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 .
DETAILED ACTION
Claims Status
Claims 1-27 and 30-45 are pending.
Applicant’s election without traverse of Group I, claims 1-37, in the reply filed on January 10, 2025 is acknowledged. Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Claims 38-45 were withdrawn without traverse as being drawn to nonelected inventions.
Claims 1-27 and 30-37 are currently under examination.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/09/2026 has been entered.
Priority
The priority date of claim set filed on 01/09/2026, is determined to be 11/15/2021, the effective filing date of the instant application.
Claim Rejections - 35 USC § 103
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.
Claims 1-27 and 30-37 are rejected under 35 U.S.C. 103 as being obvious over Gill et al. (“Gill”, U.S. Patent Pub. No. US 2018/0163254, June 14, 2018; publication of application 15/839,597) in view of Du et al. (“Du”, A simple rapid detection method of DNA based on ligation-mediated real-time fluorescence PCR. The Analyst, 138 (19), 5745–5750) and Baynes et al. (“Baynes”; Patent App. Pub. No. WO 2008045380 A2, April 17, 2008).
Gill discloses methods and compositions for assembling a DNA molecule having a desired sequence. The methods involve contacting a DNA polymerase, dNTPs, and a plurality of pairs of oligonucleotides. The oligonucleotides of a pair have a portion of the desired sequence, and an internal sequence that overlaps and is complementary to an internal sequence of the other oligonucleotide of the pair, and, when arranged in order, they have at least a portion of the desired sequence. The oligonucleotides also have a 3′ or a 5′ primer binding sequence having a binding site for a primer. The oligonucleotides that correspond to the end oligonucleotides of the desired sequence also have a universal 3′ flanking sequence and a universal 5′ flanking sequence, respectively. The methods involve performing a first amplification reaction on the plurality of pairs of oligonucleotides; removing the 3′ and 5′ primer binding sequences from the plurality of pairs of oligonucleotides; and subjecting the plurality of pairs of oligonucleotides to an assembly reaction to thereby assemble the dsDNA molecule having the desired sequence (Abstract).
Regarding claim 1, Gill teaches methods of synthesizing a DNA molecule having a desired sequence (Para. 6).
Regarding Claim 1 step a), Gill teaches a method wherein each oligonucleotide of a pair comprises a portion of the desired sequence, and the oligonucleotides of a pair comprise an internal sequence that overlaps and is complementary to an internal sequence of the other oligonucleotide of the pair and are schematically or illustratively arranged in order, adjacent to each other and according to their internal sequences (Para. 7). Gill also teaches the overlapping portions can at least partially bind to each other by forming hydrogen bonds and thus anneal to each other at the complementary sequence (Para. 28, Fig. 1). Internal sequence reads on a variable sequence portion of desired sequence. Gill teaches a method that leverages conserved primer binding sequences at the termini of each oligonucleotide in the pair, where the conserved flanking sequences prohibit the oligonucleotide pairs from assembling with one another to form the DNA molecule of desired sequence at an initial stage and can also serve as 3′ and/or 5′ primer binding sequences (Para. 6). Conserved reads on universal. Thus, Gill teaches a method wherein the at least two oligonucleotides each comprise a universal primer binding site on a 3' or 5' end.
Regarding Claim 1 step a), Gill teaches a method wherein one or both oligonucleotides in a pair … can overlap with a third oligonucleotide (Para. 25).
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Gill teaches a method wherein the desired sequence has a 3′ end and a 5′ end, and the oligonucleotide pairs that make up the 3′ and 5′ ends of the desired sequence can also have a universal 3′ flanking sequence and a universal 5′ flanking sequence, respectively (Para. 7). Gill also teaches a method wherein oligonucleotides of the DNA molecule of desired sequence can additionally have a universal 3′ flanking sequence 120 or a universal 5′ flanking sequence 125, which can be present inside of the 3′ and 5′ primer binding sequence 110, 115, respectively (Para. 25; Fig. 1 (shown below)).Thus, Gill teaches a method wherein the at least two oligonucleotides each comprise a variable sequence on the opposing 5' or 3' end and a conserved flanking sequence in between the universal primer binding site and the variable sequence.
Regarding Claim 1 step a), Gill teaches a method wherein the oligonucleotide pairs that make up the 3′ and 5′ ends of the desired sequence can also have a universal 3′ flanking sequence and a universal 5′ flanking sequence, respectively (Para. 7 and 25). An oligonucleotide of a pair is interpreted to having complementary nucleotides. The anchor strand annealed to two complementary oligonucleotides is discussed by Du below. Thus, Gill teaches a method wherein the anchor strand comprises conserved flanking sequences complementary to those on the at least two oligonucleotides.
Regarding claim 1 step c), Gill teaches a method wherein overlapping oligonucleotides are amplified (via PCR) in a method that leverages conserved primer binding sequences at the termini of each oligonucleotide in the pair. (Para 6). PCR products of Gill are reads on having a conserved flanking sequence inside each of the 3' and 5' ends, and a variable sequence inside the conserved flanking sequences as shown in Figures 1 and 4. Thus, Gill teaches method comprising step c) performing an amplification step on the first dsDNA molecule having a desired sequence, a conserved flanking sequence inside each of the 3' and 5' ends, and a variable sequence inside the conserved flanking sequences. Although, the structure may not be exactly the same in regard to the anchor strand and two oligonucleotides, PCR amplification on the first dsDNA molecule is also discussed below in Du.
Regarding claim 1 step d), Gill teaches a method wherein the 3' and 5' primer binding sequences are removed by the action of one or more enzymes that specifically cleave the primer binding sequences, and the one or more enzymes contain uracil DNA glycosylase, endonuclease VIII, or exonuclease T, or a combination of enzymes (Para. 10). Gill suggests that a person of ordinary skill with reference to the disclosure will realize other combinations of enzymes that will yield a suitable result by substituting any or all of these enzymes since other enzymes can have the same or very similar activities (Para. 49). The function of an endonuclease reads on being able to provide additional dsDNA fragments by cleaving a specific phosphodiester bond within DNA molecules. Additionally, comprising 3' and/or 5' complementary single-stranded overhang sequences reads on being the result of some endonucleases. Thus, Gill suggests a method further comprising contacting the first dsDNA molecule with a restriction endonuclease to produce first dsDNA fragments comprising 3' and/or 5' overhang sequences comprising a portion of the variable sequence from the first dsDNA molecule.
