Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 1 of 36 PageID #: 945
`Case 1:12—cv—OO274—LPS Document 75-1 Filed 05/08/13 Page 1 of 36 Page|D #: 945
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`EXHIBIT A
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`

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`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 2 of 36 PageID #: 946
`Case 1:12—cv—OO2_74—LPS Document 75-1 Filed 05/08/13.. Page 2 of 36 Page|D #: 946
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`ENZ45ICONT;€héw 3
`
`IN.
`
`UNITED STATES PATEN‘£‘
`
`OFFICE
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`
`
`_Ex:a':'nine':
`Group Ar: unit
`H:Applican£s-
`-5
`.-
`f.Ser1a1 No.
`
`-.Filed
`
`'ii”.o:c
`
`:_-
`
`Ci
`_:
`
`;
`
`Lfohlmiee R. Brown
`.123.
`Dean L. Engelhardi et ai.
`'
`'
`'
`674,352
`
`~
`
`AUG-05.1.98?
`..
`_
`GHCUP12o
`=
`
`_
`
`I
`
`November 21, 1984
`
`g ;gefi%¥:"“*g
`
`'r¢0DiFiED HUCLEZQTEDES, METHODS 01? 1=1;.s1=gaR1_N<;=
`UTILIZING AND COMPQSITIONS_ COHTAINING
`THE SAME
`'
`'
`
`Hon‘. 5Commissione'r -of Patents
`. and Traéemarks-_.__
`Washifigton, D.C. 20231
`
`fiew york; New-Tbrk
`July 14,'_3.9a7:'
`r
`
`Sir:
`
`ms; [37 _
`
`€_L‘_.F.R..,
`
`.§I' 1 '.f11.s'-
`
`Eliis is in resp<§n$é to th_e'f offi.ce'_ Ac:.1:ion dated
`
`Zfqénuary 14,'l9E71in the abuve—iden£ifiad_patent application,
`
`Kzlwhich action was made final on page.4; but-not an page_1fi
`
`,ApplicahtS_havé céncflrrently herewith extended the_time for
`Efresponsa_tG'thatflactidn for three months up to and including
`=:Ju1y_1é,
`i9B7_hy petition and Payment'of the required fee
`
`VT
`
`[37 C.F.Ra ss 1.l36g'l}17(c)];
`
`KindlYf3m8fld the eppl§cgtiqn:gs'fqliows;
`
`3IN_TH:S?ECIF§§ATiOfl_
`
`"Pagé'S5} line 2, after “ihVéntion".'fiélete.”t"
`
`=3.anfi substitute there:for.nw;.E3amplés.2—2D, 24~2S and 32-39!
`7;3lthough axpre35ed'in'the past tafise hereifiaftgr, werefndt
`
`e in factiactuallf caxried out, whys,
`
`these-examples are
`
`? ph9phetic,.hbt actual. examples, ——.
`
`

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`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 3 of 36 PageID #: 947
`Case 1:12—cv—OO274—LPS Document 75-1 _ Filed 05/08/13 Page 3 of. 36 Page|D #: 947
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`‘,..,w...,.
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`K
`4
`i.'_
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`VIN '.13HE_ C;.'AI;_~1§
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`396;;
`
`(twice amgndedj A compound selected from fine
`
`‘ group consisting'df [compounds.comprisihg at.least.one base
`1 moiéty, said gage moiety being] a purine IOIJLQQ pyrifiidigé,
`
`= and [compoundsJvgigqbggbyidggcomprising;é.bésé,mbiéty,Isaié
`' base ;mo':'.e‘ty .beifig a'._;3ur_inIe.jD_r pyr_im_i din.e,'
`£1 sugar moiety,
`6 said_suggr moiety being ribose or'deoxyrihose, and a phosé
`
`:'phoraus—containipg mgiety, said phosphorous-containing moiety
`
`.comQrising_at"least"one_phosphordus'atom bbfifid to at least
`
`f:two oxygen atoms, at least one df said bxygéh atoms being
`
`§.bQund to said sugar-m5iétY Ethélcompdunfl h3Vin91;'fihéreiq séifll
`
`gyzimi§ine};Eur1¢§1or{nug1g9;gg§-h§§§_ddvalafitly attachea
`[tb afi-1east_pne of the base; sugar Ur.phosphorous—c¢ntaihing
` '¢qie:y3 thereto a gchamicalj moiety-{at least onc moiety}
`
`that_is p§pable_o£ [comp1éxing} chelating ians;-fifie ions
`béing capéb1e'of [self-detédting;f§el£;indica£ihg or seif;
`
`-signallingg]'§efiection [wheréih said cdfipfiund is dépablé bf
`'being'iqcprpQrat¢d intd=oli§br End Pblyhuélefltidésl»
`
`397.
`
`(twice amended) Tie compound according td
`
`@laimj396, uhexein the moiety that is capable of [complexing}
`
`chglating-ions comprises two nitrogens and-four carb¢xyl—¢on4
`
`tainipg gxgups, wheréih two of said foun carhoxy1—containing.
`In-groufis are attached.to[éach oi said pitrégéhé.
`
`398.
`
`(amended) mhe compound acéoraing to claim 397,
`
`-whegein the moiety that_is capabie d£'[cdmp1exing] chelating'
`
`'ion§fis“a carboxy—substituted ;,2}diamine.
`.
`
`2
`
`zNz.32¢2
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`

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`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 4 of 36 PageID #: 948
`5/08/13 Page 4 of 36 Page|D #: 948
`i|ed_ O
`__ Case _1:_l_2—c_v—OO_2_74—L_PS Document 75-1
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`....M,,_.‘..,g-.._._......_.‘._..9-.,..;,_;~,.u.‘_...,.__'»\
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`399.
