IN TRE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant
`
`'J:2:·1.J.st.ees c:,:f c:c:-J_-uxnk:,ia TJt!i·ve:r~s:i ty ir1 t:l)e Cit:y
`1,:~11e
`of New· York
`
`Inventors
`
`Jingyue ,Ju et. al.
`
`16/150,185
`
`Examiner: ,Jezia Riley
`
`J?iled
`
`Oct c)be :c 2 ; 2 0 l 8
`
`Art. Unit:: 1637
`
`9501
`
`r'lor
`
`:tvL.i\SSIVE PARALLEL METHOD FOR DECODING DNA A.ND RNA
`
`30 Rockefeller Plaza
`2o t.h Floor
`New York, New York 10112
`May 13, 2019
`
`EY EFS
`Commissioner for Pa.tents
`P.O. Box 1450
`A1exandrL:i., V!:1. 22313-1450
`
`SUP.PLEMEN'I'AL COMMUNICATION SUPPLEMENTING COMMt,"NICATION IN RESPONSE TO
`FEB.RUA'.RY 1.5, 2019 FIRS'l' AC'1'IO.t-1' I:NTERVIEW PILOT PROGRl'~ PRE-INTERVIEW
`COMM"'uNICATION FILED FEBRUARY 26y 2019
`
`This Supplemental
`
`c~ommunica.ti.c)rl
`
`j_s
`
`subm:i.tt.ed
`
`t:o
`
`,:iupplement
`
`the
`
`Ccmwaunicat: ion In Res;ponse To February 15, 20l9 First Action Interview
`
`Pilot Program Pre--Intervi.ew Communication filed February 26, 201.9 in
`
`con.!16<..::t.ion vvitl1 t:he abo;;re-·ider1tif.'ied applica;t.ior1.
`
`Page 1
`
`Illumina Ex. 1136
`IPR Petition - USP 10,435,742
`
`

`

`The Trustees c:,f Columbia Uni ve:t.·sity in the City of New ·'tork
`Applicant
`Serial No.
`16/150,185
`October 2, 2018
`Filed
`Ps:tge 2 of 1.0 oi: Supplemental Communication Supplementing Commun.i.cat . .i.on
`in Response to February 15, 2019
`Program Pre-Interview
`Pilot
`February 26, 2019
`
`Ct.")11;;rnur1ica ti 011.
`
`Filed
`
`I. STATUS OF CLAIMS
`
`.REMAlUi'.S
`
`The claims pending in this application are previously pending claims 1-
`
`2.
`
`1 I . TNTERVIEW St.JMMARY
`
`On May
`
`2019 the undersigned pa.rt ic:i.pat.ed
`
`T:nt:erv-iew
`
`\•,ith
`
`:Primary Exair:.in{,:r Jezia Riley in cor.,.,,."1.ectiQn with related U.S.
`
`the undersigned, a.1;:;o participated,
`
`Applicant acknowledg;es with appreciation the courtesy that: Examiner Riley
`
`extended during t.he May 1., 2019 interview.
`
`During the May l, 2019 interview, the Examiner requested that applicant
`
`f:Ue.
`
`a Supplernental Commun.ication
`
`:1.n Response
`
`to the First Action
`
`Commun i c <3-t .i. C) !l~! ma:i.led
`
`in
`
`con11.ect i.on
`
`of
`
`related
`
`lLS.
`
`Applications Nos .
`
`.16/149,098; 16/149,114; and 16/150,185 to add:1:.~ess in
`
`12,
`
`201_9
`
`c;omrru1n.i,:.::at ior1
`
`:in
`
`the March 12,
`:First Action
`Commun:Lcation issued in 1:J.S. Ap:plication No. 1.6/150,191, even though
`
`t:c->
`
`2019
`
`Act:ion Communications. The issues not included in these F1.:cst
`
`,"~ct ion
`
`Communications inc:Jude :issues relating to 35 U.5.C. §112 (a) and 35 TJ.S.C.
`
`§1:12 {b) which were raised in U.S. AppLi.cat::i.on No. 16/150, 1.9l. Subject to
`
`addressing in eac,n of these three applications, each of these issues in
`
`No" 16/150, 1.91 .
`
`.Ex,s;n:,iner Riley indi,:oated the claims pendin9 in
`
`t:hD::le
`
`applications would be a11owab1e.
`
`Page 2
`
`