However, Gill does not explicitly teach the following limitations of claim 1 comprising i) in step (a) “annealing at least two oligonucleotides to an anchor strand so that the at least two oligonucleotides annealed to the anchor strand abut one another on the anchor strand; ii) in step (b) “ligating the at least two oligonucleotides annealed to the anchor strand to produce a first dsDNA molecule”; iii) wherein the variable sequence on the dsDNA molecule comprises a cleavage site for a Type II restriction endonuclease, and the conserved flanking sequences on the dsDNA molecule comprise a recognition site for a Type II restriction endonuclease; and iv) further comprising contacting the first dsDNA molecule with a restriction endonuclease to produce first dsDNA fragments comprising 3' and/or 5' overhang sequences comprising a portion of the variable sequence from the first dsDNA molecule.
Gill teaches “it will be understood that modifications and variations are encompassed within the spirit and scope of the disclosure” (Para. 118). Thus, one of ordinary skill in the art would be motivated to combine the teachings of Gill with teachings that modify the invention to achieve similar function of assembling a DNA molecule having a desired or predetermined sequence.
Regarding limitations i) and ii) of claim 1:
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Du discloses a large number of sensitive techniques such as DNA self-assembly technology have been developed toward DNA detection in recent years (abstract) and methods for specific detection of DNA with short length (Pg. 5746 Para. 3, Principle of the ligation-mediated PCR, scheme 1 (shown below)).
Regarding claim 1 steps (a-c) and 21, Du teaches methods wherein the detection system includes two steps, the ligation reaction and PCR amplification. Du teaches probe A and probe B are designed to be partly complementary to half-sequence of the target DNA at the 3′- and 5′-terminal, respectively. Du also teaches probe A and probe B can partly hybridize with the target DNA and then are connected together by the catalytic activity of T4 DNA ligase. Du teaches the ligation reaction product is further assayed by PCR amplification (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR). Probe A and B read on oligonucleotides abut one another as depicted in the figure above. Target DNA reads on the anchor strand comprising a variable desired sequence. Thus, Du teaches a method comprising the limitations i) annealing at least two oligonucleotides to an anchor strand so that the at least two oligonucleotides annealed to the anchor strand abut one another on the anchor strand and wherein at least a portion of the at least one variable sequence on the anchor strand is complementary to at least a portion of the variable sequences on the at least two oligonucleotides; and ii) ligating the at least two oligonucleotides annealed to the anchor strand to produce a first dsDNA molecule.
Regarding limitation iii) and iv) of claim 1:
Baynes discloses the design and synthesis of nucleic acid libraries containing non-random mutations or variants. Aspects of the invention provide methods for assembling libraries containing high densities of predetermined variant sequences. Certain embodiments relate to the design and synthesis of nucleic acid libraries that express a predetermined polypeptide from a library of nucleic acids having silent sequence variants. Certain embodiments relate to the design and synthesis of nucleic acid libraries that express predetermined RNA variants that encode the same polypeptide sequence. (Abstract)
Regarding claim 1, Baynes teaches a method comprising “designing nucleic acids (e.g., oligonucleotides) that are useful for constructing a library of desired (predetermined) variants. Figure 3 A schematically illustrates a design of an oligonucleotide useful for methods of the invention… each oligonucleotide fragment includes two primary elements: target and utility elements. In some embodiments, a target element may include a variable region and a constant region on at least one end of the variable region. In some embodiments, a variable region is a segment of sequences that encode a peptide, within which one or more residues are selectively varied. In the diagram of Figure 3 A, a variable region is indicated in dark gray, flanked by constant regions shown in light gray. Additional sequences present on either end of the target sequence are collectively referred to as "utility elements". The utility elements are designed to enable or facilitate various processes involved in the construction of a library, and may include sequences useful for selection, assembly and amplification and/or other processes.” (Pg. 22, ln 3-16; Fig. 3). Baynes teaches a method comprising “sequences, which can optionally be used sequentially. In each case, amplification sequences may be designed so that once a desired set of oligonucleotides is amplified to a sufficient amount, it can then be cleaved by the use of an appropriate type IIS restriction enzyme that recognizes an internal type IIS restriction enzyme sequence of the oligonucleotide” (Pg. 22, ln 30-33). Baynes teaches a method comprising “Figure 3 A illustrates an embodiment of a configuration of oligonucleotides with utility sequences that include a pair of Type IIS restriction enzyme recognition sequences flanking an internal target sequence, and a pair of amplification sequence present on the 5' end and the 3' end of the oligonucleotides” (Pg. 23, ln 11-13). Baynes teaches a method comprising “Type IIS restriction enzymes can be used to create a desirable overhang of the oligonucleotides so as to allow subsequent assembly of oligonucleotide fragments. Type IIS restriction enzymes cleave outside of their recognition site … The distance between the recognition sequence and the proximal cut site varies from 1 to 20 bases, with a distance of 1 to 5 bases between staggered cuts, thus producing 1-5 bases single stranded cohesive ends, with 5' or 3' termini. Usually, the distance from the recognition site to the cut site is quite precise for a given type IIS enzyme” (Pg. 23, ln 19-26). "a target element may include a variable region" (Pg. 22, ln 9), "Type IIS restriction enzyme recognition sequences flanking an internal target sequence" (Pg. 23, ln 12-13) and "Type IIS restriction enzymes cleave outside of their recognition site" (Pg. 23, ln 21-22) read on the variable sequence comprises a cleavage site for a Type IIS restriction endonuclease. Thus, Baynes teaches a method comprising the limitation iii) wherein the variable sequence present between the conserved flanking sequences; and wherein the variable sequence on the dsDNA molecule comprises a cleavage site for a Type II restriction endonuclease, and the conserved flanking sequences on the dsDNA molecule comprise a recognition site for a Type II restriction endonuclease and iv) further comprising contacting the first dsDNA molecule with a restriction endonuclease to produce first dsDNA fragments comprising 3' and/or 5' overhang sequences comprising a portion of the variable sequence from the first dsDNA molecule.