`
`(twice amended) The compound accnrding £5
`
`c1aim;39B1 wherein the'mpiety'that is capable of Iccmplexingl
`. éheiaffing ions has fihe—stxu¢tural.fbrmn1a:
`
`
`
`,"wherein M is pydrogeh-Q: 3 suitable cation find féaqh Broke;
`; iinejgg Lindicates that) ig 3-hydrogen {is absent if the
`“.fioating bona is-at} 9g_the poéition an the ring to which
`'_£he.{iine3~fioating bond is attachéd} pnlg qngmef sg;q xJs;
`?i§§ihgLthe osition where.the figgfiig bdn§.i3_atta§hgdx
`Cyaim 400;-linéuz} déiate.Ucomp1exing” and insert.
`
`37?? chelating-~~.'
`
`Claim 4Q;g-line 2, délete'“compleging” and ifiééft.
`-~~ éfieiafing —-.
`
`Ciaim ébé;-line 2, aelete ”comfilexing“ and infierti
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`—r éhelafihg§—-.
`
`(amended) 5The cofipbufifi adcoiding to ciaim 398.
`404;
`:wh§:ein the~[chemip€1j méiety that is ca a§1é:ef ¢fiéia€ih
`iogg
`
`gg-cévaiefitly-attacfled to-the base, sugar or phosphdréfis—toné
`taifiing moiefiy thxough.a iinkage~groug,‘£he_fcompriaas.a
`
`.[lifikei arm} theiarm'beihg] lihkage grcug not interfering
`
`-substantially with ‘the’ c-1§'a%;'a¢ter;L's£i:: 'a'.b'ilVitg- _of. the moiety
`
`to dhelafia ions.
`
`Claim 4bs.'1ine 2, delete "linker arm"'aad.substitute
`
` -théiefbf —— linkage group ~—.
`
`'3
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`_
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`ENE . 0242;
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`-T.
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`

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`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 5 of 36 PageID #: 949
`Case 1:12—(_:v—0_O274_—LPS D0cume_n_t 75-1 Filed 05/08/13 Page 5 of 36 Page|D #: 949
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`(amended). She compbund;accfirdihg:to a1aim*396t
`§0B._
`3 further comprising'an,ion.capab1€'of_[éélfédatécting,
`selfw
`("indicating or se1£—signa1ing] defectibn;
`the ion being
`[comp1gxed_to] chelated by the moiéty.£hat is Capablé cf
`
`[comp1axing}jchel§tin97iDns.
`
`(amended) An oligoa o:”polynuc1eotide chara¢=
`415,
`‘_terized by at least one [¢hemicai] meiety [comprising at
`* least one moiety] that is capable o£_[complexing}'chelating
`giions that.gre.cap§h1a pf'[self-detecting,fseifisinfiicating at
`_self*signalling} detectibn,
`the [chemica1]_moigty being attaghed 5
`to at-least_one'nuc1eoti&e ofi the'ol§g9é or_p¢iynucleotidea
`416.
`(amendedj
`‘The Q1i§o— or'polynucleotifie according
`:9 claim 415. wh¢;ein_said_[chgmica13_moietgjthat-is-cg9ahle_g£
`"phelatin .ions'com ri5es'tw§?nit:o ens and fbur-carbqx 1:;
`
`' containing-groups, wherein twu of said four carboxxlwcontaining
`
`‘ groups are attached Eo each of said nitrogens [is a_cQmpgund
`
`-selected from a_group consisting of the Compqunds of any-one
`
`of gla.-Lms a_.9a—_4m_]..
`Ina pligqe or po1ynuc1eotide.ac¢o:ding
`417."
`(amended)
`t°T Claim 415:
`$17.11-F=r*a.3‘L:¥l..*.:?.1=?.£:¢h¢mi+=ai3'
`
`
`.m9is=tY..m,__..__,..2th'att-==-is<.='a ab.Lm.g?{.~'=-°.f.5
`. chelating iqns [is] further comprises aimoietg aglaciéd from
`E tfie gropp consisting %f a sugar moiety; g_phosphq:ou$«containing
`Z moiety andfa combination of the two.
`.418.
`(amended) Eng oligoé gr ppiypucleotide according
`tn c1aim.415; wherein the féhémigéilImofiéfyafhat-ig,éqEg§;§hg:_
`:1 chelating ions fufthe:_qomprises_d fiolgwei bfi é firdtein;
`T
`-ciaim 419,
`line 2, delete "=sti.~'anda:ccv'
`:(bo'th. otidur~.
`ranceafi.an&'subs€iEute§the:éfor —- strandefia—~ (both pccurréhdési
`
`4"
`
`'En2-_..o'2-42
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`'
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`

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`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 6 of 36 PageID #: 950
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` , Case 1:12-cv-00274-LPS Document _75__-1. _ Filed 05/08/13 Page 6 of 36 PageID #: 950
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` ' 7VIV' ‘gm .=.._¢.~_» II"-#1:’. _
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`REMARKS
`
`Applicants have_determined that {ha examples set
`
`forth at pages 55-81; except Examples i, 2I,'2g, 2a,_30, 31,
`
`40} are "paper". rather_than "working exampies" [Manual of
`fatant Examining Prdcedure'§ 608{O1(q)) and may, therefore;
`
`"he inqqr;egt1y.¥%presgntea'by use cf the past tanséy By
`
`this Amendmentggatplicantsfcall this_inadfiertent_misatatemén£
`
`to the attention of*the_Examing:, apd.aventua;1y to the public
`Te-sfiouid this applipaticn issue as a patent;
`_Althbugh,
`appli—=
`
`cants fie hot-believe that the Examiner has relied on the
`
`'? tense of fifie examples in he: examination 65 this applicatidn,
`
`ui‘théy-specificaliy'request tHat'the Examine:HredonEidefi'fihis
`Iapfilication-in View of theifi-disclQsure'Qf thqse'pape; examples.
`
`‘A
`
`'See_Roh_m .9 Haas ‘Co;
`
`v-__. gqstal Chemical co".--,_ :722 F.2d 1555,
`
`T 31572 (Fed-.~cix.
`
`-1933;
`
`-gpplicants?havé_amended various ofjthe claimsjof
`
`"this-app1ication~to_pver¢ome the ohjfictions and rejectiona
`
`fiadé by the Examiaet, _As:we-shaliydemonstrate; nbne ofi these
`
`§mahdments;adds*ngw'mapfie; to the-application, and_app1icants
`
`requeat entry'of fihem.