`

`The Tr-:..ist.ees 01: Columbia University in the City of New York
`Applicant
`Serial No.: 16/150,185
`Filed
`October 2, 2018
`Page _., of 10 of Supplemental Communication Supplemer:tin•:J Communication
`:in Response t:o February 15, 2019 First Action Interview
`Pilot
`Pre-Inte::eview Communication Filed
`J?rogx:arn
`February 26, 2019
`
`III. GBVIOTJSNESS--TYPE DOUBLE PATENTING
`
`In resp,::;nse to t.he obviousness-type double patent.ing rejection of pendin9
`
`claims l-2 over claim l of TJ_ S. Pa.tent: No. 9, 71.9, 139 set forth in the
`
`Feb~r-l1a.r~:l-
`
`J..5 r
`
`2 Ol 9 Fi2~st Actior1 Ir1ter,rieiv I;ilot Pro£:r:c-21:1'n Pre-Ir1tex~v iew~
`
`Cornmunication,. applicant., without: conceding
`
`the correctness of
`
`the
`
`Examiner's rationale for this rejection, tiled a Te:rm:Lnal Dirn::1aimer
`
`with respect co U.S. Patent No. 9,719,139, the reference patent cited in
`
`2019,
`
`Accordingly, applicant maintains this rejection shou1d be w:Lthdrawn.
`
`IV. R.EcJECTION FOR INDEFINITENESS
`
`Although claims
`
`l-·2
`
`\"/ere not
`
`re:i ect:ed under 35 U.S. C. §112 (b) as
`
`indef:i_n::. te ,;,.pplicant responds as i t such a rej ecticn had been and the
`
`same issues had Deen
`
`:rai;;ied as were raised in U.S. Application No.
`
`16/15-0,191. P,pplicant's response fcllov,s:
`
`1~ .. Tl:u~ tern1 ,.,..,srnallH
`
`The Examiner indicated that t.he terir:_ '-'sma.11"
`
`i:n the claims is a relative
`
`defined by the claim; t.hat the specif:i.cat:i.on does not provide a standard
`
`for ascertaining U1€
`
`reqt:dsit:e degree and one c,f ordinary E:kil1 in the
`
`art woitld not be reasor1ab:J.y apprised of the scope of the invention. The
`
`Examiner fu:rther stated that the specification does not dei: in;:, "small"
`
`and provides only
`] -
`ax~t J_ sa.:n ¥-l011. _ct not: know which other groups meet t.he l:Lmi;:.,;1.tion "sma11 '' .
`'
`
`two exarr:ples, MOM ether and allyl, and a skilled
`
`Applicant: notes that a relative term
`
`:Ls not automat.icaJ.1y :indefinite
`
`[MPEP 2175.0S(b)J. More
`
`importantly, applicant maintains
`
`that
`
`the
`
`specification of t:he subject: appJ_ icat:ion at: page 4, lines 10-32; page 5,
`
`lines l--32; paqe 6, lines 1.-27; ctnd pa9e 13, lines 3--ll, taken t:oget.he:t·
`
`Page 3
`
`

`

`Trie T:r:tistees Cif Col 1.1mbia tlr_!_i 1rersi ty"' in tl:1e c:it.y.., c..1£ Netv '\tc)rk
`Appliccmt
`Serial }Jo ..
`16,/150 ,f ·_t85
`(tctober 2".' 201.8
`Filed
`Pa.ge 4 of 10 of Supplemental Commurncation Strpp:l.ementing Communication
`in Response to February lS, 2019 .First .Action Inte:cvie,,v
`Fre- Interview Ce:mmunication
`?i.:1-ot
`Pro,;;·,'vr.
`Fi Jed
`February 26, 2019
`
`with FIG. 1 referred to at page 4, line 31 of the applicat~an, set forth
`
`a z;tandard for assessing whet:he::c a 3' -0 capping group is "small" based
`
`on it.::, ability to fit into the active site of a polymera::;e, .A::f of October
`
`6, 2000,
`
`the person of ordinary skill in the art ( ''POS1l.") reeding the
`
`specification would have u.i.,derstood th.aL "smaLl" referred t:o the ability
`
`to fit into the active site of the poly1nerase defined by reference 1:o
`
`the three-dimensional structure ,::hewn in FIG.
`
`..:.. . The POS.i~t would have
`
`furtb::r unden:itood that FIG.
`
`1 corresponds to FIG.
`
`6 of previous,ly
`
`published Pelletier ei· a1. (Sci eric:e, Vol. 264, June 2,:1, 1994, 18 91···1903)
`
`cited at. pa-:.ie 4, 1.ine 30 of the appl.ication. The POSA wc)uld a1::;o have
`
`understood that Pelletier et al. disclosed, on pa.,ge l903, the preci.se
`
`coordinates of t:he struct.ure of the polyme.rase in "Rei:erences and Notes"
`
`lOl and, in T~~b1e 3 on page 1897 ..
`
`the distm1.ces between the sugar cl: 1:.he
`
`nucleotide analogue and t.he key <:tmino acid::; in the active site or: the
`
`polymerase. See also paragraphs 11 ·· 13 of the acGompanying Declaration of
`
`cJingyue ,Ju, Ph.D. signed May 2, 2017 and submitted in connection with
`
`U.S. App1:icaticn No. 15/380,311., now U.S. Pat.ent No. 9,719,139. A copy
`
`of this Declaxat:ion is attached hereto as Exhibit. .1, including copies of
`
`Rxhibi.ts A-E referred to t.herei:n clnd at:ta.ched her.et'-', Exhibit B is a
`
`copy of Pe11et:i.e.r et: al,
`
`With t.:he benefit of applicant's specification, a POSA in October 2000
`could have readily deterrni.ned whether any given E when present as OR {a
`3' -0 capping g:t:oup) was small by
`t:he published
`
`thi:3 ~=ta,,F·,:-~rd 1.rning
`
`coordinates and avai:L:1b1e 2:oftware such as Chem3D Pro. More specifically,
`
`using tJ·d.s app:coach the POSA wQu:Ld have know:n that the space available
`
`around the 3' pos:1t1on cf a deoxyribose in the active site of
`
`t:be
`
`polymera.se was approximately 3. 7A in diameter. By t:his standard, R
`
`,;,.rhen
`
`present as OR would need to be less than 3. 7A in diameter, Cons:Lst:e:ntly,
`
`t.he POSh would have known that. the two examples in the application, MOM
`
`and Allyl with diame1:se.:t:s of 2,J.A and 3.0A, respectively, would fit in
`
`[See also
`
`paragraphs I4~.1t:; of the Declaration of ,:Tingyae Ju, Ph.D. and the .l1,nal'.;/B:i.S
`
`discussed therein and attached to the Declaration as Exhibit C.J
`
`Page 4
`
`