Furthermore, Baynes teaches a method comprising “adjacent variant positions on separate nucleic acids may be combined by ligation by using a complementary nucleic acid that overlaps at least the adjacent 5' and 3' regions. The complementary nucleic acid may be used to hybridize to the adjacent nucleic acids and provides a substrate for ligation (Pg. 25 ln 30-33). Thus, Baynes also teaches the limitations i) annealing at least two oligonucleotides to an anchor strand so that the at least two oligonucleotides annealed to the anchor strand abut one another on the anchor strand and wherein at least a portion of the at least one variable sequence on the anchor strand is complementary to at least a portion of the variable sequences on the at least two oligonucleotides; and ii) ligating the at least two oligonucleotides annealed to the anchor strand to produce a first dsDNA molecule.
Gill, Du and Baynes are considered to be analogous to the claimed invention as they are in the same field of methods of assembling a DNA molecule of a predetermined sequence. Therefore, it would be prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the methods of synthesizing a DNA molecule having a desired sequence comprising: a) at least two oligonucleotides each comprise a universal primer binding site on a 3' or 5' end, and a variable sequence on the opposing 5' or 3' end, and a conserved flanking sequence in between the universal primer binding site and the variable sequence; and wherein another oligonucleotide comprises conserved flanking sequences complementary to those on the at least two oligonucleotides, and further comprises at least one variable sequence present between the conserved flanking sequences, and wherein at least a portion of the at least one variable sequence on an oligonucleotide is complementary to at least a portion of the variable sequences on the at least two oligonucleotides; and step c) performing an amplification step on the first dsDNA molecule having a desired sequence, a conserved flanking sequence inside each of the 3' and 5' ends, and a variable sequence inside the conserved flanking sequences. as taught by Gill to incorporate the method of annealing at least two oligonucleotides to an anchor strand wherein at least a portion of the at least one variable sequence on the anchor strand is complementary to at least a portion of the variable sequences on the at least two oligonucleotides and ligating the at least two oligonucleotides annealed to the anchor strand as taught by Du and the method comprising the variable sequence on the dsDNA molecule comprises a cleavage site for a Type II restriction endonuclease, the conserved flanking sequences on the dsDNA molecule comprise a recognition site for a Type II restriction endonuclease and ligation of two adjacent oligonucleotide annealed to an anchor strand; and contacting the first dsDNA molecule with a restriction endonuclease to produce first dsDNA fragments comprising 3' and/or 5' overhang sequences comprising a portion of the variable sequence from the first dsDNA molecule as taught by Baynes to provide a method of synthesizing a DNA molecule having a desired sequence according to the limitations of claim 1. Thus, these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of synthesizing a DNA molecule having a desired sequence.
The teachings of Gill, Du and Baynes are documented above in the rejection of claim 1 and 21 under 35 U.S.C. 103. Claim 2-27 and 30-37 depends on claim 1. Claims 3, 4, 15, 32, 33, 34 and 35 depend on claim 2, which depends on claim 1. Claims 5, 6, 16 and 25 depend on claim 4, which depends on claim 2, which depends on claim 1. Claims 7 and 17 depend on claim 6, which depends on claim 4, which depends on claim 2, which depends on claim 1. Claims 9, 10, 14, 20 and 22 depend on claim 8, which depends on claim 1. Claim 11 depends on claim 10, which depends on claim 8, which depends on claim 1. Claim 12 depends on claim 101, which depends on claim 8, which depends on claim 1. Claim 31 depends on claim 30, which depends on claim 1. Claim 37 depends on claim 36, which depends on claim 1.
Regarding claim 2, Baynes teaches a method comprising “The overlap between the overhanging ends can be from about 1 nucleotides long to about 10 nucleotides long. A preferred length for the overlap is between 2 or 4 nucleotides long. One should appreciate that if the two overhanging ends perfectly match each other, there will be no additional diversity in the predefined sequence to be assembled” (Pg. 40 ln 5-8). Baynes teaches a method comprising “one or more nucleic acid fragments that each were assembled in separate multiplex assembly reactions (e.g., separate multiplex oligonucleotide assembly reactions) may be combined with one or more additional nucleic acids (e.g., single or double-stranded nucleic acid degradation products, restriction fragments, amplification products, naturally occurring small nucleic acids, other polynucleotides, etc.) and assembled to form a further nucleic acid that is longer than any of the input nucleic acids” (Pg. 85 ln 18-23). Baynes also teaches a method comprising “the first nucleic acid fragment may be combined with one or more additional nucleic acid fragments and used as starting material for the assembly of a larger nucleic acid fragment” (Pg. 17 ln 13-15). Thus, Gill, Du and Baynes teach a method further comprising providing at least one additional dsDNA fragment comprising a 3' and/or 5' overhang sequence that is at least partially complementary to an overhang sequence of at least one of the first dsDNA fragments.
Regarding claim 2, Gill teaches a method comprising the overlapping portions can at least partially bind to each other by forming hydrogen bonds and thus anneal to each other at the complementary sequence (Para. 28, Fig. 1). Thus, Gill, Du and Baynes teach a method comprising: annealing the first dsDNA fragments and at least one additional dsDNA fragment by the 3' and/or 5' overhang sequences.