`
`The Objection;an6_Réjeqti6n.Under
`
`Tfie-Examiner has 6bjec£é5'£o;fihe specificati6n~9h
`
`the grounds thgti
`"LT]he specifibafion as prigiha;1yefiled.fiees‘not
`provide_support for the-invention as is new claimed,
`The héqly added structural-formulas to replace
`the fo1:m_u'1as' in claims 2.9.9;-492 and, 4‘-36-40? are‘;
`‘directed tn.a-canfiguration not shown-in the
`=specification.fl
`"Ciaims 399+4i4jand:416" stand xejected'£or thegsame reason;
`
`The_;efe;enpe ya "cqnfigurationfl in the Office
`
`_ Action of Janu3fy'i4; 19$? suggests that Examiner Brown bee
`
`lie§ed=that~epp1icantg gere_attempting=to intrqduce into the
`
`5
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`ENZ.0242
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`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 7 of 36 PageID #: 951
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`._.cIaims a,stefeodhémical specificity. Applicants were'nof.
` 1nstead; applicafiis in the amenément.of Augnst.2o, 1986 were
`ifgsimply complying witfi;fihaix_directive_pf Examine: Love in
`
`
`
`‘E brevieué office Aati§fi_th§tg Vfiydgoggns shouid bé pufi_qn
`.*:the_cyclphexyl structural formulas-in-the claimafig ;Th$s_is
`figavidenced by the ian§uag¢ added to-ciaim 399 by the Augusi-26
`3 Amendinexifi:
`""9-a.'eh.br:_a1Een.line indica‘ées- -that a hydrvgam is
`' absent if the flogting-5QQd_is_ai ffig pfisition qh the ring
`
`tb'which'the-liné ié §€t§c§g§3”
`
`.H§gavar,
`
`to avnid any_con-
`
`fu5ipn,_app1icants.have now amended the claims in response
`to tha;Efiaminer'é bbjection. Es'amended(
`the claims recite
`
`:hg'§yfirogen andlothgr substituents.and each ring position
`
`fiithout sterép~SpeCificifyw
`
` 3Thé fiefiéctiQn§§)5finfigr 35 U.$.U.j§ 112
`
`
`F#i“5.h
`;Ei§st and Second 3arg_
`
`C1aims_396-419 standlréjeéfied‘under'35}Q.5.CL § 1121
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`‘ figs; ang sgcondfparagraphs. mhe Examine:Ps gositicn i5 as
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`; folléysy
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`"[T]he,qLaimed]invantiQfl is not descrihéd in such
`full, c1ear,=concise and exact-terms_as to enable_
`any person skilled in the art to make and'usé the]
`same, and/or for.£ai1ing-to-particularly point out
`and fiistinctly':laim thg subject matfier which '”'
`applicgnt regards as the inventidny mhe rajectibn
`has been fiulljyexplaigzed in _t1ie;l_a_s‘E-." o£'£i:_:_é. actinn
`and all the terms and reasons ar& again adhered
`to.
`-In addition; the terminology 'capabie of
`being incorporated‘ is,a1so functional, and the
`(term ’if‘-renders the claims a1terHative{
`
`I986 hav¢-
`“Applicant's arguménts'filed August 25,
`been_ful1y cdngidered_but they_are:not,dgemed to
`be pérsuasive._ The_claimg in their pxesenx fnxm
`.are ccnsidered to be.an]invitatiOn to one skilledw
`‘in.fiha apt to conduct further Experimentation tp
`find what'groups'such g$"a Linker arm',,'ae1£~
`-detecting‘,,Pself~indicating‘,
`‘a sugar moiety‘,
`.etc. would be ope:able—harain...Tha $tatut§.
`'
`'
`requires the_app1icants to partiqularly point~out
`and disginctly c1aim_their:inventioh and this
`-requirement has not been_mat by the claims in
`their present form,”
`"
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`6
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`ENZ.0242
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`..-».m+.,...,._‘;.,'_V_‘..,_«.g,...-‘.,._::7...w..,,M‘,W,vvdrftr‘?-r‘“.,__.,_......_A,A..__._..__._.3~.:n.»aw:,.,;.m;'4.-'..:",._
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`-«._u.-‘_.._..
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`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 8 of 36 PageID #: 952
`_=C_a_se__1;12—_cv—OO274¢LPS Document _7_5-1 Filed 05/08/13 Page 8 .0f 36 Page|D #2 952
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`.
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`f
`E
`5
`9
`3
`V
`V
`Q
`g
`3
`?
`i
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`'9
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`Each Qf the-terms_ohjgcted to_has been fully and
`
`.'.I‘hu5_', jthe claimed
`._-' d1e.a3rly"de£ine'd in the specification.
`: nuélgotides Q: thg_am§n¢ed c$aimS_are'defined_by specifiic
`
`'suga;s (rihqse or deoxyfiboge)L specifiic bases (purine3br”
`
`'_ pyr:igz_1i%iine;)' and S12-=:'c1i'£i_c_. p1.mspb°r_0us~ c-0:.1tainin9.'g:o.ups:;
`
`the sgecificatibnfl against which the claimg
`3 Furthermore;
`must he gbnstruedi speqificaiiyfdfifines the nuQleotides~of
`this ihventionf E;g;; page $5! lines I-SE
`"By way of-sfimméry, as indicated herginahqverwith
`respect to'the maka~up of the Various special
`nualeotides in accordance with this invention,
`"the special nucleptides can be_descrihed as coma
`prising a phosphoric acid moiety P, a sugar moiety
`S-and a base moiety B, a purine or a pyrimidine,
`which combinatiofl of P-S—B i5 wall knpwn with
`1:e_spe_ct_‘to and defines _-~I1U.¢lee"ti:.3es-_, both:-deo'xy—
`Iibonuqleotides-and rihonucleDt;égS.“
`
`Becauaé fihe amenéed élaifig recite nucleotides,
`
`the
`
`r‘ term "sugar moiety“ which modifies-hficledtidés i; got vague,
`
`the specific sugars claimeé
`T_As set férth in the amen&ed claims,
`:f are deoxyribose.and ribose (see also structural ibrmulas at
`.- spe¢ificétion'pa§eI92; see also p..93, 1ines’i4 and.15; p, 94,
`
`'_ lines 28 and 29). 5Thé term.”pfi§§ph§#ofi5 cantaifiing moiety“-
`
`1 is also well definéfiv it r¢fer$”t¢'thq5é phbsfifidrdfis-cbfifiaihihy _
` '-grpgpa_whigh arfiinarily occur in nucleptides (e{g¢,‘specifi%
`
`
`
`c.a..tior'.i:.n-. 93-: :1=inef10>T-.
