throbber
iIN THE UNITED STATES PATENT AND-TRADEMARK OFFICE
`
`CERTIFICATE OF MAILING
`
`I hereby certify that this RESPONSE TO OFFICE ACTION is being deposited with the United States
`Postal Service on the date indicated below with sufficient postage as First class Mail in an envelope
`addressed to: Commissioner of Patents and Trademarks, Washington, D.C. 20231.
`
`Donald G. Lewis, R g. 28,636
`
`Date d
`
`e"posit
`
`Title:
`
`Encoded Combinatorial Chemical Libraries
`
`Inventors: Richard Lerner, Kim Janda, and Sydney Brenner
`
`Filed:
`March 30, 1992
`Serial No.: 07/860,445
`Examiner:
`Campbell, E.
`
`Art Unit:
`
`1807
`
`Commissioner of Patents and Trademarks
`Washington, D.C. 20231
`
`Sir:
`
`Response to Office Action
`
`Responsive to the Office Action, dated 02/22/1994, please
`enter the following amendments:
`Amendments
`
`1.
`
`In the Claims:
`Please cancel claims 2-6, -10, 2- 6, and 1 without
`prejudice.
`Please amend claims , 7-8, 17, 19, and 23 as follows:
`(Twi e amended) A bifunctional molecule according to the
`form a -B-C, wherein A is a polypeptide [biochemical
`po
`B is a linker molecule operatively linked to A and
`C, a
`i an identifier oligonucleotide comprising a
`seq enc of nucleotides which [sequence] encodes and
`identifi s [the structure of biochemical polymer] said
`olv eti e A.
`
`060 KK 08/22/94 07860445
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`1117
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`840.00 CK
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`1
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`Page 1 of 17
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`ILMN EXHIBIT 1044
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`SCRF 293.0
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`7. The ifunctional molecule of claim 1 [2] wherein said
`identifier oligonucleotide C [has a nucleotide sequence
`accor ing to the formula P1-(Z,),-P2, where P1 and P2 are
`nucleo ide sequences that provide] includes PCR primer
`bindin sites adapted to amplify [the polymer] said
`identif er oligonucleotide C.
`
`8. The b fun
`al molecule of claim 7 wherein said [P1 and P2
`each o
`'a sequence that defines] identifier
`olion
`cle ti2e C, when incorporated into a PCR-amplified
`rovides [a] restriction endonuclease
`du lex DNA ra ent
`sites [site
`when present in a PCR-amplified duplex DNA
`fragment] fo removing said PCR primer binding sites from
`said identifi r oligonucleotide C by restriction
`endonuclease leavage,
`
`G'
`
`1/
`
`17. The j1brary of claim 11 wherein each of said species of
`bifu
`'al
`molecules in said plurality is present in a
`relat e equivalent [molar equivalents] of from 0.2 to 10.0,
`relati
`to an average amount of each species within the
`library.
`
`A method for identifying a biochemical polymer [chemical
`structure] that participates in a preselected binding
`interaction with a biologically active molecule to form a
`binding reaction complex, the method [, said chemical
`structure being present in a library of bifunctional
`molecules according to claim 11,] comprising the steps of:
`Al providing a library of bifunctional molecules: each
`bifunctional molecule having the formula A-B-C. wherein
`A is the biochemical polymer, B is a linker molecule
`operatively linked to A and C, and C is an identifier
`oligonucleotide comprising a sequence of nucleotides
`
`3)
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`
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`Page 2 of 17
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`

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`SCRF 293.0
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`which encodes and identifies the biochemical polymer A;
`then
`bi [a)] admixing in solution said library of bifunctional
`molecules of said step (a) with the biologically active
`molecule under binding conditions for a time period
`sufficient to form the [a] binding reaction complex;
`then
`cI [b)] isolating the binding reaction complex formed in
`said step (b) [step (a)]; [and] then
`amplifying the identifier oligonucleotide C of the
`bifunctional molecule within the binding reaction
`complex isolated in said step (c) by means of PCR; and
`then
`el [c) determining the nucleotide sequence of] sequencing
`and decoding the identifier oligonucleotide C amplified
`in said step (d) [and thereby] for identifying the
`biochemical polymer [chemical structure] that
`participated in the preselected binding interaction.