`

`Applicant
`Serial No.
`Filed
`Page 5 of
`
`The Tx·uste~e_s ()f C~c-1urnbia University ir1 tl1e City" of I\Je';;~
`16/150,185.
`Oct~ober 2, 2018
`1-0 of Supplemental Communication Supp1eme-nt.ing Commun.icat.io:n
`in Response to February 15, 2019 F'irst Act: ion Interview
`Pre- Interview Comrm.u,icat:ion Filed
`Pilot
`Prog:t·i-:un
`February 26, 2019
`
`·~tor}:
`
`Using this· st:.andard the POSA also would have knowr~ which other 3' --0
`
`"(cid:157) pr·i,19 groups meet the definition "small 1
`
`'
`
`a.nc have the c;t:her features
`
`recitt:~d
`
`i11 tr1e c:la iras and t<ef:Juldf
`
`for example f ha-ve :read.ilz~ det.erminr:;cl
`
`that groups such as Methylth:i.omethyl and Azidomethyl were "small" and
`
`wou.ld i::Lt: in the active site while a group such as a 2-T<J.itx·obenzyl group
`
`which has a diameter of SA was not "srna.11··, and would not. fit into the
`
`a.ct:i·ve ::;i te of the polymerase, [See also pa:rag:t:aph 17 of t:be Decla:ca. tion
`
`of 0-ingyv-e ,.Tu, Ph.D. and t.he ~1nalysis attached thereto as E;,d1ibit C.J
`
`l•.s Dr. ,Tu opi:nes,
`
`t:he POSA reading the subject application and relying
`
`on information publicly known as of October 2000 would have known th;c,t
`
`tb.t! st.a.riciarcl fo:r assessi:r1g 1---1l1et.her an1.r specific.; 3-: ~O ca.ppir1•9 g1-c;-:..1f)
`
`i:r1 a
`
`nucleotide s:u1alogue was "small" was whether it has a diameter less than
`
`3. 7A so that it would fit into the active s:i.te cf t:he :i:x::iJ.yTae:ca.se.
`
`[See
`
`also paragrar,:,b 18 of the Decla,rati.on of Jingyue Ju, Ph.D.]
`
`Therefc..ore, the meaning of "small" would not have been indefinite t:.o the
`
`POSA. To the contrary, 1.ts rnea.nir:g· would have been reasonably certain to
`
`i:.he POSA to the extent: required by 3S U, S. C, §J.12.
`
`B, The term "R"
`
`The Examiner indicated t:.hat the dE,Lin:i.tion of: R 1.n the claims is unclear,
`The Examine.r.
`
`a.cknov1ledged
`
`that
`
`the c,laims recite
`
`some £unct.io.na1
`
`characteristics of R but. a,;;sert.ed that: the,:ie funct iona.1 }.imitations do
`
`not set i:c:-rth well-defined boundaries of the in-vention because t.bey cm1.y
`
`state a problem solved DT a. 1:esult achieved,
`
`As an initial matb;;r: applicant: points out that in the claims;
`
`R is
`
`tu.rt.her defined as a small, chemically cleavable, chemica.1 group capping·
`
`t.he
`
`' j ,
`
`_,
`
`oxygen of the su_;;ar of: a nucleotide analoguE:,
`
`(2} R does not
`
`group, an ester group, or an allyl ether group, Further, in the stru.ct1Jres
`
`:in t:he claims, R is shov.-n as covalent:ly hound to the 3' ()xygen, W:ith the
`
`meaning of "'sma.11" defined as indicated in the preceding sect.ion a:ad t:he
`
`Page 5
`
`

