DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-20 have been cancelled. Claims 21-40 are currently under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The priority date is December 23, 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 19, 2023 is being considered by the examiner. The signed IDS form is attached with the instant office action.
Drawings
The drawings were received on January 19, 2023. These drawings are acceptable.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 37-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No.11,591,629 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are of overlapping scope. The claims of the issued patent are drawn to a method for synthesizing a nucleic acid, comprising: providing an initiator having a 3′ end having an unprotected hydroxyl group; providing a nucleic acid polymerase having at least a conservative catalytic polymerase domain of a family-B DNA polymerase; providing a nucleotide monomer; and exposing the initiator to the nucleotide monomer in the presence of the nucleic acid polymerase and a metal cofactor which is a bivalent cation, and in the absence of a template, such that the nucleotide monomer is incorporated to the initiator, wherein the family-B DNA polymerase is a Thermococcaceae DNA polymerase. The initiator has a sequence selected from a non-self complementary sequence and a non-self complementarity forming sequence. The initiator is linked to a solid support and has a 5′ end linked to the solid support. The solid support is a material selected from the group consisting of a microarray, a bead, a column, an optical fiber, a wipe, nitrocellulose, nylon, glass, quartz, a diazotized membrane, a silicone, polyformaldehyde, cellulose, cellulose acetate, paper, a ceramic, a metal, a metalloid, a semiconductor material, a magnetic particle, a plastic, a gel-forming material, a gel, a nanostructured surface, a nanotube, and a nanoparticle. The initiator is exposed to the nucleotide monomer at a temperature ranging from 10° C. to 90° C. The initiator is exposed to the nucleotide monomer at a pH of not less than 8.0 (see claims 1-14, particularly claims 1-6).
Claims 21-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 17/354,543 (reference application; US 20210317424 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are of overlapping scope. The claims disclose species that overlap for use in the method and in the kit composition. The claims of the copending application are drawn to a method for synthesizing a nucleic acid, comprising: providing an initiator having an unprotected nucleoside base and a 3′ hydroxyl group at a 3′ terminus; providing a nucleic acid polymerase having at least one conservative catalytic polymerase domain of a family-B DNA polymerase; providing at least one nucleotide monomer; and exposing the initiator to the at least one nucleotide monomer in the presence of the nucleic acid polymerase, at a temperature ranging from 20° C. to 90°, and in the absence of a template, such that the at least one nucleotide monomer is incorporated to the initiator to form the nucleic acid. The initiator can be linked to a solid support and has a 5′ end linked to the solid support. The solid support is selected from the group consisting of a microarray, a bead, a column, an optical fiber, a wipe, nitrocellulose, nylon, glass, quartz, a diazotized membrane, a silicone, polyformaldehyde, celluloses, cellulose acetate, paper, a ceramic, a metal, a metalloid, a semiconductor material, a magnetic particle, a plastic, a gel-forming material, a gel, a nanostructure surface, a nanotube, a nanoparticle, and a combination thereof. The nucleotide monomer has a phosphate group comprising a monophosphate, a diphosphate, a triphosphate, a tetraphosphate, a pentaphosphate, a hexaphophate, and a combination thereof. The claims are also drawn to a kit for synthesizing a nucleic acid, comprising: an initiator having an unprotected nucleoside base and a 3′ hydroxyl group at a 3′ terminus; a nucleic acid polymerase having at least one conservative catalytic polymerase domain of a family-B DNA polymerase; and at least one nucleotide monomer; wherein the kit is used through exposing the initiator to the at least one nucleotide monomer in the presence of the nucleic acid polymerase, at a temperature ranging from 20° C. to 90°, and in the absence of a template, such that the at least one nucleotide monomer is incorporated to the initiator to form the nucleic acid. The kit, wherein the initiator is a single stranded nucleic acid. The kit, wherein the nucleic acid polymerase further has a 3′ to 5′ exonuclease domain. The kit, wherein the family-B polymerase is selected from the group consisting of family-B DNA polymerase of Thermococcus kodakaraensis (KOD1), a family-B DNA polymerase of Pyrococcus furiosus (Pfu), and family-B DNA polymerase of Thermococcus litoralis (Vent) (see claims 1-21).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 37-40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zuo et al. (Biochemistry (2011) 50:5379-5390; 1/19/2023 IDS NPL document #1).