`
`In ordér'to clarify the scépé.of.theif.inventiQn{
`
`~ applicants have alga amended the cigims td'Bubétitute the
`téxm “¢helating":fqr the term Ucomfiiexihg;U The specification
`
`teachgg tge use_q£_gompoqnd§ capablegcf ghelating a.vaxiety
`
`T qf.iQna for tha purp0§e'of labeling hudleotides (specification;
`
`L p, 32! zines-6-11). Moreovex, the term ”ohe1ation“ has av
`fuspecifig meaning.
`A cheiate is “I@]omp0und in-fihich the
`:}'samé méle¢u1§'is_afitache§ to g cgntga; atom at two differenfi
`
`T; poix';ts_,_ -férmipg
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`1a'1_:ruc:t~._1_:¢_,-_ at least one -such attacxhment
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`

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`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 9 of 36 PageID #: 953
`_ _C_a_se 1:1_2-_c_v_-_O_O27_4-LPS Document 75-1 Filed 05/08/13. Page 9 of 36 PageID #: 953
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`3
`%
`$9
`E§
`i
`E:
`E_
`@‘
`"£6
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`i being a ccqrdipatign linkage.,.;" H; Bennett, Concise.dhemicgl
`;,and Technical Dictionary-(Zd-ed. 1952); Thus,
`tfie use di
`
`‘E-the-texm-Fchelation” in the claims overcomes the rejectibn
`:_dfE£he claims as-eitfiéfzQQdfiIy_bxbad-ox”indeterminate.
`
`Applicants have also amended_the_claima to_rep1aca
`V: the terms “Seif~dé£ecfiinq,_§elf~indicating ax self-signalling"
`
`" by the term “deteétébla" far the-purpose éf’clarifica£ion,
`
`f The spécificaiion is rgplete with_examplés oi such detectable
`Q ioné.
`To site but one ihsianqég page $2 describés the labeling
`
`:f ofjuridine tfighosphate wiih.a phgygting agent so'as-to signal
`
`Z thé binding of 5 prcbé cbntaihing that nucelotide toja target
`
`5 p¢lynucleotifie sequence-by—chelation {O detectable metal
`
`: ions;
`
`Finally, applicahts have amended.the claims to-
`
`”-_replace the.teIm “linker arm“ with thg term "lihkage-grQup";
`
`In the binlogidallshienées, it is Wei;-recognized that func=r
`
`tion ig £he_criti¢a1 e1emént.necessary ta describe-a cpmpounaw
`The-term fllinkaga group" connotes specific.function:
`a gzoup
`
`connecting a bas¢_or”nucleotidé'to a ché1a£ihg.moiety-while
`not interfering suhstafitially-with th§-charabiéiistic ability
`of fhe chélating;moiety{s ability to chelate'iens.
`.This amendaa
`meht'i§ £n1ly-gupportg$_in the spéqificatibn;
`see? e.g7,_p; 113 :
`zines lOr23g
`The-definition of "linkage grdup" in the amended.
`T_ claims is-in no way an invitatibn té dfié skil1éd“in'€hé art
`- ta conduct further:§xpa;imgnfi;ti§p'to find what-grougs would
`be'qge:ahlefi
`Thefifi has béen, afidjcgptipues ta be; nq reason
`:5
`to bg1iéVe~that any-particular "linkaga group“'with§fi thg
`-B claimed class is inoperdtive, Furthar,
`the use of the fierm
`
`" Ulinkaqe group“ in the Glfiims i$gfuilY G0mmeflEP§3te with the
`
`Z} scope of the'teh¢hin§5-of-fihis application,
`
`The texm_is
`
`3-
`
`ENZ;O242
`
`
`
`
`
`
`
`
`
`=.;_Lr'-=’.:'.:,".':'-:..r:.’"'*...L...'.»L-‘Lfi.'z4:»»_‘«‘~":_'6"_'V"‘f’-1m«_(_«=~__»-5-
`
`

`
`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 10 of 36 PageID #: 954
`
`
`
`,-.=.'..~,..-_..-,w.-‘.;.t_g..__a-“
`
`
`
`
`
`-:IThe_term is algo consigtent with the use af the term'”1inking
`
`I grqup" in the art.
`
`For_él1 of these reasons the amenfied
`
`-'
`
`:a1a;ims are 1'3.3t<5Iita1?l-é.'1indé'::' 35- iu.s'.£':.
`
`"s-i'1'2".;
`
`mm-‘e spiaizifically‘, the many disc'lpsu;es in the
`:E:specificatian with.réspé¢tIto.the wide :ange o£_af6m9 and
`
`-;£unctiona1ities a¢céptab1a.ih a linkage group incluée, for
`
`”'¢3amplg:
`
`@{:]t is generailyiprefexred that thé-chémida1-
`Ilifikage_inC1ud¢ an olefinic_bond_at_th8 ¢'PQSi§
`tion relative ta B”'[p,.l1;.1ines-12-14].
`
`=fl[Among linkage grcups that can be used aze]
`olefin linkage-arms with other‘modi£iabie func-
`;tionalities'such as.thiol,.carboxy1ic.acid, and
`epoxide-functionalities"-[p.'12, lines'lF4J.
`
`VI£.is even more preferred that thé'chémical
`;inkage;gx¢up be derived.from a primary.amina.
`and.have the structurg --CHfi~NH— 1;,“ [pf 11;
`-line5 2§r25].