Regarding claim 2, Gill teaches a method of DNA assembly reaction in Fig.1. The molecule (150) depicted at the bottom of the figure shows a conserved flanking sequence inside each of the 3' and 5' ends, and a variable sequence inside the 3' and 5' conserved flanking sequences that is longer than the variable sequence on the first dsDNA molecule. Thus, Gill, Du and Baynes teach a method including, a second dsDNA molecule comprising a conserved flanking sequence inside each of the 3' and 5' ends, and a variable sequence inside the 3' and 5' conserved flanking sequences that is longer than the variable sequence on the first dsDNA molecule. Ligating the annealed dsDNA fragments to produce a second dsDNA molecule is discussed below in view of Du et al. below.
Regarding claim 3, Gill teaches existing techniques often involve the parallel synthesis of oligonucleotide fragments with a subsequent assembly of the fragments into a larger DNA molecule (Para. 3) Gill also teaches a method wherein oligonucleotide pairs utilized in the invention can be synthesized through any convenient method (Para. 30; Fig. 3). Parallel synthesis can be reads on a convenient method for synthesis. Gill also teaches methods wherein a first (and optionally second and subsequence) amplification reaction(s) can be performed on the plurality of pairs of oligonucleotides until a suitable quantity of pairs of oligos are present (Para. 26). Thus, Gill, Du and Baynes teach a method wherein the at least one additional dsDNA fragment is the product of a parallel DNA synthesis reaction.
Regarding claim 4, the claim requires the same steps of claim 2 to produce a third dsDNA molecule. Gill teaches production of multiple dsDNA molecules as Gil teaches a method that allows multiple nucleic acid constructs to be assembled (Para. 59).
Regarding claim 5, the claim requires the same steps of claim 3 to produce a third dsDNA molecule. Gill teaches production of multiple dsDNA molecules as Gil teaches a first (and optionally second and subsequence) amplification reaction(s) can be performed on the plurality of pairs of oligonucleotides until a suitable quantity of pairs of oligos are present (Para. 26).
Regarding claim 6, the claim requires the same steps of claim 2 to produce a fourth dsDNA molecule. Gill teaches production of multiple dsDNA molecules as Gil teaches a method that allows multiple nucleic acid constructs to be assembled (Para. 59).
Regarding claim 7, the claim requires the same steps of claim 3 to produce a fourth dsDNA molecule. Gill teaches production of multiple dsDNA molecules as Gil teaches a first (and optionally second and subsequence) amplification reaction(s) can be performed on the plurality of pairs of oligonucleotides until a suitable quantity of pairs of oligos are present (Para. 26).
Regarding claim 8, Gill teaches a method wherein each oligonucleotide of a pair has a portion of the desired sequence, and the oligonucleotides of a pair also have an internal sequence that overlaps and is complementary to an internal sequence of the other oligonucleotide of the pair (Para 19). The internal sequence reads on a portion of the desired sequence. Gill also teaches a method wherein the oligonucleotide pairs can at least partially bind to form couplets (Para 19). An anchor strand annealing to at least two oligonucleotides abut one another is discussed in view of Du below. Gill teaches a method wherein when the plurality of pairs of oligonucleotides are arranged in order, adjacent to each other and according to their internal sequences they comprise at least a portion of the desired sequence (Para 19). Gill teaches methods where any number of oligonucleotide pairs or couplets described herein can be amplified and/or assembled (Para. 55). Thus, Gill, Du and Baynes teach a method wherein step a) further comprises annealing at least two paired oligonucleotides to a paired anchor strand so that the at least two paired oligonucleotides bound to the paired anchor strand abut one another on the paired anchor strand.
Regarding claim 8, Gill teaches a method wherein the oligonucleotides of a pair or couplet also have a 3′ or a 5′ primer binding sequence, and the nucleic acid of desired sequence has a 3′ end and a 5′ end, and the oligonucleotide pairs or couplets that correspond to the 3′ and 5′ ends of the nucleic acid of desired sequence can additionally have a universal 3′ flanking sequence and a universal 5′ flanking sequence, respectively (Para 19). An anchor strand annealing to two at least partially complementary oligonucleotides abut one another is discussed in view of Du below. Thus, Gill, Du and Baynes teach a method wherein the at least two paired oligonucleotides comprise a universal primer binding site on a 3' or 5' end, and a variable sequence on the opposing 5' or 3' end, and a conserved flanking sequence in between the universal primer binding site and the variable sequence; and wherein the paired anchor strand comprises conserved flanking sequences complementary to those on the at least two paired oligonucleotides, and further comprises at least one variable sequence, and wherein a portion of the variable sequence on the paired anchor strand overlaps with a portion of the variable sequence on the first anchor strand. Ligating the at least two paired oligonucleotides annealed to the anchor strand is discussed below in view of Du et al. below.
Regarding Claim 8 step e), Gill teaches a method that involves performing a first amplification reaction on the plurality of pairs of oligonucleotides or couplets in the mixture ( Para. 19). Thus, Gill teaches step e) performing an amplification step to produce a paired dsDNA molecule of desired sequence.
Regarding claim 8 step e), Gill teaches a method wherein the oligonucleotides of a pair or couplet also have a 3′ or a 5′ primer binding sequence, and the nucleic acid of desired sequence has a 3′ end and a 5′ end, and the oligonucleotide pairs or couplets that correspond to the 3′ and 5′ ends of the nucleic acid of desired sequence can additionally have a universal 3′ flanking sequence and a universal 5′ flanking sequence, respectively ( Para 19). Thus, Gill, Du and Baynes teach a method wherein a paired dsDNA molecule of desired sequence, comprising a universal primer binding site at a 3' and 5' end, a conserved flanking sequence inside each of the 3' and 5' ends, and a variable sequence inside the conserved flanking sequences that partially overlaps with the variable sequence of the first dsDNA molecule.
Regarding claim 9, Gill teaches a method wherein couplets or oligo pairs, or any number of couplets as described herein, can be amplified and assembled, and in some embodiments from the same pool of synthesized (or parsed) oligonucleotides ( 59). Annealing reads on generally being the first step in an amplification method. Thus, Gill teaches wherein the at least two oligonucleotides and first anchor strand, and the at least two paired oligonucleotides and paired anchor strand, are annealed in a simultaneous reaction in the same pool.