`

`The Trustees of Columbia. Un:i.ver,:iit:}" in t:he CH:y er New York
`Applicant
`Serial No,
`16/1.50, 185
`Filed
`October~ 2; 2018
`Page 6 of lO of Supplement:a.l Com1nunication Supplementing Cornmunicat. ion
`in Response t:o Febn1ar·,r 15, 20l9 First Action Interview
`Pilot
`Program
`Filed.
`Comnru.n:i.c:at:LCJn
`Pre--Interview
`February 26, 2019
`
`two examples provided in the application, ,:he POSJ\. would readily know
`
`which chemical capping groups could be R since the size (diameter) and
`other properties required by tb.e cla:i.ms would be easily determined in
`
`t.he cont:.c:,xt cf t:he claims as a whole, In this regard, applic:arit empbas1.zes
`
`that there is not.hing wronq wit.h using functional languz~ge to define
`
`feat1..i.res so l.ong as the invention recited ::..n
`
`t:he c1aims ::..s not being
`
`defined enr:.irely b:{ functional features
`[MPEP 2173, 05 {g)}
`there is nothing wrong with usi.ng neg::it:i.ve limitationr:s [MPEP 2173, 05 (i) l.
`
`S i:ni l a.:r· 1 y~· r
`
`Moreover,. prior art: as of Octobe:t: 2000,
`
`including Tsien
`
`(WO 91/06678,
`
`M·;.iy 16, 1991) and Stemple
`
`(WO 00/.53805, September 1.4, 2000),
`
`:i.dentify
`
`numerous chemically cLeavable, 3' -0 capping chemical groups, each ot
`
`wh:icb could be readily evaluated to de:t:erm.i.n.e whether it was "sm.a.11" and
`
`also whet:.ht:=r it ffH::t c,tl1e:r st:t-uctural recr-uire-ments of tt1e (Jlcairns su.:c}-1 as
`
`"is not a metho:xy group or an er:it:er group"
`
`f.contr&.1.-y to the teachings of
`
`Tsien that such g-:t:oups could be used in sequencing by synthes:i.s] and
`
`~•does not. conta~in a ketc:n:1e g:t'C)llf)'"' The POSA would have 1.m.derstood, with
`:not:. have found its
`
`t.he. meanin9 of· R and \./'Ou]_d.
`
`r·easonably certainty,
`
`meaning unclear.
`
`[See also pa.ragraph 19 of the Declaration of ,:ri ngyue
`
`The Examiner acknowled~1ed
`characterist:i.cs of Y but that these funct i.ona.:L
`
`sorne
`
`functional
`
`:l. im:i.t:a t:.:i.oxw do not set
`
`i·.J•,.cst·
`
`r:J1e
`
`cla.ita
`
`rec 1. tes
`
`forth well-defined bou:ndarie.::i (·--F
`
`_,[·"-
`
`the invention because they only
`
`a pro.b:Lern ;;,olved or a result ac:hieved.
`
`App1:Lcant initially points out: that: Y i,,, a.:Lso defined in the claims as
`a chemica,lly cleavab1e, chemical linker and a POSA wou.ld ha,.,e reach ly
`
`~ ! with reascM1ably c:erta:i.rity,
`u.nderst:cod the meaning of V
`
`35 U.S. C. §ll2. App1:i.can.t further points out that the scope of the cla.:i.m.s
`
`sihou:Ld not. be equated with ind;::U.nit:ec.e::,t,
`
`(MPEP 21 73. 0·1] ,
`
`A:pplicant further point.s out. t:ha.t. Stemple and Tsien disclose examples Gf
`
`Page 6
`
`

`

`The Tr·u::it:ees of Colurnbia University in t:he City of New York
`Applicant
`Serial No. 16/150,185
`Filed
`October 2, 20l8
`Page 7 of 10 of Suppleme:nt:.al Corrnir:.rn.:i.caci.o:n. Suppleme:n.t:ini,.J Communication
`in Response to February 15, 2019 First. J;.ct:ion Int.erv:iew
`Pre- Int.er.,.v ... iel.-.1
`ComrrrtJ,nicat ion
`fJj_ lc)t.
`Pro:;5rarn
`1:7iled
`February 26, 2019
`
`chemically cleavable, chemical linkers. Therefore, the POSA would have
`
`readily understood the meaning oi: a chemically cleavable, chemical linker
`
`(Y) .
`
`In addition,
`
`the structures in the c1a.ims show
`
`t:he structural.
`
`features of covalent: bcrrKls joining Y to a specific position on the base
`
`at one end and to the fluorescent tag at the other end. AppJ. .. icant also
`.. ,
`l , 8' 10, and 15.l\ of
`fa.mi1L"r with. both the
`term
`
`directs tf1t:: Exarni:r1e:t"' r:s atte11tior1 to B~IGS ..
`
`t-he
`
`application,
`
`'The POSA v10Llld have be.en
`
`chemically c:teavabJ.e, chemical linker and numerous examples from the
`prior art and
`1,,Jo1-1ld h .. a.-..,.re
`its n1ea11.ing ~litl1 reasonable
`[See also paragraph 20 of the Dec:Lara.t.ion of ~Ti.ns1 ue ,T,.1,
`
`·:..1r1t:ierst()Od
`
`certai.nt:y.
`
`Ph,D,]
`
`Do Concltwion
`
`Based on the preceding rem;;,rks and the accompany i.ng Dec:Laration of'
`
`,Jingyue Ju, Ph.D.
`
`irn::1ud:i.ng-
`
`the E:xhibits attached to the Declaration,
`
`definitenes,;; imposed by 35 U.S. C. §112 (b) and requests that the Examiner
`
`reconsider and withdraw thi:=1 grou:nd of re:lection.
`
`V. RE,.TECTIO.N FOR FAILURE TO COMPLY WITH WRITTEN DESCRIPTION REQUIREMENT
`
`Although t.he clc:d.ms were not rejected under 35 U.S.C. §112 (a; for failin,3
`
`t:D ,::omp.1.y with the written description re~-u:i.rement applicant re~3ponds as
`
`if S•~tvh c,_ rej,::c;::Lo:n had been and the same issues had been raised as were
`
`In. support of this rejection the Examiner indicated t:,hat variables R and
`
`Yin the c1a.ims are defined functionally but.Lac.Ka clear--cut indication
`
`of the scope of the subject matt.er embraced by t:he claims; and that in
`
`this cas;;;,
`
`t.be ,::pecificati.on does not provide the particular struct.1..,re,,,
`
`that accomplish the functions :cecit:ed in the clairas with the exception
`
`of two exampl.es of R and one example of Y. The Examiner further a:=1sert.ed
`
`that the skilled artisan would not be apprised that: the inventors had
`
`possession of the fu:Ll scope of the claimed invent.ion at the time the
`
`Page 7
`
`