`
`Einaily;
`
`tha_examp1es of spedifié linkage grdups
`
`xecited in the application cénfirm that fhe claimed ihVen-
`
`tion 1:-no; ;imi§¢d to particular linkage groups.
`
`Ihoae
`
`illustrative linkagp'groupS.inc1udé carbgn, hydrogen,;nitiogen
`
`and-oxygen atoms.
`They a1sp.includé carbqna¢arbon-éifigle
`aga aofible gangs; carbon—nit:bgen.sihglé bonds, bérbdnrhydrb»
`
`_ahén fiingle bonds and}carbon:bxygan_singie‘bondé.
`
`'E,g-,
`
`.
`
`-CH=CH4CH_—NH—.and CH:CEeCH +0-CH'sCHéCH_rNH—
`2
`2_
`2 l
`2
`6H
`
`' (p- 11,
`
`line 2é—3o}.
`
`-Thé term “linkage g:oup"=aS uaeé in the amendgd.
`
`: claims is.also-consisteni wifih1how'fihpSe;ski11ed.;n thejart
`
`§.uée thé terms “linkers” ané ”linka§é_grQups" in reagents_fQ:
`
`9
`
`4.A.A_‘.w.,A.M;_-...-..,7;,5”_L.'M.‘Am-W1-_—'-u-_
`
`E
`1
`if
`4,
`
`"The linkage or group.jdining moiety A,tp base 3
`may include any of the well known honas including
`Carbonécarbon single bonds,,cérbon—carbqn double
`"bonds, cafbqn—nitrbgen-single hands,_br.carbun#
`oxygen single bonds” [p. 11, lines 9~l2}.
`
`.ENz;e242
` _a1sb fhily suppdrted by numeroug éxamp1gfi_in'the appiigation.
`
`

`
`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 11 of 36 PageID #: 955
`Case 1:_12—cv—OO274—L_PS Document 75-.1 . Filed 05/08/13 Page lleof 36 Page|D #: 955
`
`
`
`use ififbiqlbgical assays. Thesq-terms,are'recognized by the
`: art, éé they'a:é7¢laime§-ifl-this;application; ta he Qf'no
`
`"consequence except with zespedt:td their poesih$e'éé1eterious
`
`effect on the'hiologicai fufictibn cf the adtive compqhghts
`theY_link in the reagent+ Accozainglyi cla£ms.to reagents
`
`for‘use ifi_hib1bgi¢a1 assays are routinely granted wifihqut
`
`limifatibfi'fid a bartibular Markush grbup_of’1inkers.
`
`Eqr example; United_States patent 3;B52,157-(copy
`
`-gttacheg)_refers to;enzymé~h¢hnd~iigands and their age in
`sccmpetieian assays ta detectj1igandeTat-low concentrations
`
`'
`
`in-analytes Ecol. 2; lineslseysa].
`
`"As-xeciégd in the I15?
`
`3 patent; the ligahd may Be bduhd to the enzyme with.a “iihking
`
`grdup" [gql..3.
`
`lines 4-9].
`
`‘However; the afi2yme»bound-ligana
`
`3 must still=bg_capab1q:qf_binding in a competitive fashioh to
`
`R
`
`spegiiagc _:_a_¢_;p1§m;;_sites_ -;:p_r;:t:1g;_-ligand" i_co1'. j3,_ lines 9_-u;
`and the enzyme-must-remain active.[cdl; 3, Lines 27~3;];.
`Q Tens;
`like-applicants!'c1aimed:comp6unds,
`the funcfioaal
`4; _a_t_f;ributes= off? the -"157 __’pa_te_nt'g ¢n_zyme~1so'una+1i;,gands are
`Mfiéxfifidfihf.
`The *1S75patentis Examples of 5linkégéCgroupsU
`-_is alsdlmuch like apglicgpts‘ gtfiuctuxal desgriptions citefi
`{ abbvé. E3g.¢
`'”The iIfikifl9 group (axcluding'théjatoms'derived
`"from the ligahfi and en2ymé)} when ether than a
`'direct.bond is involved, will be of from.about
`one to §0'atoms +,parbon..hydrogen¢“nitrogen”
`oxygen; phesphorousp and sulfur — more usually
`four to zoratpms; ..
`.
`... .
`..
`..
`... H
`
`21.513.-__ ‘the’
`'“‘9c..>.».I.1.'1-
`.e
`Qfieffié,eightlagrbbn-atcmsaan
`h.etefinatom1s'- .anc_1 'fre.:'f»r,:11_:ia:_1t31f5*-: '0
`Parbcn at Te and f$Em%9né.$
`_
`..
`HhiéhlfirE:okygen;“$fil£dr an‘
`Iéuveiikf
`us1e1a.:3-;l1r'===a1:3r«_1f:-r.IT1-wnir.-i---n trdgmx}-. Th?‘ m€>s'li..
`hgfigrgfiuhgiiénglitiésgpxagefit.ih.the linking graup
`‘are ' en~oxé¢m:b'¢11¥-l qr-"-fl1i.r>..c:-a'1.:b,9.n1z;!.: .-easneizlm imi-136:-I
`
`_e
`”:'rs_i-_'d'ati;e:}‘
`ai<;a*z_oe-,'. rim may ._[co':L". 13?‘,
`
`...~z'a};.-rt
`'
`'
`
`
`
`
`
`'
`
`in
`
`'
`
`ENz,o242
`
`

`
`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 12 of 36 PageID #: 956
`C_a_se_l:l2—_cv—OO274—LPS Document 75-1 Filed 05/08/13 Page 12 of 36 Page|D #: 956
`
`j consistent wi-thl this aescrip_tion,- 't_n_;.= claims of. we -:15"?
`
`"patent are also not limited to particular‘li§king_gr9gps»
`
`fin fact, Claim i recites'cn1y'that "~x* is a-bond cr'a linkh
`
`*jifi§ grbup" {Claim 1,.cdi, 73,
`
`iihe.3S].