Regarding claim 10, Gill teaches a method wherein the 3' and 5' primer binding sequences are removed by the action of one or more enzymes that specifically cleave the primer binding sequences, and the one or more enzymes contain uracil DNA glycosylase, endonuclease VIII, or exonuclease T, or a combination of enzymes (Para 10). Gill suggests that a person of ordinary skill with reference to the disclosure will realize other combinations of enzymes that will yield a suitable result by substituting any or all of these enzymes since other enzymes can have the same or very similar activities (Para. 49). The function of an endonuclease reads on being able to provide additional dsDNA fragments by cleaving a specific phosphodiester bond within dsDNA molecules. Additionally, comprising 3' and/or 5' complementary single-stranded overhang sequences reads on being the result of some endonucleases. Gill also teaches a method wherein after removal of the 3' and/or 5' primer binding sequences the resulting oligo pairs (or couplets) have overlapping, complementary regions with the adjacent pair(s) of oligonucleotides or couplet(s) and the set can be assembled into the nucleic acid molecule of desired sequence (Para 51). Thus, Gill, Du and Baynes teach a method further comprising contacting the first dsDNA molecule and the paired dsDNA molecule with a restriction endonuclease to produce at least one dsDNA fragment and at least one paired dsDNA fragment, each comprising at least one 3' and/or 5' overhang sequence; and wherein at least a portion of a 3' or 5' overhang sequence from the first dsDNA fragment is complementary to at least a portion of a 5' or 3' overhang sequence from the paired dsDNA fragment.
Regarding claim 10, Gill teaches a method comprising the overlapping portions can at least partially bind to each other by forming hydrogen bonds and thus anneal to each other at the complementary sequence (Para 28, Fig. 1). Thus, Gill, Du and Baynes teach a method of annealing the at least one first and paired dsDNA fragments by their complementary overhang sequences.
Regarding claim 10, Gill teaches a method wherein after removal of the 3' and/or 5' primer binding sequences the resulting oligo pairs (or couplets) have overlapping, complementary regions with the adjacent pair(s) of oligonucleotides or couplet(s) and the set can be assembled into the nucleic acid molecule of desired sequence (Para 51). Assembled into the nucleic acid molecule of desired sequence reads on assembled into any desired length and nucleotide composition. Gill also teaches a method wherein an assembled dsDNA molecule comprises the desired nucleic acid sequence, and in some embodiments the couplets that make up the 3' and 5' ends of the desired sequence can also have a universal 3' flanking sequence and a universal 5' flanking sequence, respectively ( Para 12). Thus, Gill, Du and Baynes teach a method comprising a conserved flanking sequence inside each of the 3' and 5' ends, and a variable sequence inside the 3' and 5' conserved flanking sequences that is longer than the variable sequence on the respective first dsDNA molecules. Ligation to produce a second dsDNA molecule is discussed below in view of Du et al. below.
Regarding claim 11, the claim requires the same steps of claim 10 to produce a third dsDNA molecule. Gill teaches constructs produced by the methods can also be subsequently assembled into larger DNA molecules, by the same method or using other methods (Para 6).
Regarding claim 12, the claim requires the same steps of claim 10 to produce a fourth dsDNA molecule. Gill teaches constructs produced by the methods can also be subsequently assembled into larger DNA molecules, by the same method or using other methods (Para 6).
Regarding claim 13, Gill teaches a method wherein the overlapping region in an oligonucleotide pair can be at least 5 bp, 5-12 bp, etc., but any suitable length of overlap can be used (Para 31). The range 8-12 bp is comprised in the 5-12 bp range, but any suitable length is actually covered by the teachings of Gill. The overlapping region reads on the complementary variable region of the desired sequence. Thus, Gill, Du and Baynes teach a method wherein the first dsDNA molecule comprises a variable sequence of 8-12 base pairs.
Regarding claim 14, Gill teaches a method wherein the overlapping region in an oligonucleotide pair can be at least 8 bp, 5-12 bp, etc., but any suitable length of overlap can be used (Para 31). The range 8-12 bp is comprised in the range from 5-12 bp, but any suitable length is actually covered by the teachings of Gill. The overlapping region reads on the variable region of the desired sequence. Thus, Gill, Du and Baynes teach a method wherein the paired dsDNA molecule comprises a variable sequence of 8-12 base pairs.
Regarding claim 15, Gill teaches a method wherein the overlapping region in an oligonucleotide pair can be from 5-20 bp, about 12 to about 35, etc., but any suitable length of overlap can be used (Para 31). The range 14-18 bp is comprised in the range from 5-20 bp, but any suitable length is actually covered by the teachings of Gill. The overlapping region reads on the variable region of the desired sequence. Thus, Gill, Du and Baynes teach a method wherein the second dsDNA molecule comprises a variable sequence of 14-18 base pairs.
Regarding claim 16, Gill teaches a method wherein the overlapping region in an oligonucleotide pair can be at least 20 bp, about 12 to about 35, etc., but any suitable length of overlap can be used (Para 31). The range 24-32 bp is comprised in the at least 20 bp, but any suitable length is actually covered by the teachings of Gill. The overlapping region reads on the variable region of the desired sequence. Thus, Gill, Du and Baynes teach a method wherein the third dsDNA molecule comprises a variable sequence of 24-32 base pairs.
Regarding claim 17, Gill teaches a method wherein the overlapping region in an oligonucleotide pair can be at least 80 bp, from about 20 to about 100 bp, etc., but any suitable length of overlap can be used (Para 31). The range 90-100 bp is comprised in the at least 80 bp, but any suitable length is actually covered by the teachings of Gill. The overlapping region reads on the variable region of the desired sequence. Thus, Gill, Du and Baynes teach a method wherein the third dsDNA molecule comprises a variable sequence of 90-100 base pairs.