`

`Applicant.
`The Tr-ustees of Columbia University· in the City of New "York
`Serio,.l J:Jo.
`16 /150, 1.85
`October 2, 2018
`Filed
`Page 8 of lO of Supplement:a:L Communication Supplement.ing Communicat:i_cn
`in Response to February 15, 2019 First Action Interview
`Program
`Pre--Intervie,M Co1nmunicat:ion Filed
`Pilot
`February 26, 20l9
`
`app1 ication was filed because the scope or: the c1-aims is much larger
`
`than the examples given and the specification does nDt 1:n:ovide structure(cid:173)
`:t·elationships or guidance for compounds other
`funct: L:in
`than those
`
`exernp 1 if i ed .
`
`According i:.o MPEP 2163, possession of a c:la:Lmed inventi,:__,n is shewn by
`
`describing the invention with all of its features. Among
`
`t.he factors
`
`supporting t:he presence of o.n adequate wt:itt:en description in this case
`are the following:
`
`1. t"I'here is literal st1pport for t.he claims a.s
`
`i~f1c)~111
`
`i:t1 1:J:te c1a.irn support
`
`t:able attB.ched hereto as Ex.hibl.t 2 _ Even though literal st.1pport (haec
`
`the presence Df an adequate written description. As noted in MPEP
`
`21.63, 0,1,
`
`the Examiner has t:he burden to establish lack of writ:t:en
`
`description, -which '.Ls presumed to be present when th,:; claim has lit:eral
`
`support.
`
`2. There are e:xarnr.,les of the claimed invention showing the invent::.cm was
`
`comp1e,t:e. See especially FIGS. 7, 8, 10, and 15A of the applicati,,:m.
`
`3 _ The invention wo.s _.__ew3-.f for patent:Lng as evidenced by the grant. of
`
`related claims i:n .related patents having the ,,,;:une spec:i fica.Lion {U _ 3.
`
`Patent No.
`
`i.ssl1ed
`
`'-Jar1u.a:ry 16, 201s; u .. s~ Patent
`
`·t,J{) ~
`
`9:725:480I
`
`:L!:;.s"t.1ed Itugust 8) 201.7; T]_.S. Pat:..ectt
`
`l\Jc:•~ 9,71.9,139,
`
`issued.
`
`2017;
`
`Patent. No.
`
`isst1ed August
`
`l..; 2017;
`
`U.S. Patent_ No. 9,708,358, issued JuJy 18, 201-7).
`
`4.. The ;~c;of)t ()f r:rte claims is r1ot. rn:uel1 1.a:rg·e:r: th.an the exan1ples gi ~ren ~
`
`:rn this regard, there a1:e estimated to be not more than ten R g::coup::i
`
`{chemicaLty cleavable, 3'-·0 capping grcup:::)
`
`t:hat meet the criteria
`
`c-;f
`
`the clairnr~ a.r1<i
`
`t:~\'(~· c .. ::ce exempl:ifiecl,
`
`I:n tb.is cor1te:xt
`
`tl1e:ce is
`
`also p;;,ra,3rapr, 22 of the Declaration of ,Jinqy·ue Tu., Ph_ D.]
`
`Page 8
`
`

`

`Applicant
`Ser:ial No.
`F:iled
`PagB 9 of
`
`The T:n::.st:ee;;; of Columbia University in the City of New York
`16/150, 185
`October 2, 2018
`10 of supplemental Communication Suppleme:nt::Lnq Communication
`:Ln Response to February 15, 2019 First Action Interview
`Pilot
`Commt.micat::ion Filed
`Prog:t:am
`Pre- Interview
`February 26, 2019
`
`To
`
`support.
`
`this
`
`x~e] e-:.-~t: 1 ()11 ~
`
`the Exam.iner also referred
`
`t:o
`
`Lhe
`
`reJ ect.ion.
`
`A <'
`
`.0
`
`cl:Lsc:11::;sed
`
`above,
`
`the
`
`indefiniteness
`
`rejection ;:,honld be withdrawn,
`
`The i::ugg-estion that the claims merely rec:Lt:ed the solution to a problem
`or a desired result using functional language is misplaced since t.he
`claims recite specific chemical structures most of which are fixed and
`highly precise with the varia.ble groups well defined.
`
`In this ca.se,
`
`t.he presence of examples is important: evidence of an
`
`adequate written description and establishes that the inventors were in
`the POSA would have
`
`the
`
`claimed~
`the compounds
`
`immediately
`
`.envi,,,:Loned
`
`in
`
`the claims based o:n
`
`t:he
`
`spec:i f:i.cation, drawings, and examples.
`
`[See also paragraph "'-'.> of the
`
`Deel a.rat ion of Jingyue ,.Ju, Ph.D.]
`
`In conclusion, applicant has clearly sho,qn th2tt
`
`tr1e
`
`i.nvenco:cs were in
`
`possession of the cdaimed invention. The rejection for failure to provide
`
`l's.pplicant maintains that a11 grou.n(1s of rejection set forth in the
`
`February 15, 2 01.9 First. Act ion Interview Pilot Program Pre-Int:ervie,,v
`
`Coinmunication have been ove.r.come cmd eaxnestly solicits allowance of the
`
`claims pe:nd:tnq in the application,
`
`Page 9
`
`