Zuo teaches a method for synthesizing a nucleic acid (methods are provided for performing a terminal transferase reaction in a template-independent manner (see Abstract and p. 5380, column 1, lines 21-26), comprising: providing an initiator having a 3’ end having an unprotected hydroxyl group (oligonucleotides comprising only dT or dA nucleotides are provided as an initiator for template-independent synthesis, p. 5382, column 2, lines 24-26 and p. 5388, column 1, lines 19-24); providing a nucleic acid polymerase having at least a conservative catalytic polymerase domain of a family-B DNA polymerase (the B-family DNA polymerase DpoI polymerase of the hyperthermophilic archaeon, Sulfolobus solfataricus was provided for performing the terminal transferase reactions, p. 5380, column 1, last line to column 2, line 2 and column 2, lines 15-20); providing a nucleotide monomer (nucleotides were provided as specified, p. 5380, column 2, lines 15-20 and p. 5382, column 2, lines 24-28); and exposing the initiator to the nucleotide monomer in the presence of the nucleic acid polymerase and a metal cofactor which is a bivalent cation, and in the absence of a template, such that the nucleotide monomer is incorporated to the initiator (in the presence of an initiator such as (dT)20 or (dA)20, the Dpo1 polymerase and a nucleotide, incorporation of the individual nucleotides to the 3’ end of the initiators was observed, p. 5382, column 2, lines 24-47, p. 5388, column 1, lines 19-24), Figure 6A and B and Figure 8).
Zuo teaches a method wherein the initiator has a sequence selected from a non-self complementary sequence and a non-self complementarity forming sequence (the preferred initiators were (dT)20 or (dA)20, p. 5382, column 2, lines 24-26 and Figure 6A and B). Zuo teaches a method wherein the initiator is exposed to the nucleotide monomer at a temperature ranging from 10°C to 90°C (the terminal transferase reactions are performed at 70°C, p. 5380, column 2, lines 15-20). Zuo teaches a method wherein the initiator is exposed to the nucleotide monomer at a pH of not less than 8.0, and wherein the metal cofactor is selected from the group consisting of Mg2+, Ca2+, Sr**, Ba2+, Mn2+, Co2+, Fe2+, Ni2+, Cu2+, Zn2+ and combinations thereof (the terminal transferase reactions are performed using a glycine buffer at pH 8.0 and comprising 5 mM Mg(CH3COO)2 (p. 5380, column 2, lines 15-20). Zuo teaches a method wherein the nucleic acid polymerase further has a 3’ to 5’ exonuclease domain and is a family-B DNA polymerase selected from the group consisting of a bacterial family-B DNA polymerase, a eukaryotic family-B DNA polymerase, an archaeal family-B DNA polymerase, and a viral family-B DNA polymerase, or wherein the 3’ to 5’ exonuclease domain of the family-~B DNA polymerase is inactivated (the polymerase may be wild-type or exonuclease deficient (exo-) Dpo1 of Sulfolobus solfataricus, p. 5380, column 1, last line to column 2, line 2 and column 2, lines 15-20). Zuo teaches a method wherein the initiator is in single-stranded form, and wherein the initiator has at least five nucleotides (the initiator may be a homopolymer such as (dT)20 or (dA)20, wherein detectable TdT activity was obtained using homopolymeric DNA substrates of greater than 10 bases, p. 5381, column 2, last six lines, p. 5382, column 2, lines 24-26 and Figure 6A and B). Zuo teaches a method wherein the nucleotide monomer has a phosphate group selected from a monophosphate, a diphosphate, a triphosphate, a tetraphosphate, a pentaphosphate, and a hexaphosphate (incorporation of nucleotides on the (dT)20 or (dA)20 homopolymer substrates was observed using dATP and dTTP, but not dGTP or dCTP, p. 5382, column 2, lines 24-47).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
If this application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 21-23, and 27-33 are rejected under 35 U.S.C. 103 as being unpatentable over Kalhor et al. (US 2020/0190550 A1) and Milton et al. (US 2019/0352687 A1).
