ButnoorganizationsuedGenentechoveritsHerceptinpatent,orevenoverAvastin.BCAdidjointhesuitagainstMyriadspatent,andNBCCandFORCEhavemadestatementsopposingMyriadsman-agementofitsBRCApatents[43,63]eveniftheydidnotjointheplaintiffsinthecase.Genentechwaswise,andultimatelymoresuccessful,torecognizethedetrimentaleffectofapoorcorporateimageandtheverypracticalbenefitofanengagedcon-stituencythatcouldmobilizeclinicalresearchparticipa-tion.Genentechmovedforwardwithacollaborativeapproachtoclinicaltrialimplementation.Myriadsuna-pologeticdecisionstotestoutsidehealthprofessionalrecommendationsandtoriskalienatingnationalorgani-zationsrepresentingbreastcanceradvocatesiswherethesestoriesfundamentallydiverge[64].ConsideringthatbothGenentechandMyriadhadpatentprotection,wecanconcludethattheattributionofcauseandtheconstructionofvenalnarrativesaretosomedegreemisdirectedatpatents.Inhealthcare,companystrategyisinherentlyboundtotheconsu-mersthatitserves,regardlessofpatentprotection.Whentheproductbeingsoldissodirectlyrelatedtohealthandwellbeing,thestakesandstandardsforbenevolentcorporatebehaviorareraised.AsZoeChristopher,aresourceliaisonforBCAstatedinhercontributiontotheAmericanCivilLibertiesUnionTakeBackyourGenespubliccampaign,Itakebackmygenessothatprofitwillnotbeattheexpenseofslives[65].WespeculatethatitisprimarilyMyriadsfailuretoacknowledgethis,notjusttheirpatentprotection,thathascontributedtotheproble-maticescalationofthedebate.Profitsoverpatientsacommonrefraininhealthcareservices,andbynomeansrestrictedtoBRACAnalysisoranyotherparti-cularproduct;neitherisitconfinedtoproductsandservicescoveredbypatents.Patentsoverpatientsisaverseofthegeneralrefrain.ItisnonethelessinstructivethatwhenGenentechencounteredopposi-tionfromactivists,itrecalibrateditsstrategyfordevel-opingHerceptin;whenMyriadencounteredsimilaropposition,itlargelyignoredit,counteredit,orattrib-utedittomisinformationorlackofunderstanding.WhatMyriaddidnotdowaschangeitsplan,orevenitsrhetoric.SummaryAmicuscuriaeandfamousco-discovereroftheDNAdoublehelixJamesWatsonconcludedhisbyquotinghisownwords:TheHumanGenomePro-ject...isaspreciousabodyofknowledgeashumankindwilleveracquire,withapotentialtospeaktoourmostbasicphilosophicalquestionsabouthumannature,forpurposesofgoodandmischiefalike[66].InboththescientificandpoliticalaftermathoftheHumanGenomeProject,Watsonsassertionhaslargelyheldtrue.AstheMyriadcasehighlights,thesocial,ethical,andlegalimplicationsofgenomicsarecontinuallyemerging,evendecadesafterthediscoveryofDNA.Forasmuchasresearchhasdiscoveredandpromisestodiscover,inex-perienceaboundsandthesequestionslinger:theidea-lizedpromiseofasimplecorrelationbetweengenotypeandphenotypeisgraduallybeingreplacedbyamoresophisticatedunderstandingofthescienceandthedisci-plinarymaturitytoacceptwhatwillperhapsalwaysremainamystery,thecomplicatedrelationbetweengen-otype,biologyandhealth.Byanalogy,thishistoryalsosuggestsaneedforsophisticationofhowtheaccompa-nyingsocialnarrativesofthatsciencecometobecon-structed.Ifthismysteryexistsinthescience,surelywecanexpectthesamedegreeofuncertaintyintheethicalandlegalramificationsofthatscience,includingthewaybusinessstrategiesarecraftedandadjusted(ornot).SeveralstrategicdecisionscontributedtoMyriadabysmalcorporateimage.BycomparingMyriadsdeci-sionstothoseofGenentechandOncorMed,itbecomesapparentthatthestoryisnotjustaboutpatents.Therearemanypointsofcontention,andthefullweightofscontroversialbusinessmodelshouldnotbeattributedtopatentsalone.ArgumentsaboutpatentablesubjectmatterareplayingoutbetweentheAmericanCivilLibertiesUnionanditsplaintiffsandMyriadandthedefendantsinthecasebeforetheUSSupremeCourt,butourpurposehereistostressthattheMyriadcaseisanexceptionalone,andnottherule.Thelegaldebatehasfocusedsolelyonpatents,butMyriadwaslargelysuedbecauseofitsbusinessmodel:patentspro-videdalegalscapegoat.WhilemanywouldagreethatMyriadshouldbeheldaccountableforthepracticesthatpatentsdidindeedallowthemtopursue,thelegalcon-sequencesareultimatelynotonlyaimedatthevehicledrivingthesepractices,butalsoatthepublicroadthisvehicleisutilizing,thepatentsystem.Inshort,thiscom-parativecasestudyshowsitisnotonly-orevenmainly-aboutthepatents.Theriskofapatent-centerednarrativeisthatthecru-cialnuancesofthisstorywillbelostinmonomaniacalattentiontowhethergenescanbepatented,totheneglectofbusinesspracticesthatareequallytoblame.BaldwinandCook-DeeganGenomeMedicinehttp://genomemedicine.com/content/5/1/8Page12of14 Thesocialissuesthathaveaccompaniedthevigorous,oftenacrimonious,debateaboutgenepatentshavebothlegalandmoralelements,andthatdebatewillgoon,regardlessofcourtdecisionsintheongoingBRCAlawsuit.Thepublicdebatehasbeenimpoverishedintworespects,byassuming:(1)thatthecauseoftheproblemsunderlyingthedebateareinherentlyduetopatents;and(2)thateliminatinggenepatentswillsolvethosepro-blems.Patentscontributeandenablebusinesspractices,butmanygeneshavebeenpatentedthatdidnotleadtothesameproblems.ThestoryoftestingisaboutbusinessdecisionsthatdidindeedrestonenforcingexclusiverightsintheUSmarket-butthestoryisalsoaboutfailingtoincludeadvocacyorganizationsanddis-regardinghealthprofessionalstandards.Patentsmatter,butsodobusinesspractices.BCA:BreastCancerAction;BIC:BreastCancerInformationCore;CAFC:CourtofAppealsfortheFederalCircuit;FDA:FoodandDrugAdministration;FORCE:FacingourRiskofCancerEmpowered;NBCC:NationalBreastCancerCoalition;NCI:NationalCancerInstitute;SEC:SecuritiesandExchangeCommission;USPTO:USPatentandTrademarkOffice.RC-Dconceivedofthepaper,helpedtodraftandeditthemanuscript,andparticipatedinitsdesign.ALBhelpedtodraftandeditthemanuscript,andparticipatedinitsdesign.BothauthorsreadandapprovedthefinalRC-DisresearchprofessoranddirectorofGenome,Ethics,Law&Policy,InstituteforGenomeSciences&PolicyandSanfordSchoolofPublicPolicyatDukeUniversity,Durham,NC,USA.ALBisaresearchaideinGenome,Ethics,Law&PolicyatDukeUniversity,wheresheispartoftheCenterforPublicGenomics.CompetinginterestsLBdeclaresnocompetinginterests.RC-Disonthelistofexpertswhoagreetheydonothaveanyfinancialsupportinanyformfrompharmaceuticalormedicaldevicemanufacturersduringthepastfiveyearsandthattheydonothaveotheraffiliationsorfinancialinvolvementsthatwouldpresentaconflictofinterest.Athreememberboarddecideswhethertoacceptapplicants[67].Heaccordinglydeclaresnocompetinginterestsforthisarticle.AcknowledgementsResearchreportedinthispublicationwassupportedbytheNationalHumanGenomeResearchInstituteoftheNationalInstitutesofHealthunderAwardNumberP50HG003391,andbytheEwingMarionKauffmanFoundation.ThecontentissolelytheresponsibilityoftheauthorsanddoesnotnecessarilyrepresenttheviewsoftheNationalHumanGenomeResearchInstitute,theNationalInstitutesofHealth,ortheKauffmanFoundation.ThispaperresultedfromaconferenceconvenedbytheInstituteforHealthLaw,UniversityofAlberta,atBanff,Alberta,May2012.WethankTimCaulfield,TaniaBubela,E.RichardGold,JuliaCarboneandmanyCanadiancolleaguesfortheirinsightsandhospitality,includingviewsofmoose,bears,andbighornsheepandhikesthroughthesnowsofLakeLouise.Received:8August2012Revised:19December2012Accepted:31January2013Published:31January2013AssociationforMolecularPathologyv.U.S.PatentandTrademarkOffice,702F.Supp.2d181(S.D.N.Y.2010).2.VorhausJCaD:PigsFly:FederalCourtInvalidatesMyriadsPatentClaims.TheGenomicsLawReport.Volume2012.Editedby:VorhausD.RobinsonBradshaw2010.AssociationforMolecularPathologyv.U.S.PatentandTrademarkOffice,653F.3d1329(Fed.Cir.2011)..PetitionforWritofCertiorari,AssnforMolecularPathologyv.MyriadGenetics,Inc.,No.12-398,(U.S.Sept.25,2012)..DocketFilesforAssociationofMolecularPathology,etal.v.MyriadGeneticsInc.,etal..al..docketfiles/11-725.htm].6.DocketFilesfortheAssociationofMolecularPathologyetal.v.MyriadGeneticsInc.,etal..al..docketfiles/12-398.htm].7.EisenbergR:Howcanyoupatentgenes?.AmericanJournalofBioethics8.ParthasarathyS:BuildingGeneticMedicine:BreastCancer,Technology,andtheComparativePoliticsofHealthcare.Cambridge,MA:MITPress;9.GoldER,CarboneJ:MyriadGenetics:Intheeyeofthepolicystorm.Geneticsinmedicine:officialjournaloftheAmericanCollegeofMedical10.DaviesK,WhiteM:Breakthrough:theracetofindthebreastcancer1996,310.11.Williams-JonesB:Historyofagenepatent:tracingthedevelopmentandapplicationofcommercialBRCAtesting.HealthLawJournal12.CaulfieldT,Cook-DeeganRM,KieffFS,WalshJP:Evidenceandanecdotes:ananalysisofhumangenepatentingcontroversies.NatBiotechnol13.CaulfieldT,BubelaT,MurdochCJ:Myriadandthemassmedia:thecoveringofagenepatentcontroversy.GenetMedGenentechandChairman/CEOLevinsontoReceiveNationalBreastCancerCoalitionsCorporateLeadershipAward..Award..gene/news/press-releases/display.do?method=detail&id=4890].15.GusellaJF,WexlerNS,ConneallyPM,NaylorSL,AndersonMA,TanziRE,WatkinsPC,OttinaK,WallaceMR,SakaguchiAY,etalApolymorphicDNAmarkergeneticallylinkedtoHuntingtonsdisease.Nature1983,306:234-238.16.StephensJC,MadorML,CavanaughML,GradieMI,KiddKK:MappingtheHumanGenome:CurrentStatus.17.RobertsL:Therushtopublish.WoosterR,NeuhausenSL,MangionJ,QuirkY,FordD,CollinsN,NguyenK,SealS,TranT,AverillD,etalLocalizationofabreastcancersusceptibilitygene,BRCA2,tochromosome13q12-13.19.WoosterR,BignellG,LancasterJ,SwiftS,SealS,MangionJ,CollinsN,GregoryS,GumbsC,MicklemG:IdentificationofthebreastcancersusceptibilitygeneBRCA2.20.TavtigianSV,SimardJ,RommensJ,CouchF,Shattuck-EidensD,NeuhausenS,MerajverS,ThorlaciusS,OffitK,Stoppa-LyonnetD,etalcompleteBRCA2geneandmutationsinchromosome13q-linkedNaturegeneticsTavtigianetal.Chromosome13-LinkedBreastCancerSusceptibilityGene.USPatent6,033,857.FiledMarch20,1998andissuedMarch7,A.Futrealetal.MaterialsandmethodsrelatingtotheidentificationandsequencingoftheBRCA2cancersusceptibilitygeneandusesthereof.USPatent6,045,997.FiledNovember25,1996andissuedApril4,2000.D.Shattuck-Eidens,etal.LinkedBreastandOvarianCancerSusceptibilityGene.USPatent5,693,473.FiledJune7,1995andissuedDecember2,1997..