`

`Applicant
`'l'he Trust.e,,,s of Columbia University in the City of New Yo:r.k
`Serial No.
`l.6/150,lSS
`October 2, 2018
`Filed
`Page 10 of 1.0 of Supplemental Communica.t.:Lon Supplementing CcHnrm.111.ica.tion
`in R,::sponse to February 15, 2019 First Act:l.cn Int:erview
`Pilot
`Program Pre-Interview· Communication
`FiJ.ed
`February 26, 2019
`
`If a telephone inter.v:i.e'<J would be of assistance in advancing prosecution
`
`of the. sub:ject application, app:L:icant:' s t.mdersigned. attorney invites the
`
`Examiner to telephone him at the number provided betow,
`
`No fee is deemed necessary in conw;;ct.:ion with
`'f
`-
`'
`ar1}( :tee is
`Supplemental
`aut£1<>r'i za t. io:n. i ,s
`i
`hereby gi.ven to charge the arn<Yc.1nt of a:ny :,such fee to Deposit 1'.:2count: No,
`
`t:.he filing of this
`
`03-31.25 ..
`
`CertificaLe of TranS3tl.i$sion
`hereby
`certify
`that
`this
`I
`correspondence is betn.g tJ_ .. ansmitted
`via
`t.he Elect.ronici F.1.l ing Systetn
`(EFS.)
`t"
`tl1e
`Patent
`and
`TJ,S.
`Trademark Office on Jviay 131' 2019.
`
`Respect.fully submitted,
`
`,Tob(1 P. 1 White
`Regi\it:i\it.:i.on No, 28,678
`Attorney for Applicant
`Cooper & Dunham LLP
`30 Rockefeller Plaza
`20::. 1, F1c,or
`New York, New York 1 o Ll.2
`(21.2) 278-04·00
`
`Page 10
`
`

`

`....._ ______ U_._S_._S_e_.r_la_l_N_o_._1_6_1_'15_0.,.,.;,c...."l_8_5 ________________ S__,uep,_o_rt _________ --1
`[0016] "each different nucleotide analogue comprises
`i. A thymine deoxy-r!bonucleoUd,2 analogue having the
`(a) a base selected from the group consisting of
`structure:
`adenine, guanine, cytosine, thymine, and uracil, and
`thek ana!ogues; {b) a unique label attached through a
`c!eavab!e !inker to the base or to an analogue of the
`base; (c) a d,~oxyflbose; and {d) a cleavable chemicai
`group to cap an -OH group at a 3'-poslbon of the
`deoxyTibose"
`
`CLAIM SUPPORT TABLE
`
`DkL 62239·BZA6AD
`
`.
`
`~-----·" ~,✓
`
`OR
`
`[0036] "FIG 2A-2B: . .,A, C, G, T: nucleotide
`triphosphates comprising bases adenine, cytosine,
`guanine, and U1ymine; d, deoxy; dd, diaeoxy; R,
`c!eavab!e chemical group used to cap the -OH group; Y,
`;;:!eavab!e linker"
`
`F!G.2B:
`__ /'l -
`dT\
`0 - R
`
`tag-4 {Unk to the base)
`
`(Block the 3'-0H group)
`
`}
`
`;.~---~ :~
`
`0
`
`t
`jJ
`J-
`
`'"}
`
`?
`t · O
`!·
`
`wherein R
`(a} represents a smaU, chemically claavable chernica!
`group capping the oxygE>n at the 3' position of the
`deoxyribose ot the deoxyr!bonuc!eotide
`
`F!G.7
`
`[OO'S3] "!n one embodiment, the unique labe! is attached
`through a cleavabie linker to a 5--positlon o! . , . thymine"
`(0000] "More recent ,,ivork ln the !i1erature expioring
`DNA sequencing by a synthesis method is mosUy
`focused on designing and synthesizing a
`photoc!eavab!e chemical moiety that ls linked to a
`fluorescent eye to cap the ;:,'•OH group of
`dceoxynudeoside trlpt1osµr1at0s {dNTPs) (\f\felch et aL
`19~9). Umitecl success for the incorporation of the 3'(cid:173)
`modified nucleotide by DNA polymerase is reported,
`The reason is th.::1t the 3'~oosit!on on the deoxvriQQ§.s;~ is
`very dose to the amino acid residues in the active S!te
`_QfJl:!~_poivmerase, and the polymerase is therefore
`sensitive to modification !n this area of the deoxy-ribose
`ring. On the other hand, it is known that modified DNA
`pc,lyrnemses (Thenno Sequenase and Taq FS
`polymerase) am abiB to recognizi:.: rn .. icle,Jth:!es with
`extensive modmcations with bulky groups such as
`1m~ergy transfer dy'es at the 5-pc,sition of the pyrimidines
`(T and C) and at the 7-p,:.:isition o1 purines (G and A)
`(Rosenblum et aL ·1997, Zhu et al. 1994). The ternary
`cornp!exes.of_rat.DNA polymerase, a DNA ternpifl.J:ft:
`primer, and dideoxycytidine triphosphatejqdCTPl have
`been determined (Pelletier et al. i 994) which suoports
`this fact As shown in F!G. 1, the 3-0 structure indicates
`that the surrounding area of the 3'-position of the
`deoxyrlbose ring in ddCTP is very crowded. whHe there
`is ample space for rnodiHcation on the 5~posmon the
`cyjldlne base:'
`
`[0007] "The approact1 disclosed in the u.msent
`application is t-0 make nudeotlde analogues by !inking a
`unique label sud1 as a fluorescent dye or a roass tag
`through a cleavable linker to t!1e nucleotide base or qft
`analogue of the nucleotide base, suct1 as to the 5-·
`position of the pyrimidines F and C) and to the?(cid:173)
`position ot the purines (G and A}, to use a small
`deavab!e chemical moiety to cap tr:e 3~-0H grcui::: ot t'.1f,
`ft.ppl,e:1r.t: r r:0 f n;stoos ,:-,f Cc!i;rn::na
`P'<llge 1 of 10
`Ur:iversity in 1110 City of New Yom
`U.S. Seri,11 No.: H3/i50, 185
`FHed: October 2~ 201B
`Ell'hibn2
`
`Page 11
`
`