Kalhor teaches a method for adding one or more selected nucleotides to an oligonucleotide initiator having an extendible 3′ terminal nucleotide (i.e. an initiator with a 3’-end having an unprotected hydroxyl group), comprising providing a reaction mixture with the initiator, one or more selected nucleotide triphosphates, and a DNA polymerase which can be Thermococcus litoralis (Vent) DNA polymerase (i.e. a family-B DNA polymerase configured to incorporate the nucleotide monomer to the initiator) ([0007]-[0015]; [0023]-[0031]; [0059]-[0072]). Kalhor teaches that the method comprises adding the nucleotides to the initiator strand in a template-independent manner (e.g., [0007]; [0010]; [0023]).
Kalhor teaches that the DNA polymerase can be Thermococcus litoralis (Vent exo-) DNA polymerase having D141A/E143A mutations that inactivate 3’-5’ exonuclease activity ([0029]).
Kalhor teaches that the nucleotide triphosphates to be added to the initiator can have blocking groups or reversible terminators ([0030]-[0031]).
Kalhor teaches that the reaction can be carried out at a temperature ranging from 10-80 °C, e.g. 37 °C ([0026]).
Claims 21-23, and 27-33 differ from Kalhor in that: the claims are to a kit comprising the initiator, nucleotide monomer, and nucleic acid polymerase having at least a conservative catalytic polymerase domain of a family-B DNA polymerase (claims 21-23, 27, 29-33); and the blocking moiety is a 3’-O-blocking moiety (claim 28).
Milton teaches methods similar to that of Kalhor for extending an oligonucleotide strand in a template-independent manner using a DNA polymerase which can be Thermococcus litoralis (Vent exo-) DNA polymerase (entire doc, including [0007]-[0109]; [0286]). Milton further teaches kits for carrying out the methods, wherein the kits can comprise reaction reagents/materials corresponding to any of the method steps ([0115]; [0377]). Milton also teaches that the nucleotides added during the method can be reversible terminators comprising a 3’-O-blocking group ([0288]-[0305]).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to prepare a kit as taught by Milton for carrying out the oligonucleotide extension method of Kalhor because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to prepare a kit of reagents/materials for carrying out the method of Kalhor in order to provide a commercially available product to enable one to perform the method. Preparing a kit of reagents/materials for carrying out the method of Kalhor would have led to predictable results with a reasonable expectation of success because Kalhor teaches a method utilizing the instantly claimed components, and preparing a kit of such components would require only aggregating/assembling known materials into a single package.
Kalhor teaches that the initiator is formed by providing a first oligonucleotide strand and a second oligonucleotide strand under conditions wherein the strands anneal to form a double stranded oligonucleotide initiator having an extendible end on the first oligonucleotide strand to which the monomer is added (e.g., [0009]-[0015]). It would have thus been obvious in making a kit for carrying out the method of Kalhor to provide as part of the kit a single stranded oligonucleotide initiator (i.e. the first strand) for which the DNA polymerase is configured to incorporate a nucleotide monomer at the 3’-end.
Kalhor teaches that the reversible terminator(s) used in the method are known in the art (Kalhor, [0031]), and it would have been obvious that any such reversible inhibitors known to be useful in similar methods, including those with 3’O-blocking moieties as taught by Milton, could be used in the kit of the cited combination.
The cited combination of Kalhor and Milton teaches a kit having each of the claimed components, including the same Thermococcus litoralis (Vent) DNA polymerase, a nucleotide monomer and a single-stranded oligonucleotide having an unprotected 3’OH group. The claims are drawn to a product which is not limited by its intended use. The cited references make obvious a kit including each of the claimed components, and thus renders the claims prima facie obvious.
Claim(s) 21-36 are rejected under 35 U.S.C. 103 as being unpatentable over Zuo et al. (Biochemistry (2011) 50:5379-5390; 1/19/2023 IDS NPL document #1) and Ybert et al. (US 2019/0264248 A1; 1/19/2023 IDS, Patent Application Publication #1).
