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`
`IN THE UNITETZ STATES PATENT AIID TRAI)
`
`('/
`brrirARK OFFI
`
`181
`CE
`
`Art Unit: rc7 fr,
`Examiner: A.
`
`) ) ) ) )
`
`)
`
`Applicant(s): Jannis G. Stawianopoulos, et al.
`07 /607,347
`October 30, 1990
`position and Kit
`ployrng Chemically-
`Pollmucleotide
`
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`,sePtember 27, 1991
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`EldleLBnlocr
`
`and Trademarks
`
`ts
`t
`
`RESPONSE UNDER 37 CFR FI..T15
`
`Dear Sirs:
`
`Please enter this response to the Office Action of March 28,
`f991. This response is being timely filed with a Request for a
`Three-Month Extension of Time and the fee therefor. Accordingly,
`this response is being timely filed.
`
`AIVIEND fiIIS APPLICATION AS FOLLO\ITS:
`In the $neclfrcatlon:
`
`Page I of the speciftcation, line l, as amended by preliminary
`" delete "is"
`amendment of Octo
`1990, line 2, after "
`which issued as U.S. Pat. No. 4,994,373 on February
`d
`19, 1991. which was filed
`as --
`
`Page I of the specification, line 1, delete "This is a continuation-in-
`part of applicants' pending United States pale6t application, serial
`. .,/
`number 46L,469, filed January 2I, 1983." /
`In the Claims:
`P1ease amend the claims as follows:
`//
`Claim 28, Line 1, after "Claim", delete "4O" and insert --27--. /
`Claim 30, line l, after "Claim", delete "42" and insert --29--. /
`Enz-7(CrPlC2'...-..-...
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`,/
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`:"';:
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`Page 1 of 12
`
`HOLOGIC EXHIBIT 1026
`Hologic v. Enzo
`
`

`
`Jannis G. Stawia-*,, rpoulos et al.
`Serial No.: 07 /607,547
`Filed: October 30. f99O
`Page 2 (Amendment Under 37 C.F.R. S1.115 - September 27, 1991)
`
`Ctaim 33. A composition of matter which comprises a transparent
`or translucent non-porous system further comprising a double-
`stranded polynucleotide which is immobilized on a solid support
`wherein one of the strands is chemically labelled and capable of
`generating a soluble signal.
`
`Claim 34. The composition of claim 33 wherein the solid support
`is contained within the transparent or translucent non-porous
`system.
`
`(v Claim 35.
`
`comprises:
`
`A method for detecting a polynucleotide sequence which
`
`hybridizing a polynucleotide or oligonucleotide probe,
`which is in single-stranded form and has attached
`thereto a chemical label comprising a signalling moiety
`capable of generating a signal, to said pol5mucleotide
`sequence;
`
`fixtng said hybridized polynucleotide to a solid support
`which comprises or is contained within a transparent
`or translucent system; and
`
`generating and detecting a signal charactertzed in that
`the transparent or translucent system is non-porous
`and the generated signal is a soluble signal.
`
`Enz-7(CI.PlCg
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`Page 2 of 12
`
`

`
`Jannis G. Stawiar.{rpoulos et al.
`Serial No.: A7 /607,347
`Filed: October 30, 1990
`Page 3 (Amendment Under 37 C.F.R. S1.1 15 - September 27 , I99Ll
`
`REMARKS
`
`Reconslderation of the above-identified application is
`respectfully requested. The status of the claims is as follows:
`Claims 27-32 are pending in this application. In addition,
`Applicants have added new claims 33-35 based on the case as filed.
`Accordin$y, claims 27-35 are presently under examination in this
`application.
`
`Applicants would like to acknowledge that the original
`numbering of the instant claims was not in accordance with 3z CFR
`SI.126. Applicants appreciate that the Examiner has undertaken
`to renumber claims 40-45 as 27-32. respectively. All of the instant
`claims, including the dependencies of claims 28 and Bo, conform
`to the renumbered format. Any inconvenience caused bv this
`original oversight is sincerely regretted.
`
`Applicants have updated the present status of the parent
`application, serial No. 071385,986 which issued as u.s. patent No.
`4,994,373 on February 19, 1991, by including the present status of
`the case in the instant specification. Further, Applicants have
`deleted the previous first line in the specification after the title
`which contained the reference to serial Number A1l,4og, to avoid
`duplication with the amended language in the preliminary
`Amendment and to accurately set forth the current status of the
`parent application which issued after the instant application was
`filed on October 30, tgg0. Finally, Applicants appreciate the
`courtesy extended by the Examiner in presenting the explanation
`of t,}.e two digit prefix which indicates the series of a particular
`application in the PTO numbering system for pending applications.
`Applicants will endeavor to use the prefix reference in the future to
`more accurately speci$r the application in qdestion in pTO
`correspondence.
`
`E;nz-7(CIP)CZ
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`Page 3 of 12
`
`