Regarding claim 18, Gill teaches a method wherein the overlapping region in an oligonucleotide pair can be at least 5 bp, but any suitable length of overlap can be used (Para 31). The range 5-6 bp is comprised in the at least 5 bp, but any suitable length is actually covered by the teachings of Gill. The overlapping region reads on the variable region of the desired sequence. Thus, Gill, Du and Baynes teach a method wherein the third dsDNA molecule comprises a variable sequence of 4-6 base pairs.
Regarding claims 19-20, anchor strand annealing to at least two complementary oligonucleotides abut one another is discussed in view of Du below. Gill teaches a method wherein the desired sequence has a 3′ end and a 5′ end, and the oligonucleotide pairs that make up the 3′ and 5′ ends of the desired sequence can also have a universal 3′ flanking sequence and a universal 5′ flanking sequence, respectively (Para 7). Thus, Gill suggests a method wherein the anchor strands comprise the sequences complementary to the conserved flanking sequences on the at least two oligonucleotides on the 3' and 5' ends.
Regarding claim 21-22, Gill teaches a method wherein one or more amplification steps can be performed according to any appropriate PCR method (Para. 45). PCR amplification on a ligated construct is discussed in view of Du below. Thus, Gill suggests a method wherein the amplification step is performed by the polymerase chain reaction (PCR).
Regarding claim 23, Gill teaches a method wherein the oligonucleotides of the pair of are of equal length, or within 10% or 20% or 30% or 40% or 50% length of each other, and the same percentage overlap values can be used (Para 53). The variable sequence reads on matching the same length if it is complementary to two other oligonucleotides and has the same percentage overlap. Thus, Gill, Du and Baynes teach a method wherein the variable sequence is equal to the lengths of the variable sequences on the at least two oligonucleotides.
Regarding claim 24-25, anchor strand annealing to at least two complementary oligonucleotides abut one another is discussed in view of Du below. Gill teaches a method wherein the desired sequence has a 3′ end and a 5′ end, and the oligonucleotide pairs that make up the 3′ and 5′ ends of the desired sequence can also have a universal 3′ flanking sequence and a universal 5′ flanking sequence, respectively (Para 7). Thus, Gill suggests a method wherein the anchor strand comprises a variable sequence present in between the two sequences complementary to the conserved flanking sequences on the at least two oligonucleotides.
Regarding claim 26, anchor strand annealing to at least two complementary oligonucleotides abut one another is discussed in view of Du below. Gill teaches a method wherein each oligonucleotide of a pair comprises a portion of the desired sequence, and the oligonucleotides of a pair comprise an internal sequence that overlaps and is complementary to an internal sequence of the other oligonucleotide of the pair and are schematically or illustratively arranged in order, adjacent to each other and according to their internal sequences (Para 7). Internal sequence reads on a variable sequence portion of desired sequence. Thus, Gill, Du and Baynes teach a method wherein at least two oligonucleotides bound to the anchor strand abut one another on the anchor strand at their variable sequences
Regarding claim 27, Gill teaches a method wherein any suitable length of overlap can be used in an oligonucleotide pair (Para 31). The variable sequence can be reads on any sequence as it is not defined in the instant specification. Thus, Gill suggests a method wherein the portion of the variable sequence on the anchor strand that is complementary to the conserved flanking sequence on the at least two oligonucleotides comprise 2-6 nucleotides as Gill suggests that there can be any suitable length of an overlap.
Regarding claim 30-31, Gill teaches a method wherein each oligonucleotide of a pair has a portion of the desired sequence, and the oligonucleotides of a pair also have an internal sequence that overlaps and is complementary to an internal sequence of the other oligonucleotide of the pair that can at least partially bind to form couplets ( Para 19). The at least partially bind reads on alternate nucleotides can also be present. Thus, Gill, Du and Baynes teach a method wherein the anchor strand comprises 4-6 degenerate nucleotides and the degenerate nucleotide is a randomized or universal base.
Regarding claim 32, Gill teaches existing techniques often involve the parallel synthesis of oligonucleotide fragments with a subsequent assembly of the fragments into a larger DNA molecule (Para 3) Gill also teaches a method wherein oligonucleotide pairs utilized in the invention can be synthesized through any convenient method (Para. 30; Fig. 3). Parallel synthesis can be reads on a convenient method for synthesis. Thus, Gill, Du and Baynes teach a method wherein the at least one additional dsDNA fragment is from a parallel synthesis reaction.
Regarding claim 33, Gill teaches a method wherein the 3' and 5' primer binding sequences are removed by the action of one or more enzymes that specifically cleave the primer binding sequences, and the one or more enzymes contain uracil DNA glycosylase, endonuclease VIII, or exonuclease T, or a combination of enzymes (Para. 10). Gill suggests that a person of ordinary skill with reference to the disclosure will realize other combinations of enzymes that will yield a suitable result by substituting any or all of these enzymes since other enzymes can have the same or very similar activities (Para. 49). The function of an endonuclease reads on being able to provide additional dsDNA fragments by cleaving specific phosphodiester bonds within DNA molecules. Additionally, comprising 3' and/or 5' complementary single-stranded overhang sequences reads on being the result of some endonucleases. Thus, Gill, Du and Baynes teach a method wherein the 3' and/or 5' overhang sequences comprise the portion of the variable sequence from the first dsDNA molecule.
Regarding claim 35, Gill teaches a method wherein the oligonucleotides of a pair also have an internal sequence that overlaps and is complementary to an internal sequence of the other oligonucleotide of the pair that can at least partially bind to form couplets (Para 19). Thus, Gill, Du and Baynes teach a method wherein the at least one additional dsDNA fragment comprises a variable sequence at least partially complementary to the variable sequence from the first dsDNA molecule.
Regarding claim 2, Du teaches the ligation reaction product is further assayed by PCR amplification (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR). Thus, Thus, Gill, Du and Baynes suggest a step required to produce a second dsDNA molecule.
Regarding claim 4, Du teaches the ligation reaction product is further assayed by PCR amplification (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR). Thus, Gill, Du and Baynes suggest a step required to produce a third dsDNA molecule.