,In.24.Cook-DeeganR,DeRienzoC,CarboneJ,ChandrasekharanS,HeaneyC,ConoverC:Impactofgenepatentsandlicensingpracticesonaccesstogenetictestingforinheritedsusceptibilitytocancer:comparingbreastandovariancancerswithcoloncancers.GenetMedMed26.FisherB,CostantinoJP,WickerhamDL,RedmondCK,KavanahM,CroninWM,VogelV,RobidouxA,DimitrovN,AtkinsJ,etalTamoxifenforpreventionofbreastcancer:reportoftheNationalSurgicalAdjuvantBreastandBowelProjectP-1Study.JournaloftheNationalCancer27.KauffND,SatagopanJM,RobsonME,ScheuerL,HensleyM,HudisCA,EllisNA,BoydJ,BorgenPI,BarakatRR,etalRisk-reducingsalpingo-BaldwinandCook-DeeganGenomeMedicinehttp://genomemedicine.com/content/5/1/8Page13of14 oophorectomyinwomenwithaBRCA1orBRCA2mutation.TheNewEnglandjournalofmedicine28.JohnConleyDV,RobertCook-Deegan:HowWillMyriadRespondtotheNextGenerationofBRCATesting?.GenomicsLawReport.Volume2012.Editedby:VorhausD.Robinson,Bradshaw,2011.29.MyriadGeneticsLaboratoriesI:MyriadGeneticsSECAnnualReport,FormWashington,D.C.:UnitedStatesSecuritiesandExchangeCommission;30.BazellR:Her-2:TheMakingofHerceptin,aRevolutionaryTreatmentforBreastCancer.1998,240.31.SlamonDJ,GodolphinW,JonesLA,HoltJA,WongSG,KeithDE,LevinWJ,StuartSG,UdoveJ,UllrichA,etalStudiesoftheHER-2/neuproto-oncogeneinhumanbreastandovariancancer.32.SzaboL:BreakoutdrugHerceptinbringsnewageinbreastcancercare.USATodayGannettCompanyInc.;2008.33.Piccart-GebhartMJ,ProcterM,Leyland-JonesB,GoldhirschA,UntchM,SmithI,GianniL,BaselgaJ,BellR,JackischC,etalTrastuzumabafteradjuvantchemotherapyinHER2-positivebreastcancer.TheNewEnglandjournalofmedicineGenentechAnnouncesFullYearandFourthQuarter2008Results..Results..ex99_1.htm].35.BosklopperE:AntibodyDrugs:TechnologiesandGlobalMarkets.Wellesley,MA:BCCResearch;2012.AssociationforMolecularPathologyv.U.S.PatentandTrademarkOffice,702F.Supp.2d181(S.D.N.Y.2010).DeclarationofArupaGanguly,Ph.D..Ph.D..brca_Ganguly_declaration_20090826.pdf].37.Klausner,RichardandCritchfield,Gregory:MemorandumofUnderstandingbetweenMyriadGenetics,Inc.AndtheNationalCancerInstitute.LakeCity,UT:MyriadGeneticsandtheNationalCancerInstitute;1999.38.EisenbergR:PublicResearchandPrivateDevelopment:PatentsandTechnologyTransferinGovernment-SponsoredResearch.VirginiaLaw39.MuellerJ:TheEvanescentExperimentalUseExemptionfromtheUnitedStatesPatentInfringementLiability:ImplicationsforUniversityandNonprofitResearchandDevelopment.BaylorLawReview2004,:917-981.TwitterreportfromtheGenomes,Environments,Traits(GET)Conference,Boston,MA,April27,2010..2010..com/wp-content/plugins/as-pdf/generate.php?post=3231].41.RebeccaFarkasDG,MargaretEaton:MyriadandOncorMedandthemarketingofthefirstgenetictestsforbreastcancersusceptibility.Alto,California:StanfordGraduateSchoolofBusiness;2004.42.ChoMK,IllangasekareS,WeaverMA,LeonardDG,MerzJF:Effectsofpatentsandlicensesontheprovisionofclinicalgenetictestingservices.JMolDiagn43.FriedmanS:TestimonytoUSPTOonimpactofexclusivegenepatents.FacingOurRiskofCancerEmpowered;2012.AnOpenAccessOn-LineBreastCancerMutationDataBase..Base..research.nhgri.nih.gov/bic/].45.Cook-DeeganR,ConleyJM,EvansJP,VorhausD:Thenextcontroversyingenetictesting:clinicaldataastradesecrets?.Europeanjournalofhumangenetics:EJHGUSPTORoundtableWrittenCommentary..Commentary..advocacy/current_action/documents/USPTO_Jan