Zuo teaches a method for synthesizing a nucleic acid (methods are provided for performing a terminal transferase reaction in a template-independent manner (see Abstract and p. 5380, column 1, lines 21-26), comprising: providing an initiator having a 3’ end having an unprotected hydroxyl group (oligonucleotides comprising only dT or dA nucleotides are provided as an initiator for template-independent synthesis, p. 5382, column 2, lines 24-26 and p. 5388, column 1, lines 19-24); providing a nucleic acid polymerase having at least a conservative catalytic polymerase domain of a family-B DNA polymerase (the B-family DNA polymerase DpoI polymerase of the hyperthermophilic archaeon, Sulfolobus solfataricus was provided for performing the terminal transferase reactions, p. 5380, column 1, last line to column 2, line 2 and column 2, lines 15-20); providing a nucleotide monomer (nucleotides were provided as specified, p. 5380, column 2, lines 15-20 and p. 5382, column 2, lines 24-28); and exposing the initiator to the nucleotide monomer in the presence of the nucleic acid polymerase and a metal cofactor which is a bivalent cation, and in the absence of a template, such that the nucleotide monomer is incorporated to the initiator (in the presence of an initiator such as (dT)20 or (dA)20, the Dpo1 polymerase and a nucleotide, incorporation of the individual nucleotides to the 3’ end of the initiators was observed, p. 5382, column 2, lines 24-47, p. 5388, column 1, lines 19-24), Figure 6A and B and Figure 8).
Zuo teaches a method wherein the initiator has a sequence selected from a non-self complementary sequence and a non-self complementarity forming sequence (the preferred initiators were (dT)20 or (dA)20, p. 5382, column 2, lines 24-26 and Figure 6A and B). Zuo teaches a method wherein the initiator is exposed to the nucleotide monomer at a temperature ranging from 10°C to 90°C (the terminal transferase reactions are performed at 70°C, p. 5380, column 2, lines 15-20). Zuo teaches a method wherein the initiator is exposed to the nucleotide monomer at a pH of not less than 8.0, and wherein the metal cofactor is selected from the group consisting of Mg2+, Ca2+, Sr**, Ba2+, Mn2+, Co2+, Fe2+, Ni2+, Cu2+, Zn2+ and combinations thereof (the terminal transferase reactions are performed using a glycine buffer at pH 8.0 and comprising 5 mM Mg(CH3COO)2 (p. 5380, column 2, lines 15-20). Zuo teaches a method wherein the nucleic acid polymerase further has a 3’ to 5’ exonuclease domain and is a family-B DNA polymerase selected from the group consisting of a bacterial family-B DNA polymerase, a eukaryotic family-B DNA polymerase, an archaeal family-B DNA polymerase, and a viral family-B DNA polymerase, or wherein the 3’ to 5’ exonuclease domain of the family-~B DNA polymerase is inactivated (the polymerase may be wild-type or exonuclease deficient (exo-) Dpo1 of Sulfolobus solfataricus, p. 5380, column 1, last line to column 2, line 2 and column 2, lines 15-20). Zuo teaches a method wherein the initiator is in single-stranded form, and wherein the initiator has at least five nucleotides (the initiator may be a homopolymer such as (dT)20 or (dA)20, wherein detectable TdT activity was obtained using homopolymeric DNA substrates of greater than 10 bases, p. 5381, column 2, last six lines, p. 5382, column 2, lines 24-26 and Figure 6A and B). Zuo teaches a method wherein the nucleotide monomer has a phosphate group selected from a monophosphate, a diphosphate, a triphosphate, a tetraphosphate, a pentaphosphate, and a hexaphosphate (incorporation of nucleotides on the (dT)20 or (dA)20 homopolymer substrates was observed using dATP and dTTP, but not dGTP or dCTP, p. 5382, column 2, lines 24-47).
However, Zuo does not teach a method wherein the initiator is linked to a solid support and has a 5’ end linked to the solid support, wherein the solid support is selected from a microarray, a bead, a column, an optical fiber, a wipe, nitrocellulose, nylon, glass, quartz, a diazotized membrane, a silicone, polyformaldehyde, cellulose, cellulose acetate, paper, a ceramic, a metal, a metalloid, a semiconductor material, a magnetic particle, a plastic, a gel-forming material, a gel, a nanostructured surface, a nanotube, and a nanoparticle, and also does not teach a method wherein the nucleotide monomer has a removable blocking moiety selected from the group consisting of a 3'-O-blocking moiety, a base blocking moiety, and a combination thereof. In addition, Zuo does not teach a method wherein the family-B polymerase is selected from the group consisting of a family-B DNA polymerase of Thermococcus kodakaraensis KODI, a family-B DNA polymerase of Pyrecocus furious (Pfu), and a family-B DNA polymerase of Thermococcus litoralis (VentTM).