`
`The, =1se7 paieet,
`
`t1ms,-- aemc':_z1s_f;:a_{:z:es;:t1':_at'e for some
`
`-
`
`'pd1inds -agefu-1 in "bi-:sl£:>,'gica'l _assa'y*s_.
`
`€h_e
`
`£{1nc_tio_n of the‘ }1:nke-ea
`
`,_¢omponents ea ligand and enzyme u-.are important,-hotjthe
`
`: linking_group that connects them, except to the exfient ihat
`
`9 the linking.group physically connects two moieties without
`
`3 ihterfEring.with their respective £unctions.* _Fur the same
`':'reeé6fis;.ifi.a§plicéfitS!Zdiéimed compounds-fha5fuhcfiQn of"
`i thefcdmponentsfi;;rbase'c:'nucleotiE9 éhd qheletifig mdiety:—~
`fl'afejimportant, not the linking.grcup that connects-them.
`
`I Ihusg_appJicants' claims should net he.1imited to particular
`
`_linkage groups.
`
`}$n_other'Uz'iité:i states paitexitfi eiiiusjtrating the art-
`
`recognized and accepted fabt'fhat ih-reégéfitg.fqr use in.
`
`'biqlQgi¢al assay$_fhé;fhnction_of the cdmpanangs, aot.tha
`
`iinking group_conneqting them, is paiafidfint ié United states
`'_pg;ent 4,151,515 (copy attédhed). The-I515 patent refers to
`
`a-biqlQgigaIjasegy.q§ing a ligandLanalog~£Iuorescer t0.compete
`
`-with the ‘ligand in an éntibbdy binding? asézij
`
`[¢.o.1_, 2',
`
`linea-
`
`j14._a2::_,. A_s"str1'-1ctuxa3.’ly :ec:1t_e_c1_;";n the E515 'p'a‘t;—mt,
`
`the
`
`if:}ga_n'a anaiog is c'onn_ec:tjec1 to_ _the fluoréscér "w:Lthf'a linking
`
`- 9:§t9'up_ =?i'=e
`
`
`
`‘A'di§ision.of thejapplication that iééuéd Hs_the:?l57
`5 *
`‘patent has‘also‘i§sued, That-patent,_United States patent.
`No-.
`-4,2,03,BD_2_ (copy at_t_a,che;i),j,
`e1_sp'r_:_J.2_a.i_m$ ‘‘'—}{—_‘’f”.' as _aj bQ_I1_d_
`orfa “linking group,@
`
`'1_1
`
`E1»1z..o24_2 V
`
`
`
`>4.1'».-.-1.~
`.-3
`4
`
`

`
`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 13 of 36 PageID #: 957
`Case Wl;l_2-C_V-_O_O27_4_-L__PS D0cument_75-1 Filed 05/08/13 Page 13 Of 36 Page|D #2 957
`
`
`
`
`
`,m.....::,_..,....m.-,M,.,..:‘4.......:£...=..__.:'__._.;'_{#5.‘
`
`hnorma11y_o£ from 2-to 8 atoms.cthez than hydro»
`ganp more.usua11y of from 2 t9 4 atoms 9th¢r'than
`Ihyarbgén,ané being free of atomsIother.than'
`'
`carbpn,'hydxogen; oxygen. sulfur anfi nitrogen,
`and preferably having a non—oxocarbony-group as
`part of the linking functidnality"'[cQ1, 6,
`lifieS'&9eS6}.
`
`This-description df;fiSefu1'“linking'grdfips“.is
`Furthere
`
`j quita'analogous td £hat;in.the pending applicatifin.
`
`T; more:
`
`the czaims as thé =s1s patent, Iike the claims of'this
`
`i ‘application,.are diréctéaIto.the funcfiional requirements pf
`the compohehte cf the bioldgical taagent :~ ligand.analog
`
`' and filuurescer «h nqtfia Markush.g:oup of linkérsf
`
`“ agd_anélogs£1uare£getg_wherein said ligand
`
`_“
`[09 1
`-§p¢ciE§¢a1I§.recogni%ah1é by 5" .qnti-
`ligflhdriflfld fihe liga9fi=fifia1¢gianfi.flu6re ‘er aré
`l;hkéflTsfi' 1¢1ept1y Clasg bj'a linking grdup; 59
`fih ,
`tam s1mqLtaneaus~hin&ing“o£.autiliganfi and
`antibnfiy iv flug§esc§;~
`stéxigélly inhibitefl .;w"
`{g;a;m 1..¢a1, ma, lines Zaaazj,
`
`still another United‘Statés'fiatent_i11ugtrating
`
`;; thqt,in:réagén§$ useful in'hio1bgical assays the linking
`:3 grqup nged_not_be_limited,to_gpacific_compounds is'Ufiitgd
`ThéjP16S pafient
`f states p§pent.4;376;165'(copy'attachéd),
`": claims énzyméélabelled compdfifida having an organic"prosthetic
`
`T group cbnnected to'a hapten by a linking group [glgim liq
`1 Again, the Lifixing group is brdad1y'Iecitad in the specifi-
`
`_ggtipn_{g,g;gj¢pl,‘11, 1in¢ E5 to col, ;é,.1in§ 23; Again;
`
`.thg plaimg;_1ik¢gapp1icants?_c1aims: requixe-anly that the-
`comppnenta connectéfi_by the iihking-q:9up.r¢tain their bi0~
`
`logical £unction'{C1aim 1; col; 22;'lineS'13¥17};
`
`"{Sjai&'hapten;and.$ai§ prpéthetic'group are
`coupled thrcugh.said linking grpup-at.a:site-on
`the hapten-away from its specific binding site-
`and atja site ¢n the prdsthetic»group.away from
`itsagcfiive-binding site for the apqénzyme-"
`thus, this patent also fiemonst:ates'tyq§ "linkage gxoup$" in
`Tfiayy
`Zbioiogibai compounda need not be~claimed stxucturally;
`
`:
`
`yfmay, and should be, claimed by-function.