Regarding claim 6, Du teaches the ligation reaction product is further assayed by PCR amplification (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR). Thus, Thus, Gill, Du and Baynes suggest a step required to produce a third dsDNA molecule.
Regarding claim 8, Du teaches the steps annealing the anchor strand to two complementary oligonucleotides abut one another, ligating the two complementary oligonucleotides annealed to the anchor strand and PCR amplification of the ligated product as described above in claim 1 as taught by Du (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR). Thus, Gill, Du and Baynes suggest steps required to produce a paired dsDNA molecule of desired sequence.
Regarding claim 9, Du teaches probe A and probe B are designed to be partly complementary to half-sequence of the target DNA at the 3′- and 5′-terminal, respectively. Du also teaches probe A and probe B can partly hybridize with the target DNA. The probes are reads on oligonucleotides and the target DNA reads on the anchor. Thus, Gill, Du and Baynes suggest the at least two oligonucleotides and first anchor strand, and the at least two paired oligonucleotides and paired anchor strand are annealed.
Regarding claim 10, Du teaches the ligation reaction product is further assayed by PCR amplification (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR). Thus, Du suggests a step required to produce a second dsDNA molecule.
Regarding claim 11, Du teaches the ligation reaction product is further assayed by PCR amplification (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR). Thus, Thus, Gill, Du and Baynes suggest a step required to produce a third dsDNA molecule.
Regarding claim 12, Du teaches the ligation reaction product is further assayed by PCR amplification (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR). Thus, Du suggests a step required to produce a fourth dsDNA molecule.
Regarding claim 19, Du teaches probe A and probe B are designed to be partly complementary to half-sequence of the target DNA (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR). The target DNA reads on the anchor strand(s). Probes are interpreted to be the two oligonucleotides. Thus, Gill, Du and Baynes teach wherein the anchor strands comprise the sequences complementary to the conserved flanking sequences on the at least two oligonucleotides on the 3' and 5' ends.
Regarding claim 22, Du teaches the ligation reaction product is further assayed by PCR amplification (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR). Thus, Gill, Du and Baynes suggest the amplification step is performed by the polymerase chain reaction (PCR).
Regarding claim 24, Du teaches probe A and probe B are designed to be partly complementary to half-sequence of the target DNA (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR). The target DNA reads on the anchor strand(s). Probes are interpreted to be the two oligonucleotides. Thus, Du suggests the anchor strand comprises a variable sequence present in between the two sequences complementary to the conserved flanking sequences on the at least two oligonucleotides.
Regarding claim 25, Du teaches probe A and probe B are designed to be partly complementary to half-sequence of the target DNA (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR). The target DNA reads on the anchor strand(s). Probes are interpreted to be the two oligonucleotides. Thus, Gill, Du and Baynes suggest the anchor strand comprises a variable sequence present in between the two sequences complementary to the conserved flanking sequences on the at least two oligonucleotides.
Regarding claim 26, Du teaches probe A and probe B are designed to be partly complementary to half-sequence of the target DNA at the 3′- and 5′-terminal, respectively. Du also teaches probe A and probe B can partly hybridize with the target DNA (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR; Scheme 1 shown above). The target DNA reads on the anchor strand(s). Probes are interpreted to be the two oligonucleotides. Thus, Gill, Du and Baynes teach wherein the at least two oligonucleotides bound to the anchor strand abut one another on the anchor strand at their variable sequences.
Regarding claim 27, Du teaches probe A and probe B are designed to be partly complementary to half-sequence of the target DNA at the 3′- and 5′-terminal, respectively. Du also teaches probe A and probe B can partly hybridize with the target DNA (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR; Scheme 1 shown above). The target DNA reads on the anchor strand(s). Probes are interpreted to be the two oligonucleotides. Thus, Gill, Du and Baynes suggest wherein the portion of the variable sequence on the anchor strand is complementary to the conserved flanking sequence on the at least two oligonucleotides.
Regarding claim 30, Du teaches probe A and probe B are designed to be partly complementary to half-sequence of the target DNA at the 3′- and 5′-terminal, respectively Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR). The target DNA reads on the anchor strand(s). Probes are interpreted to be the two oligonucleotides. Partly complementary reads on other nucleotides can be present. Thus, Gill, Du and Baynes suggest wherein the anchor strand comprises 4-6 degenerate nucleotides
Regarding claim 36, Du teaches probe A and probe B can partly hybridize with the target DNA and then are connected together by the catalytic activity of T4 DNA ligase (Pg. 5746, Para. 3, Results and discussion-Principle of the ligation-mediated PCR; scheme 1 shown above). Thus, Gill, Du and Baynes teach a step of ligating the at least two oligonucleotides bound to the anchor strand.
Regarding claims 34 and 37, Baynes teaches a method wherein chemical
ligation also may be used and one or both ends of the adjacent nucleic acids may need to be modified appropriately to provide a substrate for a chemical ligation reaction. (Pg. 26, ln 2-4). Thus, Gill, Du and Baynes teach a method wherein the step of ligation occurs spontaneously.
Response to Arguments
Applicant' s arguments filed 01/09/2026 (Pg.12-16) with respect to claim 1-27 and 30-37 have been considered but are not persuasive. To clarify some instances argued in the response filed 01/09/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Gill does not teach or suggest a method involving "annealing at least two oligonucleotides to an anchor strand so that the at least two oligonucleotides annealed to the anchor strand abut one another on the anchor strand," and "wherein the at least two oligonucleotides each comprise a universal primer binding site on a 3' or 5' end, and a variable sequence on the opposing 5' or 3' end," as claimed.” (Pg. 12)
Response: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicants’ argument: "Since escaping the sequence constraints imposed by restriction enzymes to permit the use of a larger number of primer binding sequences and achieving scarless removal (achieved by not using restriction enzymes) are goals of Gill, Gill does indeed teach away from their use in the invention to obtain the stated advantages. " (Pg. 13).