`
`dl
`
`&
`
`wherein [said determining] said step
`The method of claim
`dj comprises the following substeps [steps of]:
`i) amplifying the identifier oligonucleotide C isolated in
`said step (c) by [forming] a polymerase chain reaction
`(PCR) [amplification product from the sequence of the
`isolated identifier oligonucleotide]; and then
`ii) [determining the sequence of] sequencing and decoding
`the PCR amplification product of said substep i[,
`thereby determining the sequence of the identifier
`oligonucleotide] for identifying the biochemical
`polymer that participated in the preselected binding
`interaction.
`
`- I
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`1
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`Irt
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`I I" 1
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`r
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`!}r
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`Page 3 of 17
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`Please add the following additional claims, i.e., claims 27-
`
`33:
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`SCRF 293.0
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`27. T e bifunctional molecule of claim 1 wherein said
`po peptide A has a length of from'4 to 50 amino acid
`res dues.
`
`28. The b'functional molecule of claim 27 wherein said
`identi fier oligonucleotide C has from 8-400 nucleotides.
`
`29. The bif nctional molecule of claim 1 wherein said
`polypept de A has a length of from 3 to 8 amino acid
`
`30.
`
`31.
`
`claim 29 wherein said
`has from 6-64 nucleotides.
`
`claim 29 wherein
`otide C employs hexanucleotides
`id residue within said
`
`32. The bifunctional molecule of claim 1 wherein
`said identifie oligonucleotide C employs non-biological
`codons for e coding said polypeptide A.
`
`33. The bifunctional m ecule of claim 1 wherein
`said bifunctional olecule is water soluble and unattached
`to any bead.
`
`_
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`_
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`_ ._ ~_
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`_ LI
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`_
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`I _ __ __ __L_
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`Page 4 of 17
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`SCRF 293.0
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`Remarks
`Applicant thanks the Examiner for withdrawing the deposit
`requirement, for withdrawing the utility rejection of claims 1-23
`under 35 U.S.C. § 101, for withdrawing the rejection of claims 1-
`3 and 7-23 under 35 U.S.C. 112, second paragraph, pertaining to
`the use of the terms "chemical moiety", "biologically active
`molecule", "isolating the complex", and "binding means", and for
`withdrawing the rejection of claims 1-23 under 35 U.S.C. 103 as
`obvious over Lam in view of Scott.
`Examiner's rejection of claim 9 under 35 U.S.C. 112, second
`paragraph pertaining to the use of the term "proximal to" is
`obviated by Applicant's cancellation of claim 9.
`In the Office Action dated 05/06/93, there was an election
`of species requirement with respect to claim 4. Claim 4 has been
`canceled. However, Applicant herein elects the species directed
`to polypeptides. Claim 1 has been amended to reflect this
`election.
`Only two outstanding issues remain, viz.:
`1. Claims 1-23 are rejected under 35 U.S.C. 103 on new
`grounds as obvious over Lam in view of Scott and
`further in view of references by Warren, Dattagupta,
`and Mullis; and
`2. Claims 1-23 are rejected under 35 U.S.C. 112, first
`paragraph, on the basis that the specification does not
`enable the recited claims.
`
`Rejected under 35 U.S.C. S103 for Obviousness:
`Claims 1-23 are rejected under 35 U.S.C. §103 as obvious
`over Lam in view of Scott and further in view of references by
`Warren, Dattagupta, and Mullis.
`Applicant respectfully
`traverses this rejection.
`The invention is directed to encoded combinatorial libraries
`
`
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`Page 5 of 17
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`

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`SCRF 293.0
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`comprising a plurality of bifunctional molecules and to protocols
`for screening such encoded combinatorial libraries.
`Lam discloses bead linked peptide libraries; Scott discloses
`phagemid libraries; Warren discloses enzyme labelled
`oligonucleotides employable for identifying hybridization
`products; Dattagupta discloses a signal amplification system for
`immunoassays using DNA as a scaffolding for fluorescent probes;
`and Mullis discloses PCR.