`
`:2
`
`M
`
`ENZ.G242'
`
`

`
`
`
`
`
`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 14 of 36 PageID #: 958
`Case 1:12—cv—OO_274—|__PS Document 75-1 Filed 05/08/13 Page 14 0f_36 Page|D #: 958
`
`
`
`
`X-_.-,f_-,:,__,,;
`
`._#,fi,.;_:;.-,;,,,,,......_.{..-_,,._,_._.,,,;.:.:..e..+,._..,.:.;;;:,,:.
`
`._.-4..-.—-'y_,:.::.'.._..;,_;,;:;;:'._.¢_r
`
`._.
`
`_____
`
`_'-j_;'.;-_.-c..
`
`,.._,,..__.:r._;.r
`
`,-,
`
`Fpxvalg-pfifithe above reasons --.the disclosure Q£_
`
`the specificaticn¢ the specific cdmpounds_ili§§trated in the
`',SfiECifififition-andfffie art‘s rec¢gpitien~thEt} f0f‘reaqénts
`':'us§£ui in $ig19gieaiLa§says, functibn, not structure ofi the"
`:51;pkage'g;bfip;
`ie'gaxampfini ~~ fihe.c1aims_emplaying the
`gflte-mgr. 11-n1;a_ge_ gisdup. should he Ia}.-léwed;
`-
`hppiicafits have also amended claim 399 to eliminate
`fl£theIwdrd-“if? ifi response to the—Examiner!5'objection that
`
`':fihé.¢1aim wag eltarnative.
`
`"
`}'Ihe:Re"eotion=s. gage:-35 Uf§iCJ § 19gHa
`
`
`Claim§~396e&OS stand rejected under 35=U.S.C; §I1G2§a)
`, or (h) as being_afiticipated~bg.RobihsIet.a1., Cariicc at al;
`
`’e(‘893'and T566), Gohlke at al-; Buckmann, Japanese_patents
`
`for_
`e {'2a3:and3?999} and the British patentg all of retard,
`::_th¢f:easons sfiatefi in_fha-iast Office Action 4-thaf §hé'ihStanf
`L. sfibjegt fiaffier is claimed-so broadly that it.reads an the
`Qatent disclosures; Claims 396»4u5?and 463—419'stande;ejected
`-as-abvious‘in'view.of those.documents.
`
`Ap§EiCants—havB amended.the'c1aims to ze£er1sgeci§;—
`
`calljito purinesT pyrimidines.afid"nuc1ebtides that are'chax~
`
`acteriéed'b§.mdiefiéé fhdt'hfe‘¢fipab1e'o£.chelatiag ions.
`.As we shail demonstfafié,
`fihbse améh&e&'c1aims.cl¢a¥ly'diS~
`tihéuiéh ever the cited docufients,. Applicants; accordingly,
` §fe§fiést that the Examiner reconsider the refieQticnB=of the
`
`fi amfinded claims.
`R9bifis at 31,, Unified Stateslpatent 47Q33{4QC,
`E d9es_nqt di§gluse:purines,"pyrimidines or nucleotides linked
`L'to chelatoxg; Rathexy Robins xeienafitojE-amfnpcarbamoyl and
`
`-—carbonyl-analogs‘of adenpsine 3‘g5'5cyglid_phpsphate. That
`
`ejist_aéenine,nuc}eatides qhepe fiheeéu posifiiun o£:edenine is.
`}”substitu£ed;wifih 7fiBC0RHR or:NHcogR3 respectivexyfi
`.Ro§ins
`
`13
`
`_.
`
`_ENZ-U34?
`
`

`
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`
`
`
`
`
`
`
`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 15 of 36 PageID #: 959
`Case 1:12-CV-00274-LPS Document 75-1 Filed 05/08/13 Page 15 Df 36 Page|D #2 959
`
`
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`
`
`:d6eg'nét.sgggé3t that such subsiitfienis are cépablé of che-
`lating iens.
`.Norehas.the,Examinei ppintéd td ah? éviaencé
`
`that {hey have thaf property} Thué, Rpbins daes nétlantie
`f cipété or suggesf apfilicants’ amenfied claims,
`
`Cazricb e+;'.'a1.. united‘ States patents; 4,2-1_3,;é393 -and
`
`_I4,255;S66.do=hQt iesdribe Gr suggest ddmpdufidé withih tha=
`
`’;s¢QpeIof applicants‘ amended_claimh.
`
`c§rricd're£er$ to flavin
`
`:adenine dinucleetide_(FAfiJ:dérivativ¢s fdf usexin detecting
`
`- ligand binding reactiong in hom¢geneaua,type immunoassays-
`§'Carricp §oes.n§t suggéat that'thé_substituants cn'it$ FAD
`
`deriVativé§'afé Capable sf che1atinq_idn5.
`
`‘Hence,
`
`the'Caxrico
`
`e;dQgumenta'gre;alsQ'unIelatedUto_thejcomppunds Gf_appligap:sf
`
`L_amen&éd claims and do.not rendér themfufipaténtable.
`
`IG¢hlK¢.B3 filmgfinififid $i$t8S'D3t6Ht'4a373r%53« 3130
`
`Zsdcesfinot;renéer.appli¢ants’ émen&ed_¢l§ima unfiafientables
`
`In
`
`fsohike,
`
`:iBQnuciease»indqééd'hyérolySiS_éf_thé[phfiSphate
`
`_ ester of §urine'or pyrimidine ana1ogs.is said to-yield species
`‘ capafiie bf fluoremetric or Specfroppetdmetric detection.
`
`eefigfilke fines not sugggst'that the_substituent5 on_his purine
`e'§;3fiYrimidine analqgg are capable of cheiafiifig ions; Aacor§~
`
`-'ingly} Gohlke flee; net agtfltépafig pr repfigr-appli¢ants* cfaims
`
`e_ébvious.
`
`Buckmann United States'patent 4,443{S94 re£gr5't9
`i_ aéenifie-based coenzymes:(AHPq-ADP‘ ATP, NAD and NADP)'for
`
`§fi§¢dhméht3tb macromolecular carriers; sfich as fiextran.
`
`efidkmgnn does not suggest fihai £§e;Sufi§fiitfi§ntSgfihét:éharac~
`§;..;:s.ga_. his cpenmes are carpable-of _c}'1_é1éL:t:‘L:1_g"_ipiiS,::
`ae;j1¢j_¢,.