Response: In response to the argument that Gill teaches away, Gill does not teach away for the use of restriction enzymes. Gill merely suggests that in some embodiments this version of method can be performed. The examiner notes, as stated in the same paragraph as cited in the argument that Gill teaches away, that Gill teaches “Nevertheless, in some embodiments restriction sites and restriction enzymes can be located on the 3' and/or 5' primer binding sequences and used to conduct the methods.” (Para. 24).
Applicants’ argument: “The Office provides no statement of a reasoned motive for the proposed combination of references other than the conclusory "to provide a method of synthesizing a DNA molecule having a desired sequence" (Office Action mailed 9/9/25, p. 11, line 3). Combining Du with Gill changes the principle of operation of Gill, and therefore there is no motive to make the combination” (Pg. 13) and “that if the proposed modification or combination of the prior art would change the principle of operation of the prior art invention being modified, then the teachings of the references are not sufficient to render the claims prima facie obvious” (Pg. 14).
Response: In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as stated above in the revised rejection under 35 U.S.C 103, Gill teaches “it will be understood that modifications and variations are encompassed within the spirit and scope of the disclosure” (Para. 118). Thus, one of ordinary skill in the art would be motivated to combine the teachings of Gill with teachings that modify the invention to achieve similar function of assembling a DNA molecule having a desired or predetermined sequence (Pg.7) and Gill, Du and Baynes are considered to be analogous to the claimed invention as they are in the same field of methods of assembling a DNA molecule of a predetermined sequence. Therefore, it would be prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the methods of synthesizing a DNA molecule having a desired sequence comprising: a) at least two oligonucleotides each comprise a universal primer binding site on a 3' or 5' end, and a variable sequence on the opposing 5' or 3' end, and a conserved flanking sequence in between the universal primer binding site and the variable sequence; and wherein another oligonucleotide comprises conserved flanking sequences complementary to those on the at least two oligonucleotides, and further comprises at least one variable sequence present between the conserved flanking sequences, and wherein at least a portion of the at least one variable sequence on an oligonucleotide is complementary to at least a portion of the variable sequences on the at least two oligonucleotides; and step c) performing an amplification step on the first dsDNA molecule having a desired sequence, a conserved flanking sequence inside each of the 3' and 5' ends, and a variable sequence inside the conserved flanking sequences. as taught by Gill to incorporate the method of annealing at least two oligonucleotides to an anchor strand wherein at least a portion of the at least one variable sequence on the anchor strand is complementary to at least a portion of the variable sequences on the at least two oligonucleotides and ligating the at least two oligonucleotides annealed to the anchor strand as taught by Du and the method comprising the variable sequence on the dsDNA molecule comprises a cleavage site for a Type II restriction endonuclease, and the conserved flanking sequences on the dsDNA molecule comprise a recognition site for a Type II restriction endonuclease and ligation of two adjacent oligonucleotide annealed to an anchor strand as taught by Baynes to provide a method of synthesizing a DNA molecule having a desired sequence. Thus, these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of synthesizing a DNA molecule having a desired sequence.(Pg. 10-11)
Applicants’ argument: “Baynes is cited apparently only to "pick out" the concept of using restriction endonucleases, but in a context different and outside of the scope of the present claims” (Pg. 14)
Response: In response to applicant's argument stated above, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Furthermore, Baynes does not only “pick out” the concept of using restriction endonucleases, in a context different and outside of the scope of the present claims. As stated above in the revised 35 U.S.C. 103 rejection, “Baynes teaches a method comprising the limitation iii) wherein the variable sequence present between the conserved flanking sequences; and wherein the variable sequence on the dsDNA molecule comprises a cleavage site for a Type II restriction endonuclease, and the conserved flanking sequences on the dsDNA molecule comprise a recognition site for a Type II restriction endonuclease and iv) further comprising contacting the first dsDNA molecule with a restriction endonuclease to produce first dsDNA fragments comprising 3' and/or 5' overhang sequences comprising a portion of the variable sequence from the first dsDNA molecule.
Furthermore, Baynes teaches a method comprising “adjacent variant positions on separate nucleic acids may be combined by ligation by using a complementary nucleic acid that overlaps at least the adjacent 5' and 3' regions. The complementary nucleic acid may be used to hybridize to the adjacent nucleic acids and provides a substrate for ligation (Pg. 25 ln 30-33). Thus, Baynes also teaches the limitations i) annealing at least two oligonucleotides to an anchor strand so that the at least two oligonucleotides annealed to the anchor strand abut one another on the anchor strand and wherein at least a portion of the at least one variable sequence on the anchor strand is complementary to at least a portion of the variable sequences on the at least two oligonucleotides; and ii) ligating the at least two oligonucleotides annealed to the anchor strand to produce a first dsDNA molecule.” (Pg. 8-10)
Applicants’ argument: “Baynes provides no disclosure of any method where alleged variable sequences contain a cleavage site for a Type IIS restriction endonuclease” (Pg. 15)
Response: In response to applicant's argument stated above, Baynes does teach a method wherein the variable sequences contain a cleavage site for a Type IIS restriction endonuclease as stated in the revised 35 U.S.C. 103 rejection above (Pg. 9). Furthermore, the teachings were further explained by the reasoning that, "a target element may include a variable region" (Pg. 22, ln 9), "Type IIS restriction enzyme recognition sequences flanking an internal target sequence" (Pg. 23, ln 12-13) and "Type IIS restriction enzymes cleave outside of their recognition site" (Pg. 23, ln 21-22) read on the variable sequence comprises a cleavage site for a Type IIS restriction endonuclease.” (Pg. 10).
Applicants’ argument: “It appears the rejection is made based on impermissible hindsight reasoning by picking out discrete disclosures from the prior art in an effort to assemble the elements of the claim.” (Pg. 15)
Response: In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion of Response to Arguments
In view of the amendments, revised rejections and above responses to arguments, no claims are in condition for allowance.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KENDRA R VANN-OJUEKAIYE whose telephone number is (571)270-7529. The examiner can normally be reached M-F 9:00 AM- 5:00 PM.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682