`The bead linked peptide libraries disclosed by Lam are of a
`type in which each bead includes only one species of peptide,
`i.e., a one bead, one peptide. Bioactive peptides are visually
`identified after binding to a soluble fluorescent labeled
`acceptor. Labelled beads so identified are isolated by manual
`extraction from the library. The amino acid sequence of peptides
`attached to extracted beads is determined by conventional
`microsequencing techniques. Accordingly, Lam teaches away from a
`need for encoded combinatorial libraries since his protocols for
`isolating fluorescent beads and microsequencing the peptides
`thereon obviate any need for encoding the peptides.
`Bifunctional molecules of the present application are
`soluble and unattached to beads except during synthesis. After
`being synthesized on beads, the bifunctional molecules of the
`present application are detached from such beads so as to form a
`library of soluble bifunctional molecules. Libraries of soluble
`bifunctional molecules can be panned against immobilized
`acceptors. Lam's bead library can not.
`Scott discloses a library of filamentous phage particles
`wherein each phage particle encodes and displays one species of a
`peptide library, i.e., one phage particle, one peptide.
`Bioactive peptides are isolated and identified by panning the
`phage library against immobilized acceptors. Isolated phage
`particles displaying bioactive peptides are cloned so as to
`amplify the peptide gene. The amplified peptide gene is then
`
`
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`Page 6 of 17
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`SCRF 293.0
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`isolated and sequenced so as to identify the bioactive peptide.
`The peptide genes encompassed by Scott's phage particle library
`employs conventional biological triplet codons only.
`Neither Lam nor Scott enables a bead based synthesis of a
`bifunctional molecule having a peptide linked to an identifier
`oligonucleotide. In particular, neither Lam nor Scott discloses
`a DNA/peptide linkage unit and the coupling and decoupling of
`such linkage unit with respect to a bead.
`In contrast, the present application discloses the coupling
`and decoupling of a linkage unit identified as 5' Branched-
`Modifier C3 or 5'BMC3 to a bead and the use of this linkage unit
`for sequentially synthesizing peptides and identifier
`oligonucleotides in an alternating fashion, i.e., each addition
`of an amino acid to the peptide is followed by the addition of a
`corresponding set of nucleotides to the identifier
`oligonucleotide for encoding such amino acid. The process may
`then be-repeated as desired, beginning with the addition of
`another amino acid to the peptide etc. This method of
`alternating synthesis for peptide/nucleotide conjugates appears
`to be novel and patentably unobvious.
`Warren discloses a linkage unit for linking an enzyme label
`to DNA. The resultant conjugate is employable for identifying
`DNA hybridization products. However, Warren does not disclose
`whether his linkage unit is capable of coupling and decoupling to
`a bead. However, his DNA/enzyme conjugate would be inoperable as
`a hybridization probe if the linkage unit were coupled to a bead.
`Additionally, Warren discloses only a DNA/enzyme conjugation
`reaction and does not teach a bead based method of alternating
`chemistries for synthesizing libraries of encoded peptides.
`Moreover, Warren teaches away from the invention of the present
`application since he teaches that the oligonucleotide must have a
`sequence complementary to its hybridization target. In
`particular, the oligonucleotide of Warren's conjugate must have
`
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`Page 7 of 17
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`,SCRF 293.0
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`one sequence only and, accordingly, is specifically incapable of
`encoding a combinatorial library.
`Furthermore, Warren teaches
`away from the invention of the present application since he
`teaches that the enzyme attached to the oligonucleotide serves,
`in the presence of substrate, to label the oligonucleotide and
`accordingly can not serve as a polypeptide library.