`
`Jannis G. Stawia,-.rpoulos et al.
`Serial No.: A7 /607,347
`Filed: October 30, l99O
`Page'4 (Amendment Under ST C.F.R. 91.1 15 - Septernber 2T, l99r)
`
`It is submitted that all of the foregoing amendments
`comprise subJect matter which Applicants are duly entitled to
`claim. No new matter has been entered thereby.
`
`Applicants have added new claims 33 and 34 to further
`deftne an embodiment of the invention which is a composition
`comprising a transparent or translucent system in which a
`polynucleotide is fixed to a solid support in double-stranded form,
`and in which one of the strands of the polynucleotide is chemically
`labelled and capable of generating a soluble signal. The transparent
`or translucent system either comprises or contains the solid
`support. New claims 33 and 34 are based upon the specification at
`page 10, lines lO-12, lines L7-25, and page 14, lines 26-36.
`Applicants thus submit that no new matter is presented hereby.
`
`Applicants have added new claim 35 to further define the
`various embodiments of the invention for fixing the nucleic acid to
`the solid support, i.e., in single-stranded or double-stranded form.
`In accordance with claim 35, the invention is directed toward the
`detection of a polynucleotide sequence by a method in which a
`probe, which is chemicalty labelled, is hybridized to a
`polyeucleotide sequence, and the hybridized polynucleotide is fixed
`to a solid support, thereby resulting in the generation of an easily
`detected and measurable soluble signal comprising or contained
`within a transparent or translucent non-porous system. Support for
`newly added claim 35 is set forth on page lO, lines 6-9 and page
`lO, lines 17-25 of the instant specification. Thus, no new matter is
`presented hereby.
`
`The above claims have been added to further define t]le
`invention. Applicants submit that these claims are fully supported
`by the instant disclosure. Furthermore, no new matter has been
`introduced by any of the foregoing claims, which comprise subject
`matter to which Applicants are duly entitled.
`
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`Page 4 of 12
`
`

`
`Jannis G. Stawia. ,poulos et al.
`Serial No.: 07 /607,347
`Ftled: October 30, 1990
`p^e.s(AmendmentUnder37c.F.R.g1.l15.September27'1991)
`
`TheExaminerhasrejectedclaims2T.S|under35U.S.C.
`$1o2(b)asbeinganticipatedbyLangeret.al.IntheofficeAction
`(pages 3-41, the Examiner stated:
`
`''I,angeret.al.disclosesabiotinlabelegpolynqc}'eotide
`probecompositionin_it'eabstract.Thdcapabitityof
`this ;h;*-i"uuv r.u"rJ-piope !g produce -a soluble
`coupled ^Tth an
`signai-is-"i" ittt ;i"ai"d.of -a-1ri!in
`indicator enzyme as diJclosed on P?g". 693^P: first
`column, lines lI-I4: Th" .pp*"tus of instant claim 31
`is inherent in tne rrybridiiatiog lsslJ methodology
`oisctosed by Langer ei al. The hybridizatio:e_on non-
`po*.t" soiid- slpports' that are transparent or
`translucent, of itrri"fil.rri*" 29-30 is disclosed by thp
`in-situ hybridizau;;;thod discussed by Langer et' al'
`ot ffi" 6i637, tt"ond column' lines l-8' A transparent
`is embodied by glasq slides
`non-porous soucr ttpfit
`"o""6-Hi;h chi6mosomes are fixed for in-situ
`"t..
`hYbridization assay'
`
`Appticantsrespectfullyrequestreconsiderationofthis
`rejection based on the following grounds'
`
`Theinstantinventionrelatestoacompositionwhich
`comprises a double-stranded polynucleotide which is immobilized'
`in which one of the strands comprises a chemical label which is
`capableofgeneratingasolu-lrlesi$nalcomprisingorcontained
`within a transparent or translucent non-porous system' The instant
`inventionisadeparturefromthepriorart.Accordin$tothe
`invention, a detectable sr:luble signal is generated using any one of a
`numberofsignalgeneratingsystemsinanynumberofdifferent
`formats. The soluble signal may be detected using a variety of
`techniques. According to the invention, chemically labelled
`polynucleotides or oligonucleotides are employed to detect analyles
`usin$ a soluble signal.
`
`Dnz-7(CrPlCz
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`Page 5 of 12
`
`