`

`Dkt 62239-BZA6AD
`
`deoxyribose to makt~ it nonreactive, i:,nd to incorporate
`the nudeotide analogues into the growing DNA strand
`as terrninat,:irn. Detection of the unique label wm yield
`the sequence identity of the nucleotide. Upon removing
`the label and the 3'-0H capping group, the po!yrnem.se
`reaction will proceed to incorporate the next nucleotide
`analogue and detect the nm,'t bas-::1."
`
`[OOOSJ "it is also desirable to use a photocleavab!e
`group to cap the 3'-0H group. Howeve.t,,Jl
`photociea:vable group is generally bulky and ttW.$. the
`DNA polymerase wm have difficulty to incorporate the
`nucieotkie a.na1Q9.HPS containina a photoc!eavable
`moiety capping the 3'-0H group. lt srnall chemical
`moieties that can be easily deaved chemica!iv w!th high
`yield can Lm used to cap tile 3'·Qtt_g_mup. such
`nucleotide analogues should ais9 L'B recognized as
`substrates for DNA polymerase. It has been reported
`tt:at 3'-0-methoxy-deoxynuc!eotides are good
`substrates for several polymerases (Axelrod et aL
`1978). 3'~0~ai!yl-dA TP was also shown to be
`incorporat~d by Ventr {{,xo·-) DNA polymerase in the
`growing strand of DNA (t,,,1etzker et aL i 994). Howev~L.
`tt.'ie pn:icedure to chemically cleave the methoxv group
`is stringent ;;md mrn:Jims ant}yj1.rous conditions. Thus. it
`is not prnct1ca! to use a rnethoxy mow o to cap the .3'-0H
`.9I9.:~JP for sequencing DNA by synthesis. An ester group
`was also explored to cap t!1e 3'-0H group ct the
`nucleotide, but it was shown to be_c!eayed t,y ttJ.§2
`nuc!eoaJhl!es in the active site in DNA polymerase
`{Canard et aL 1995) .. ChS?J1l!9-f!L.QIQ.~!PS witheiectrophHes
`such as ketone groups are notsultable for protectiQg
`t!1e 3'-0H of the nucleotide in enzymatic reactions due
`to the existence of strona nucleophiles in the
`oolvmerase. lt is known ttlat MOiv1 (~CH20Cr·b} and
`ally! (·"'.·:-:•t:H2CH=CH2) oroups can be used to cap an
`--···OH group, and can be c!eaved chemically with high
`vieid (Ireland et a.L i 986; Kama; et aL 1999) The
`approach disclosed in the nresent application ls to
`inco,porate nucleotide anali>gl....!es, whicF1 a.re labeled
`wi1h cleavab!e. unique !abeis such as fluorescent qy~~@
`or mass ta9s and where the 3'-0H is caoped with a
`c!eavable C:h£ffnieal mo!Q1){ __ §JJfh as either a MOM group
`{-GH20CHs} or an ally! group (--CH2C~r-fa), into
`the growing stranct DNA as terminators. The optimized
`nucleotide set (3'-RO-A-LABEL 1. 3'-HO-C-LABEL2, ;J'.
`RO-G-LABEL31 3'-RO-T-LABEL4, '>"there R denotes t!·ie
`ehert:ical group usi:id to cap the 3'-0H) car: then be
`used for DNA sequencing by the synthesis approach."
`
`[0035] "FIG. i '. T!1e 30 structure of the temary
`complexes of rat DNA poiyrt,E!rase, a DNA t,o!mp!ate(cid:173)
`primer, and dideoxycytidlne triphosphate (ddCTP). The
`hMt side of th;;: mustration shows the mechanism for t1le
`addition of ddCTP and the right side of the mustmt,on
`shows the active site of the polymerase. Note that the 3'
`position of the dideoxyribose :·lna ls very crowded. whHe
`arnp!e space ~s availab!e at the 5 position of the cytidine
`base."
`
`[0137] " .. a srr:a!! cieav8bie chemical group (R) to cap
`the 3'-0H group."
`'--------------·--·····················---------_......j!........ _______________________ ............,
`
`Page 2 of10
`
`Page 12
`
`