`Dattagupta discloses a linkage unit for linking DNA to
`Protein A or IgG, wherein the DNA serves as a scaffold for
`multiple fluorescent labels. Dattagupta's DNA/protein conjugate
`is employable as a signal amplification system. The protein (IgG
`or Protein A) binds to a target receptor; the DNA serves as a
`fluorescent signal. For example, the conjugate may be employed
`to amplify the signal arising from an immunoassay. However,
`Dattagupta does not disclose whether his linkage unit is capable
`of coupling and decoupling to a bead. However, his DNA/protein
`conjugate would be inoperable as a immunoassay signal amplifier
`if the linkage unit were coupled to a bead. Additionally,
`Dattagupta discloses only the conjugation of DNA with protein and
`does not teach a bead based method of alternating chemistries for
`synthesizing libraries of encoded peptides. Dattagupta teaches
`away from the invention of the present application since he
`teaches that the oligonucleotide is chemically modified to serve
`as a scaffold for fluorescent labels. More particularly,
`Dattagupta's chemically modified oligonucleotide is incapable of
`encoding a polypeptide library. Furthermore, Dattagupta does not
`disclose the alternating chemistries which enable the synthesis
`of a bifunctional molecule. And finally, Dattagupta teaches away
`from the invention of the present application since he teaches
`that the protein attached to the oligonucleotide must be a single
`ligand capable of binding to a receptor and accordingly can not
`serve as a library.
`Even if an identifier oligonucleotide were added to Lam's
`peptide, no reference enables the isolation, amplification,
`
`
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`Page 8 of 17
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`

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`SCRF 293.0
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`and/or identification of such identifier oligonucleotide. Scott
`discloses the use of viral expansion for amplifying identifier
`oligonucleotides incorporated into fusion genes. However,
`Scott's method of viral expansion is inapplicable as a means for
`expanding the identifier.oligonucleotides on bifunctional
`molecules of the present application. Mullis discloses the basic
`PCR technology. However, none of the other cited references,
`i.e., Lam, Scott, Warren, and Dattagupta, disclose identifier
`oligonucleotides capable of PCR amplification since none of these
`references disclose the incorporation of PCR primer sites into
`such identifier oligonucleotides. In contrast, the present
`application discloses the incorporation of PCR primer sites into
`identifier oligonucleotides and the use of PCR for amplifying
`such oligonucleotides.
`None of the cited references, i.e., Lam, Scott, Warren, and
`Dattagupta, provides motivation for adding an identifier
`oligonucleotide to Lam's peptide, i.e., there is no teaching that
`an addition of an identifier oligonucleotide to Lam's peptide
`would enhance the utility of such product. Indeed, there is a
`possibility that an addition of oligonucleotides to the bead
`could interfere with the sensitivity of Lam's microsequencing
`protocol for identifying the peptide attached thereto.
`None of the cited references, i.e., Lam, Scott, Warren, and
`Dattagupta, provides motivation for eliminating Lam's bead.
`Indeed, Lam teaches away from the elimination of the bead since
`Lam teaches that the bead is essential for panning, i.e., the
`bead is required for fluorescent labelling and visualization and
`for manual extraction from the library.
`The panning methods disclosed by Lam and Scott are
`incompatible with one another, i.e., Lam pans against soluble
`acceptors and Scott pans against immobilized acceptors.
`Accordingly, Lam and Scott each teach away from any combination
`with the other. Furthermore, neither reference discloses a
`
`
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`Page 9 of 17
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`

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`SCRF 293.0
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`method for panning a library using a PCR amplification step as
`specified in amended claim 19.
`In summary, the cited prior art does not render the present
`application obvious for reasons which include the following:
`1. The cited prior art does not enable a bead based
`alternating synthesis of a peptide linked to an
`identifier oligonucleotide for forming a library of
`bifunctional molecules;
`2. Even if a library of bifunctional molecules having
`peptides linked to identifier oligonucleotides were
`provided, the cited prior art does not enable the
`isolation, amplification, and/or identification of such
`identifier oligonucleotides;
`3. None of the cited prior art references provides
`motivation to link a peptide with its identifier
`oligonucleotide;
`4. None of the cited prior art references teaches or
`motivates the coupling and decoupling of the linkage
`unit of a bifunctional molecule to and from a bead;
`5. Lam teaches away from an decoupling of his peptide from
`his bead since he teaches that the bead is essential
`for panning the peptide;
`6. The panning methods of Lam and Scott are incompatible,
`i.e., Lam pans against soluble acceptors and Scott pans
`against immobilized acceptors; and
`7. None of the cited prior art references discloses a
`method for panning a library using a PCR amplification
`step as specified in amended claim 19.