`§uckman§,dbeg not.anticipate or rendgr dbviofis applidantsf
`diaims.
`
`14
`
`-ENZ.G242
`
`.5|fVI
`
`3 E
`
`
`
`
`
`....-..:,.--'''-
`
`

`
`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 16 of 36 PageID #: 960
`C359 .1.§..12.'CV-00274-LPS Document 75.-1 Filed 05/08/13 Page 16 .of 36. Page|D #2 960
`
`
`
`
`Jap_ane.s:e. patent _3_133~2_a3,. as d'e'is'c_'r_ibed'Mii1; th__é_
`
`_En=gI;_ish'1a_ng_u;aga_ Ie11;:straC._t'.p_J:o_\ri<_ied, refers tb'a1': adenine
`
`nuclécfidé Bfi'whibh-the-6—pbsifion is substituted with
`
`NHeCO—NH—R~NH2, wherein R is reférred-to as an "optienaliy
`substituted divalent hydrOcarbon.group";
`It-is Said that
`Fh3$¢.¢°mPP?¢d5 3¥é7u5¢f3l inzaffinitxichr°matographY'find as
`
`rea¢tion pafiia for enzyme rgaqtions,
`
`The patenf_neVer sug:
`
`gests that such su1asti_1:u_e:_z_'1t, is c:_a'pa_b‘1e oi" cbelaizing: ions.
` E Et'thus does not'anticipate or suggastjapplicants‘ amendgd
` dlaims.
`TE
`
`Jénanasetpatént Vfill-9§9r.aS_dé$¢ri5efi.ifi-fihe
`-English language" abstract- p_r’o_vid§'3d',
` re§z=.:1fg tic adenige nué1'eo-
`E Eides whiéh-are substituted at the 2:,
`5— or B- pogition of
`
`the purine rigg by-a_mono~ or di&iQdi@ated_phen§thyiamino
`a-mciety. These.&exivatived are-aaid Eo=be useful in'radio+
`
`_;fi@munoasséy$ when the ibdine_is radiéiahéled. The-patent
`'i:aoes;not euggest'that such substiifiéhéé are capablé of eheza-
`
`. ting'ipnsr.-Again;
`
`the-patent does h6fi7réhfiéi applicantsi
`
`'jaménded claim unpaténtabla.
`
`Imahori.et al;, United Kingdom'patent application
`7;ss:2 035 029A reieré te‘an a&énoSine.triphospHate derivative
`;1~:5~(carbo>_cye:t1:y1).Atc1=,_ said to" "be" 'u§e£u1' ‘as. a 1i;gand':for
`§;aff;ni£y chroma£ography_of_gnzymes..'mhéj6ari#ativa is said
`L_tp have a highex activity as a substraté than.bompbunds known
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`"in the prior art? Again,
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`there is_no teaching that tne_par~
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`boxyethyl anfistitfité is ddpablé of chelating_ibns,
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`'For_a11 of}these“reasons, applicants‘ amghdgd claims
`grg not gniicipated dx'renderedgofivipus by any of the.éocuments
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`cite¢TbY*thsTE3amine#s
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`Case 1:12-cv-00274-LPS Document 75-1 Filed 05/08/13 Page 17 of 36 PageID #: 961
`Case 1:12—cv—OO274—LPS Document 75-1 Filed 05/08/13 Page 17 of 36 Page|D #: 961
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`Claims 3e6—4o5 and éasrélsistatafrejected ag age-
`;_patentah1epas obvious_fb:'the same reéaohé aS,héfere:
`"The_:efeIénpeS disc1os¢ compounds_so :lusely___
`relatefl withirespect to'utility and structure to
`the-instant claimed compounds that'the Latter are
`Obvious and unfiatentable thereovar.
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`As 'Ex'ark':_i:iefiI 'B'r¢»;-m ml khoWs,. an ultimate coz'1'clu_s:E.on
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`of 'obVioi1sneSs- must be based. on fa'¢t's air‘.-:écora,_ not on:
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`_un$u§Qorte& aliegatidhS“that-d yartitular strfi¢tfixa1_mddi£i¢
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`gggiggfiié ébfiipug, N0 theo;y gf chemistry for_obvi9usnes§
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`has been relied upon by.the Examiner, nbr.has_she pointed to
`1 any evidentiary suppdrtffor fihe existence and bbvipusnggs qf
`' that-theory as'required'by law.
`Ifi re Grose et'a1;, 291 U329
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`-57'{CG?Afil979);
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`'Thg:single_mpst Significant fiheme taught{by each
`1 of~the documents cifififi; paxticularly with.:&sp§:t=to-the
`: selection of éesired anQ.p;e£erre§ 1ape1ing 5y§§ems;.is the
`- pzqgxess cf the art away from radiolahelingg
`See, egg§¢
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`lines 62568. This emphasis is remarkable
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`"in:view=¢f=the $ens;t$vity=;adioiabelfifig.gffierde in immuno-
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`' assays; Yet;-the-whole path of.researah ig the-cited referv
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`H encas.and in the Eield as-a.who1é{ gas-been fig f1nd3nan~isotopic
`'ihbeiihg sysfems Because it was‘not possible tp ofiercome the
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`'§éhééivéfi §iobiefis.assbciétad with i3Qtopic'labe1ing,
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`App1:cants claimed invéfi£ioh,.at leaéfi inzfhat
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`_embbdiment where a radioactive.iOn is-employed; is.the‘rés@1t
`e_of havihgtgurauefi-a pdth.bf researéh diametrically dppbéite
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`to thié teaching,
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`"Rather than seéking.waya to labellpgqhes
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`-wniicn -a3_ic'id isbtbpic -.1ahe113;ng, appiicants have sc'>ugh_t_ and
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`found a'Way'tO aChiefié'and'uSe the advantages-ofiisdtopic
`;_'lahéling'whileIseparating these a6vafitages,_figgrative}y and
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`ENz.o242
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`Case 1:12-cv-00274-LPS