`
`Jannis G. Stawia_.rpoulos et al.
`Serial No.: 07 /697,347
`Ftled: October 30, lggo
`Page 6 hmendment under g7 c.F.R. sr.r rs - septembe r 27, r99r)
`
`Langer et. ar. discroses a process for enz5rmaticaty
`incorporating a label into nucleic acid probes. Langer relates to the
`development of a system of detection based upon two methods with
`labelled probes, i.e., dot or blot, which results in a signal which is a
`precipitate, and in situ hybridization, which results in a signal
`which is localized or a precipitate. Lines 12-14 of Langer, in the
`abstract, specifically state that biotin-labeled pol)mucleotides,
`which are described, can be selectively immunoprecipitated in the
`presence of antibiotin antibody and staphylococcus aureus protein
`A. The reference also discloses various characteristics of the
`labelled nucleic acids in which the labels were incorporated
`enz5rmatically.
`
`In order to sustain a rejection for anticipation, a cited
`reference must discrose alr of the material elements of a claimed
`invention. For the invention at hand, it is submitted that the
`anticipation rejection should be fithdrawn because Langer et. al.
`fail to disclose at least two materiar elements of the instantly
`invention. First, Langer et. al. does not discrose or suggest,
`laimea
`rn any manner, the capability of generating a soluble signal in his
`detection methods. By way of contrast, Applicants specificaily
`teach the generation of a soluble signal as set forth in claims 2T-SO,
`and delineated in apparatus claim sl, wherein the soluble signar is
`generated by means of a signalling moiety. secondry, unlike the
`instant invention, there is no mention or suggestion in the
`reference of the generatio', via a signalling moiety, of a non-
`localized signat as set forth in the instant specification and claims.
`In fact, Langer et. al. teaches away from the instant case, since the
`signal disclosed in this reference is required to be a localized signal
`or a precipitate. Thus, quite crearly, Langer is rimited to the
`generation of an insoluble or localized signal.
`
`By way of explanation, the reference states that biotin-labeled
`pol5rmers, as disclosed therein, can be used in conjunction with
`appropriate immunofluorescent, immunohistochemical, or afftnitv
`
`Enz-7(Crp)CZ
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`Page 6 of 12
`
`

`
`Jannis G. Stawia...rpoulos et al.
`Serial No.: OT /607,347
`Filed: October 30. 1990
`Page 7 (Amendment Under 37 C.F.R. Sl.t t5 - September 27, I99t)
`
`reagents for detecting or localizing specific sequences in
`chromosomes. cells. tissue sections and blots [emphasis added].
`Further, Langer et. al. states at column 6637, lines 1-5 that,
`"Our studies have led to tJre development of a
`rapid method of gg.It3- mapping by in situ
`hybridization that uses rabbit antibiotin antibody
`and fluorescein-labeled goat anti-rabbit IgG to
`identif,v the loci of hybridized Bio-DNA probes . . .
`" [emphasis addedl.
`
`Quite clearly, I"anger's in-situ hybridization method as set
`forth on page 6637 hereinabove, while it is performed on non-
`porous solid supports that are transparent or translucent, has to be
`limited to the generation of a localized signal. In fact, Langer et. al.
`states on page 6633, lines 14-17 that,
`
`"The specificity and tenacity of the biotin-avidin
`complex has been exploited to develop methods
`for the visual localization of specific proteins,
`lipids and carbohydrates on or within
`cells."[emphasis added].
`
`By way of contrast, Applicants' signal is not localized, nor is it
`a precipitate, but it is required to be detected in a liquid media.
`The signal as taught by Langer is required to be a precipitate, or
`localized within the confinement of a cellular or chromosomal
`structure, which is completely different from Applicants' invention.
`In view of Langer's clear failure to disclose the two aforementioned
`material elernents of Applicants' invention, it is submitted that
`Langer et. al. cannot reasonably be held to anticipate the instant
`invention.
`
`Finall5t, Applicants submit that even if Langer et. al. \Mere to be
`combined with other prior art references, it would not have
`rendered the instant invention obvious at the time it was made.
`
`Enz-7(CIP)C2
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`Page 7 of 12
`
`