`
`Moreover, the cited prior art references teach away from the
`invention of the present application; the cited references are
`incompatible with one another and therefor can not be combined;
`the cited references fail to enable the claimed invention; none
`
`
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`Page 10 of 17
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`

`
`of the cited references discloses either a bead linked
`
`DNA/peptide linkage unit or a synthetic method of alternating
`chemistries for enabling the synthesis of a library of
`bifunctional molecules onto such linkage unit.
`
`SCRF 293.0
`
`Rejected under 35 U.S.C. §112, first paragraph:
`Claims 1-23 are also rejected under 35 U.S.C. §112, first
`paragraph, on the basis that they are not enabled by the
`specification. Applicant respectfully traverses this rejection.
`The scope of the enablement requirement has changed in view
`of Applicant's election of species. Since the compound claims
`have been narrowed by amendment to include only bifunctional
`molecules incorporating peptide polymers, the enablement
`requirement now covers such compounds only.
`The chemical literature cited in an Information Disclosure
`Statement, filed herewith, supports the operability the synthetic
`protocols disclosed on pages 50-61 of the Specification of the
`present application, i.e., a person of ordinary skill in the art
`can follow the disclosed synthetic protocol to produce the
`claimed molecules without resorting to undue experimentation.
`The specification discloses the use of a key linker molecule (5'
`Branched-Modifier C3 or 5'BMC3) and a method for coupling this
`linker molecule to teflon beads. (Specification, page 53, lines
`5-28.) The scientific name for 5'BMC3 is l-dimethoxytrityloxy-3-
`fluorenyl methoxycarbonylamino-propan-2yl)-(2-cyanoethyl)-(N,N-
`diisopropyl)-phosphoramidite. The Specification also discloses a
`method employing the teflon bead-coupled 5'BMC3 linker molecule
`for synthesizing a bifunctional molecule which incorporates a
`peptide and an identifier oligonucleotide encoding such peptide.
`The linker molecule 5'BMC3 was first described by Paul
`Nelson in Nucleic Acids Research (1989), vol. 17 (18), p. 7179-
`
`
`
`Page 11 of 17
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`i
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`N\
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`SCRF 293.0
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`7194 (see page 7180, compound 1). A second Nelson reference
`discloses that a precursor of 5'BMC3 can be coupled to pore glass
`beads (CPG) and employed as a bifunctional reagent employed for
`solid phase oligonucleotide synthesis and for introducing a free
`primary amine at the 3' end of oligonucleotide synthesized
`thereby. (Paul Nelson et al., Nucleic Acids Research (1992), vol.
`20 (23), pp 6253-6259.) This second Nelson reference also
`discloses that the free primary amine introduced at the 3' end of
`the oligonucleotide may be employed for conjugating amine-
`reactive labels to the oligonucleotide via the linker molecule,
`e.g., biotin esters, fluorophores, etc.. In a subsequent patent,
`i.e., U.S. Patent No. 5,141,813 (Aug. 25, 1992), Nelson discloses
`that the free primary amine on the linker molecule can also be
`employed for conjugating oligonucleotides to proteins:
`"Also, the subject invention can be used for
`attaching a label to a functional group introduced
`at the 3' terminus of a synthetic oligonucleotide.
`Labels include any reporter molecules such as
`biotin, haptens, fluorophores, proteins, enzymes,
`and antibodies. Such modified and labeled
`oligonucleotide probes can be used in any
`application where the said probe hybridizes to
`complementary sequences of a target
`polynucleotide." (Nelson, U.S. Patent No.