2013_Written_Testimony.pdf].47.AzvolinskyA:LackofBRCAtestingapprovalcreatessnagforcancerNaturemedicineTestimonytoUSPTOonimpactonexclusivegenepatents..patents..facingourrisk.org/advocacy/current_action/uspto_update.php].49.ElizabethSwisherM:AssociationforMolecularPathologyv.U.S.PatentandTrademarkOffice,702F.Supp.2d181(S.D.N.Y.2010).DeclarationofElizabethSwisher,MD.UnitedStatesDistrictCourt;2009.50.PalmaMD,DomchekSM,StopferJ,ErlichmanJ,SiegfriedJD,Tigges-CardwellJ,MasonBA,RebbeckTR,NathansonKL:TherelativecontributionofpointmutationsandgenomicrearrangementsinBRCA1andBRCA2inhigh-riskbreastcancerfamilies.Cancerresearch51.EllenMatloffRB,DanielleBonadies,etalAnOpenLettertoMyriadEditedby:RichardWenstrupM.NewHaven,Connecticut:YaleCancerGeneticCounseling;2011:.52.CohenE:Whenbreastcancertestgetsitwrong.CNNHealth:CNN;2011.NBCCRespondstoODACVoteonAvastinAvastinknowbreastcancer.org/news-research/news/nbcc-response-to-odac-vote-on.StatementoftheAmericanSocietyofClinicalOncology:genetictestingforcancersusceptibility,AdoptedonFebruary20,1996..Journalofclinicaloncology:officialjournaloftheAmericanSocietyofClinicalOncology:1730-1736,discussion1737-1740.55.FrancesViscoMS,FrancisCollins:CommentaryontheASCOStatementonGeneticTestingforCancerSusceptibility.Editedby:OncologyASoC.AmericanSocietyofClinicalOncology;1996:.56.WalshT,LeeMK,CasadeiS,ThorntonAM,StraySM,PennilC,NordAS,MandellJB,SwisherEM,KingMC:DetectionofinheritedmutationsforbreastandovariancancerusinggenomiccaptureandmassivelyparallelProceedingsoftheNationalAcademyofSciencesoftheUnitedStatesofAmerica57.KeplerTB,CrossmanC,Cook-DeeganR:Metastasizingpatentclaimson58.Scholl,etalBRCA2MutationsandUseThereof,USPatent7,993,835.IssuedbyUnitedStatesPatentandTradeOffice.USA:MyriadGenetics,Inc.;59.RobertCook-DeeganJC,JamesEvans,DanielVorhaus:TheNextControveryinGeneticTesting:ClinicalDataasTradeSecrets?.JournalofHumanGenetics2012,(forthcoming).WhatHappenedattheFdaAvastinMeeting?..Meeting?..clinicaloncology.com/ViewArticle.aspx?d=Solid+Tumors&d_id=148&i=August61.LinnA:AsTheyLayDying.SanFranciscoWeeklySanFrancisco:VillageVoiceMediaHoldings,LLC;1995.NBCCPresidentPraisesGenentechforPartneringWithBreastCancerAdvocatesinHER-2Trial..Trial..10165/64743].63.Comment43:NationalBreastCancerCoalition/FranVisco..Visco..uspto.gov/web/offices/com/sol/comments/utilguide/nbcc.pdf].AssociationforMolecularPathologyv.U.S.PatentandTrademarkOffice,702F.Supp.2d181(S.D.N.Y.2010).DeclarationofDr.MarkSkolnick..Skolnick..1:2009cv04515/345544/172/0.pdf?ts=1262043961].65.TakeBackYourGenes|AmericanCivilLibertiesUnion..Union..org/take-back-your-genes].66.WatsonJames:BriefforAmicusCuriaeJamesD.WatsoninSupportofNeitherParty.Editedby:UnitedStatesCourtofAppealsfortheFederalCircuit2012[http://www.genome.duke.edu/centers/cpg/BRCA-resources/67.LenzerJ,BrownleeS:Namingnames:istherean(unbiased)doctorinthedoi:10.1186/gm412Citethisarticleas:BaldwinandCook-Deegan:Constructingnarrativesofheroismandvillainy:casestudyofMyriadsBRACAnalysis®comparedtoGenentechsHerceptinGenomeMedicine Thorough peer review No space constraints or color Þgure chargesResearch which is freely available for redistribution www.biomedcentral.com/submit BaldwinandCook-DeeganGenomeMedicinehttp://genomemedicine.com/content/5/1/8Page14of14