`
`Jannis G. Stawial.rpoulos et al.
`Serial No.: 07 /607,347
`Ftled: October 30, 1990
`Page 8 6mendment Under 37 C.F.R. S1.115 - Septembet 27, l99Il
`
`In light of the remarks presented above, Applicants
`respectfully request reconsideration and withdrawal of the
`antcipation reJection of claims 27'31based upon Langer et. al.
`
`The Reiectton Under 85 U.S.C. Sectlon QlO2fql
`
`The Examiner has reJected claim 32 under 35 U.S.C. S1O2(e)
`as being anticipated by Ranki et. al. In the Office Action (page a),
`the Examiner stated:
`"Ranki et. al. reads on the instant claim in that a
`sandwich hybridization assay kit is disclosed where the
`probe has -a biotin chemical label, A biotin labelled
`irobe is disclosed in column 3, lines 18-22. A soluble
`signat can be generated via biotin."
`
`This ground of rejection is respectfully traversed'
`
`As set forth below, it is submitted that Ranki et. al. neither
`discloses or suggests the instant invention, aS specifically claimed
`in claim 32. Accordin$ to this claim, a sandwich hybndizatton assay
`kit is disclosed in which a polynucleotide or oligonucleotide
`sequence is detected via a probe which has a chemical label
`comprising a signalling moiety capable of generating a soluble.
`signal, and a particular sequence in single-stranded form, is
`indirectly bound to a solid support by sandwich hybridization, and
`capable of hybridizing to the probe. Support for the instant claim is
`presented in the specification at page lO, lines 12-17.
`
`The instant invention clearly is a departure from the prior
`art. According to the invention, a soluble signal is generated using
`utr'ry one of a number of signal generating systems in any number of
`different formats, an example of which is set forth in instant claim
`32. The soluble signal which is generated is detected by various
`techniques, including spectrophotometric techniques.
`
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`Page 8 of 12
`
`

`
`Jannis G. Stawiar.spoulos et al.
`Serlal No.: OT /60T,347
`Ffled: October 30. 1990
`Page 9 (Arnendment Under 37 C.F.R. St.t15 - September 22, t99ll
`
`Ranki et. al., by way of contrast, discloses a kit and a method
`for the detection of nucleic acids using a one-step sandwich
`hybridization technique [emphasis added]. This technique
`requires the simultaneous addition of two purified nucleic acid
`reagents for each target to be identified [emphasis addedl. The
`reagents are two distinct single-stranded nucleic acid fragments
`isolated from the genome of the microbe to be identifted, which
`fragments have no extensive sequence homologr in common. One
`of t.}.e nucleic acid fragments is affixed onto a solid carrier. Suitable
`solid carriers, in accordance with Ranki, are nitrocellulose sheets
`or conventional modified paper, such as nitrobenzoylorcymethyl
`paper. The only limitation on the solid carrier is that it must be
`capable of affixing nucleic acids in single-stranded form such that
`the single-stranded gucleic acids are available to hybridize \Mith
`complementary nuclejic acids and that the carrier must be easil]r
`removed from the hlrbridization mixture [emphasis added]. The
`other fragment, also in single-stranded form is labelled urith
`radioisotopes, such as 1251 and 32P, fluorochromes, chromogens
`and enzymes. After the sample nucleic acids to be identified are
`rendered single-stranded, they are contacted with single-stranded
`nucleic acid reagents. All the filters. which are porous, non-
`transparent, non-translucent matrices, in the reagent combination,
`can be added to the sample simultaneously, along with the labelled
`nucleic acid reagents lemphasis added]. Ranki specifically
`describes the attachment of,the DNA to the filters, i.e., solid
`carriers, in column 5, lines 46-68, and column 6, lines l-2.
`According to Ranki, annealing of complementary base pairs results
`in the formation of double-stranded hybrids, i.e., nucleic acid
`sample/labelled reagent and nucleic acid sample/reagent affixed to
`the solid carrier, which in Ranki's disclosure are filters. After this
`hybridization step has taken place, the solid carriers are removed
`and their labelling on the washed carriers is measured.
`
`Enz-7(CIPICZ
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`Page 9 of 12
`
`