`5,141,813, col. 3, lines 47-54)
`Clontech Laboratories, Inc., the assignee of the above
`Nelson patent, has marketed 5'BMC3 in the past and currently
`markets a slightly improved version of 5'BMC3, under the trade
`name Unilink AminoModifier, having an extended alkyl spacer arm
`for the Fmoc group. Sales literature for Clontech Laboratories'
`Unilink AminoModifier is included in the Information Disclosure
`Statement filed herewith.
`The above Nelson references confirm the operability of the
`
`
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`Page 12 of 17
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`..
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`.. . ..... ... ..
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`..... .' ' ,
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`SCRF 293.0
`
`5'BMC3 linker molecule employed in the present application, i.e.,
`Nelson confirms that, when 5'BMC3 coupled to a bead, it is
`compatible with automated DNA synthesizers and that peptides can
`be conjugated to the DNA (oligonucleotides) via the free primary
`amine on the linker molecules. Nelson also confirms the
`operability of the alternating chemistries employed in the
`present application in connection with the simultaneous synthesis
`of peptides and oligonucleotides on the linker molecule, i.e.,
`Nelson confirms the compatibility of the linker molecule's DMT-O
`protective group with automated peptide synthesis and the
`compatibility of the linker molecule's Fmoc protective group with
`automated DNA synthesis. In short, Nelson confirms the
`operability of the linker molecule of the present application for
`synthesizing oligonucleotide/peptide conjugates.
`.Nelson also evidences by inference, that, if the reactivity
`of the disclosed linker molecule is inhibited by steric
`hinderance, such steric hinderance does not render the linker
`molecule inoperable with respect to its intended purpose.
`Examiner offers the following basis in support of the
`enablement rejection:
`"With regard to these factors cited above [i.e., Ex
`parte Forman], the quantity of experimentation needed
`to determine the chemistry involved in the synthesis of
`the claimed bifunctional molecules without sterically
`hindering their reactive surfaces for which the instant
`invention is applicable has not been provided adequate
`guidance in the written description." (Office Action,
`Paper #13, page 4, paragraph 20, lines 18-24.)
`
`Applicant objects that Examiner is using an improper
`standard of enablement. Examiner appears to require not only
`that the specification provide a disclosure which enables a
`person of ordinary skill in the art to synthesize the claimed
`
`
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`SCRF 293.0
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`compounds without undue experimentation, but also that the
`disclosed synthesis be able to be practiced "without sterically
`hindering reactive surfaces for which the instant invention is
`applicable." Applicant asserts that this is an improper
`standard. Applicant asserts that a showing of practical
`operability is sufficient and that there is no obligation to
`demonstrate a complete absence of steric hinderance at reactive
`surfaces.
`In conclusion, the above references by Nelson independently
`verify the operability of the synthetic methods employed in the
`present application and prove that undue experimentation is not
`required to synthesize the claimed compounds.
`Applicant respectfully submits that claims 1, 7-8, 11, 17,
`19-23 and 27-33 are enabled by the Specification and are
`patentably unobvious over the prior art. Applicant requests that
`the Examiner enter the amendments indicated above and issue a
`Notice of Allowance with respect to the newly amended claims.
`
`Respectfully submitted,
`
`Donald G. Lewis
`Reg. No. 28,636
`The Scripps Research Institute
`10666 N. Torrey Pines Road TPC-8
`San Diego, CA 92037
`August 8, 1994
`(619) 554-2937
`
`
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`Page 14 of 17
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`

`
`r
`
`sik4
`
`INSu
`'ga94
`
`l
`
`y,
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`,:.-
`CERTIFICATE OF MAILING
`I hereby certify that this INFORMATION DISCLOSURE STATEMENT and the documents referred to as
`enclosed therein are being deposited with the United States Postal Service with sufficient postage as First
`Class Mail in an envelope addressed to: Commissioner of Patents and Trademarks, Washington, D.C. 20231 on
`the date written below.
`
`Donald G. Lekis, Fg. No. 28,636
`
`Dae f Dekosit
`
`Applicant: Lerner, et al.