Ybert teaches methods for synthesizing nucleic acids of a desired sequence in a template-independent manner comprising the steps of attaching initial nucleic acid fragments to a first support by one end of the fragment, addition of nucleotides to the other end of the fragment using a template-independent DNA polymerase, removal of undesirable reagents from the reaction medium, detaching extended fragments from the support and attaching them to a second support, and repeating the steps to obtain a sequence of the desired length (see paragraphs 32-48 and claim 18).
Ybert teaches that the first and second supports may be two distinct supports, for example, in the form of a glass sheet, a sheet of a polymer material or of beads (paragraphs 54 and 55), wherein the initial fragments are attached by functionalities on their 5’ ends to the support, leaving their 3’ ends free to react with the 5’-OH group of the first nucleotide to be added (paragraphs 60, 68 and 72).
Ybert teaches that the template-independent DNA polymerase may be terminal deoxynucleotidyl transferase, a telomerase, a translesion family of polymerases such as polymerases eta or zeta, or a PNPase (see paragraphs 14, 59 and claim 22).
Ybert teaches that the nucleoside triphosphates may be modified, such as with a reversible 3’-O-protection group and a protected nitrogenous base to prevent multiple additions of nucleotides (paragraph 64 and claims 18, 24 and 26).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to combine the methods of Zuo and Ybert since both references teach methods for template-independent synthesis of nucleic acids using DNA polymerases having terminal transferase activity. While Zuo teaches methods for template-independent synthesis using the B-family DNA polymerase isolated from the archaeal microorganism Sulfolobus solfataricus (p. 5380, column 1, last line to column 2, line 2 and column 2, lines 15-20), Ybert teaches methods for the controlled synthesis of nucleic acids of a desired sequence in a template-independent manner wherein an initial nucleic acid fragment (initiator) is fixed to a solid support (paragraphs 54 and 55), and further teaches the use of modified nucleotide precursors that comprise a reversible 3’-O-protection group to prevent multiple additions of nucleotides during a cycle of synthesis (paragraph 64 and claims 18, 24 and 26). In addition, Ybert teaches that in addition to the use of terminal deoxynucleotidyl transferase (TdT) for performing template-independent synthesis, other enzymes including the B-family translesion enzyme zeta DNA polymerase, may be used in the methods (paragraphs 14, 59 and claim 22). Thus, an ordinary practitioner would have been motivated to combine the methods of Zuo and Ybert since the methods of Zuo could be readily modified by the teachings of Ybert to perform the template-independent synthesis of nucleic acids by attaching the initiators to solid supports such as beads or surfaces or arrays comprising glass or polymers, and using modified nucleotides to control the reaction to generate products of defined length. The solid-phase methods of Ybert make it possible to retain in the reaction medium the fragments of correct sequence in preparation for succeeding cycles of synthesis to achieve products of the desired length, and makes possible the synthesis of products of very high purity, independent of the length and the nature of sequence chosen (see Ybert, paragraphs 49 and 50). Furthermore, it would have been obvious to try other B-family enzymes, including other archaeal polymerases, as Ybert suggests a number of other classes of polymerases may be successful in template-independent synthesis reactions (paragraphs 14, 59 and claim 22). In addition, Zuo suggests there may be a role for enzymes with terminal transferase activity in other archaeal organisms such as Pyrococcus furiosus (Pfu), such as for primase and double-strand break (DSB) repair (see Zuo, p. 5388, column 2, last three lines to p. 5389, column 1, line 34).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to prepare a kit for carrying out the oligonucleotide extension method of Zuo et al. and Ybert et al. because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to prepare a kit of reagents/materials for carrying out the method of Zuo et al. in order to provide a commercially available product to enable one to perform the method. Preparing a kit of reagents/materials for carrying out the method of Zuo et al. would have led to predictable results with a reasonable expectation of success because Zuo et al. teaches a method utilizing the instantly claimed components, and preparing a kit of such components would require only aggregating/assembling known materials into a single package.
Conclusion
No claims are allowed.
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/ANAND U DESAI/Primary Examiner, Art Unit 1656