`
`Jannis G. Stawiar"uPoulos et al.
`Serial No.: OZ /607:347
`Ffled: October 30, 1990
`Page ]Q (Amendment Under 37 C.F.R. S1.1 15 - September 27 , L99I)
`
`In order to sustain a reJection for anticipation, a reference
`cited must disclose all the material elements of a claimed
`invention. It is submitted that for the instant invention, the
`anticipation rejection should be withdrawn because Ranki et' al'
`fails to disclose at least two material elements of the claimed
`invention. The first element not disclosed by Ranki et. al. is the
`generation of a soluble signal within his detection system'
`secondly, unlike the instant case, there is no teaching in Ranki of
`tl.e use of a solid support to which nucleic acid sequences are fixed
`for the generaton of a si$nal within the hybridization vessel which
`is transparent or translucent. In fact, Ranki et. al' specifically
`teaches away from the instant invention in his requirement that the
`solid carrier, which is comprised of filters, be removed from the
`hybridization mixture prior to measuring the si$nal.
`
`For the following reasons, it is submitted that Ranki et' al'
`does not anticipate the instant invention. Unlike the instant
`invention, Ranki does not mention or even suggest the possibility
`of generating a soluble signal. In fact, a soluble signal could not be
`generated using Ranki's method. A liquid media generating signal
`cannot be contained within a porous matrix (filter)' Clearly' Ranki's
`requirement, as set forth in column 7, lines 27-29, for the removal
`of the solid carrier from the hybridization vessel, is in direct
`contrast to the instant invention in which the solid carrier is an
`integral component of the non-porous transparent or translucent
`system which serves as the hybridization vessel in which the
`soluble signal is generated. By way of contrast, there is no
`suggesuon or teaching in the reference of the generation of a signal
`in solution as taught by Applicants. clearly, Applicants' signal must
`be read ln solution, while Ranki's si$nal is read after the solid
`earrler ls removed.
`
`Finally, Applicants submit that even if Ranki et. al. were to be
`combined with other prior art references, it would not have
`rendered the instant invention obvious at the time it was made'
`
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`Page 10 of 12
`
`

`
`Jannis G. Stawla poulos et al.
`Sertal No.: 07 /60'r ,347
`Filed: October 30, t99O
`Page 1 1 (Amendment Under 37 C.F.R. S1.115 - September 27, l99I)
`
`Finally, Applicants submit that even if Ranki et. al. were to be
`combined with other prior art references, it would not have
`rendered the instant invention obvious at the time it was made.
`
`In light of the remarks presented above, Applicants
`respectfully request reconsideration and withdrawal of the
`anticipation rejection of claim 32 based on Ranki et. al.
`
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`Page 11 of 12
`
`

`
`Jannis G. Stawiarropoulos et al.
`Serlal No.: OT /607,347
`Filed: October 30, l99O
`Page 12 (Amendment Under 37 C.F.R. S1.115 - September 27, 19911
`
`SUMMARY AND CONCLUSIONS
`
`Claims 27-32 are presented for further examination. C1aims
`33-35 have been added by this Amendment. No new matter has
`been added by any of the new claims, amendments to the claims, or
`to the specification.
`
`This Amendment is accompanied by a request for a Three-
`Month Extension of Time. The Patent and Tfademark Office is
`hereby authorized to charge Deposit Account No. O5-f 135 for the
`requisite fee of $730.00, as set forth in 37 C.F.R. Sf .17(c). The
`Patent and Trademark Office is further authorized hereby to charge
`Deposit Account 05-1135 for any other fees required in connection
`urith this Amendment and to credit any overpayment thereto.
`
`In view of the above amendments and discussion of the
`issues, Applicants respectfully submit that each of claims 27-35 are
`in condition for allowance. A favorable and speedy reconsideration
`of their reJection is requested. If any of these claims are found not
`to be in condition for allowance for any reason, the Examiner is
`respectfully requested to telephone the undersigned at (212) 924-
`5409 to discuss'the subject application.
`
`Respectfully submitted
`
`ENZO DI.AGNOSTICS, INC.
`e/o F;nzo Btochem, Ine.
`6O Executive Boulevard
`Farmingdale, NY f 1735
`(2121 924-54A9 or (2r2) 924-9578
`
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`Page 12 of 12