`

`: I
`
`(b) does not interfere wm1 recognition of trm analogue
`as a substrate by a DNA polymerase
`
`(c) is st.able during a ONA polyrnerase reac:tii:,n
`
`(e) is not a -CH2CH,e:CH2 group
`
`wherein OR is not a methoxy firoup
`
`or an ,:ister group
`
`Dkt 62239·-BZABAD
`
`[0138] " ... the R group protecting the 3'-0H is removed
`chemlca!!y to generate free 3· -OH group with high yield
`(step 4 in FIG. 2A)."
`
`[0141] " ___ a small c!eavable chemical group {R) to cap
`t!1e 3'-0H group ... The R protecting group is then
`removed chemicaHy and washed away to ;;<enerate free
`3'-OH group with high yield {step 5 in F!G. 2B)J'
`
`[0147] " ... the 3'-0H cap group is cr,emfcaliy deaved off"
`
`[0154] "These groups can be removed chemically with
`high yield as shown ln FIG. 14 {Ireland, et aL 1986;
`Kamai et ai. 1999)."'
`[0008] "!f small chemical moieties that can be easily
`Ci6i:lVBd cherniCBJ!y with high yield C;ctn 00 US!:!d to cap
`the 3'-OH group. such nucleotide analogues should aiso
`be. recognized as substrates for DNA polymerase."
`
`[0089] "Any chemical group could be used as long as
`the group ... cioes not interfere witi1 the recognition of the
`nucleotide ana!ogu1.:, by polymerase as a substrate .. "
`
`[0089] "Any chemkal group could be used as !nng as
`tile group 1) is stable during the polymerase reactiotL.;,
`
`[0008] "Chemical groups with electrophiles such as
`ketone groups are not suitable for protecting the 8'-OH
`of the nucleotide in enzvmatic reactions due to t!1e
`existence of strong nucleopt1lles in the polymerase."
`
`[0008] ",. .a!iy! (---CH2CH-ccCH2) group[] can be used to
`cap an -OH group ... "
`
`[0008] '' .. ,Hie- 3'-0H is capped with a cleavab;e
`chemical moiety such as."an a!!y! group
`{--CH2Cl-bCHc:) ... "
`
`[0063] '·Otnioir examples includ!?s
`analogues in whicr1 a smail chemical moiety such as ...
`-CH2CH:cCH2 is used to cap the -OH group at the 3'(cid:173)
`position of deoxyribose."
`
`[0089] ··in one embodiment, the c!eavabie chemical
`group that caps the · OH group a1 the 3' --position of
`deoxyribose in tl,e nucleotide ansJogue is .. ,
`--CH2CH=CH,."
`
`This negative limitation iS pennissib!e undm MPEP
`2173.05(1). See laphi Corporation v. Netlist, Inc., 805
`F.3d i350, 1356-57, 1 "l6 USPQ2d 2006. 2DW-11 (Fed.
`Cir. 2015).
`
`[0008] "__,the procedure to chernlcaiiy cleave tr1e
`methoxy group is stringent and requires anhydrous
`i::ondit!ons, Thus, it ,s rn,:;t pract!cat to us;,, a rnetl1oxy
`group to cap the 3'-0H group for sequencing DNA by
`synthesise"
`
`[0008] "An ester group was also explored to cap the 3'-
`0H group of the nucleotide, but lt 'Nas shown to be
`
`Page 13
`
`

`

`<-
`
`i
`
`Dkt. 62~?39-BZA6AD
`.----------------------~------------ - - - - - - - - - - - - - - - - - - - - - - -~
`cleaved by the nudeophi!es in the active site iri DNA
`polymerase (Canard et aL i 995) ."
`
`wherein the covalent bond between me 3' .. oxygen and
`R is stable during a ONA polymerase reaction
`
`wherein tag represents a detectable fluorescent moiety
`[as part of structure !9.}{t~~gJ attached to the 5-position
`of a thyrnine nuc!i3otide analogue]
`
`[0007] ".-.use a smaU cleavabie chemical moiety to cap
`the 3'-0H gn>up of thi:I c!eoxyTibose to make it
`nonreactive"
`
`[0089] "Any chemtca! fF'OUp couict !:ie used as long as
`the group 1) ls stable during the polymerase m;:wtion "'"
`[OOO?'J "The approach disclosed in the present
`application is to make nucleotide analogues by !inkfng a
`unique label such as a fluorescent dye .. Jhrough a
`c1eavab!e linker to the nucleotide base m an analogue
`of the nucleotide base, such as to U,e 5-position oi the
`pyrimidines {T and C) ... ''
`
`[0036] "F!G. 2A-28,,.tr1e unfque labe!s are dyes.,.Y,
`deavable !inker;"
`
`[0041] FIG, 7 ... Eacti m.icieotide analogue ha::, a w1ique
`i!uorescent dye attached to the base through a
`. ,.cieavab!1:., linker"
`
`[0043] FKi, fLThe dye is detected and cleaved to test
`tt:0 approach. Dye1,,,Fam; Dye2,,,RSG; DyeJ:,:Tam:
`Oye<'i=Rox,"
`
`[0090] In one emoi:idlrnent, the unique !ab,,;1 that is
`cltlached to Hie nuc!eotld-e analogue is a fluorescent
`moiety ... "
`
`[0117] "In one embodiment, the unique labe! is a
`fluorescent moiety or a fluorescent semiconductor
`crystal."
`----------------------------+-----------''----------------------·····-··---·--·--
`[0036] "Y, c!eavabie !!nk0L 0
`where,n Y mpresents a chemic.ally c!eavab!e, chemical
`!inker
`
`[0007] ''linidnfi a unique !abed such as a fluorescent
`dye ... thrnugh i:'i deavabie !inker to thi:, nuclenticie base
`or an analogue of the nucieotide base"
`
`which {a) does not interfere with recognition of the
`analogue as a substrate by a DNA polymerase
`
`anct (b) is stable clur:ng a ONA polymerase reaction
`
`;and
`
`[0063] "Further exarnp!Bs include anaiog~H;S in which a
`label is attached through a c!eavabie !inker to the 5-
`position of. .. tnymir:e .. . *
`
`[0094] "ln one embodiment, the linker is cleaved by a
`chemical means."
`[0093] "ln one embodi:r,ent, the unique label is attached
`through a c!eavab!e linker to a 5,position of cytosine or
`thymine or to a ?·position of deaza-ader:ine or deaza(cid:173)
`guanine, The unique !abe! could also be attached
`through a c!eavable linker to another position in the
`nucleotide anaJogue as iong as .. . the nudeotide anaiog
`can be recognized