`
`Serial No: 07/860,445
`
`Filed: March 30, 1992
`
`For: ENCODED COMBINATORIAL
`CHEMICAL LIBRARIES
`
`) Group Art
`)
`Unit :
`
`1807
`
`) Examiner: E. Campbell
`
`) Our Ref.: SCRF 293.0
`
`SUPPLEMENTAL
`INFORMATION DISCLOSURE STATEMENT
`
`Honorable Commissioner of
`Patents and Trademarks
`Washington, D.C. 20231
`
`Sir:
`
`In recognition of their continuing duty to disclose pursuant
`to 37 CFR 1.56, Applicants hereby submit the present Supplemental
`Information Disclosure Statement and accompanying PTO Form 1449
`in compliance therewith. Copies of the references cited therein
`are also enclosed.
`Applicants understand that the interpretation given to each
`reference may differ from one individual to another. The PTO is
`therefore encouraged to independently examine the disclosed
`references. While the references provided in this Supplemental
`Information Disclosure Statement may be material pursuant to 37
`CFR 1.56, it shall not be construed to be an admission that the
`cited information is, or is considered to be, material to
`patentability unless specifically designated as such.
`
`060 KK 08/22/94 07860445
`
`S126
`
`200.00 Ch
`
`
`
`Page 15 of 17
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`,id'ti
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`Serial No. 07/860,445
`
`SCRF 293.0
`
`Applicants are filing the present statement pursuant to 37
`CFR 1.97 (c), and therefore is accompanied by Check No. 918 in
`the amount of $200.00 as payment of the fee set forth in 37 CFR
`§1.17 (p).
`Also, in accordance with 37 CFR 1.97 (g), the filing of this
`Supplemental Information Disclosure Statement shall not be
`construed to mean that a search has been made or, that if made,
`any search was complete or exhaustive, or that no other material
`information as defined in 37 CFR 1.56 exists.
`
`Respectfully submitted,
`
`Dated:
`
`(t
`
`, (rcL4
`
`By
`
`Donald G. Lewis
`THE SCRIPPS RESEARCH INSTITUTE
`Office of Patent Counsel
`10666 North Torrey Pines Road
`Mail Drop TPC-8
`La Jolla, CA 92037
`(619) 554-2937
`
`LB\C: \WP\IDS\SCR1112.IDS
`
`
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`Page 1 of 1
`
`FORM PTO-1449' U.S. DEPARTMENT" OF COMMERCE
`PATENTAND TRADEMARK OFFICE
`
`ATTY DOCKET NO.
`SCRF 293,0
`
`SERIAL NO.
`07/860,445
`
`/
`
`INFORMATION DISCLOSURE
`STATEMENT BY APPLICANT
`
`APPLICANT
`Lerner, et at.
`
`FILING DATE
`March 30, 1992
`
`GROUP
`1807
`
`EXAM.
`INITIALS
`
`DOCUMENT
`NUMBER
`
`DATE
`
`NAME
`
`CLASS
`
`SUB-
`CLASS
`
`FILING
`DATE
`
`5,141,813
`
`8/25/92
`
`Nelson
`
`4Z
`
`L 2.
`
`U.S. PATENT DOCUMENTS
`
`EXAM.
`INITIALS
`
`DOCUMENT
`NUMBER
`
`DATE
`
`COUNTRY
`
`CLASS
`
`SUB-
`CLASS
`
`FILING
`DATE
`
`FOREIGN PATENT DOCUMENTS
`
`OTHER DOCUMENTS (Including Author, Title, Date, Pertinent Pages)
`
`1
`
`2
`
`3
`
`Nelson, et at., Nucleic Acids Research, 17: 7179-7195 (1989)
`
`Nelson, et al., Nucleic Acids Research, 20: 6253-6259 (1992)
`
`"Sales Literatuare" from CLontech Laboratories, Inc., page 3 (1994)
`
`EXAMINER
`
`DATE CONSIDERED
`
`... (2-Q
`EXAMINER: InitiaC f cf'tAfon considered, wh her or not citation is in conformance fith MEP 60I; Draw line through citation if
`not in conformance and
`onsidered. Include copy of this form with next communication to Applicant.
`LB\C:\IDS\SCR11121.449
`
`
`
`Page 17 of 17

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