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 .
Office Action: Notice
Any objection or rejection of record in the previous Office Action, mailed 7/28/2025,
which is not addressed in this action has been withdrawn in light of Applicants' amendments
and/or arguments. This action is FINAL
Claim Status
Claims 1-60, 65, 68, and 70 have been canceled (11/3/2025). Claim 61 has been amended (11/3/2025). Claims 61-64, 66-67, 69, and 71-78 are pending and thus under examination (11/3/2025).
Priority
Claims 61-64, 66-67, 69, and 71-78 receive a priority date of 6/21/2019, the effective filing date of U.S. Provisional Patent 62/865,094.
Objections Withdrawn
Specification:
The objections to the specification due to the use of a trademark or tradenames are withdrawn in view of Applicant’s amendments.
Claims:
The objection to write out abbreviations completely the first time used in claim 60 is withdrawn due to Applicant’s cancellation of claim 60.
Rejections Withdrawn
Claim Rejections - 35 USC § 112(b)
The rejections of claims 57-60 and 65 under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, 2nd paragraph, are withdrawn in view of Applicant’s cancellation of claims 57-60 and 65.
Claim Rejections – 35 USC § 103
The rejection of claim 60 under 35 USC 103, is withdrawn in view of Applicant’s cancellation of claim 60.
Rejections Maintained
Claim Rejections - 35 USC § 102
Claims 61-64, 66-67, 69, and 71-78 are rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Short et al., (02/29032, published 4/11/2002). Rejection has been modified to reflect Applicant’s amendments (11/3/2025).
Regarding claims 61-64, Short teaches that sequences can be obtained or assembled from computer data bases, publications or can be determined or conceived de novo (p. 79, Paragraph 3). Short also teaches that the previously described assembly or cellular transformation includes a first probe set, each having one interrogation position corresponding to a nucleotide of interest in the reference sequence, where the second, third and fourth probe sets each have a corresponding probe for each probe in the first probe or nucleic acid sequence set, and so each also contains a total of fifty probes and the identity of each nucleotide of interest in the reference sequence is determined by comparing the relative hybridization signals at four probes having interrogation positions corresponding to that nucleotide from the four probe sets (p. 82, Paragraph 3). Also, Short teaches that the previously mentioned nucleotide of interest or target sequence includes the variability of the variable regions of both the heavy and light chains is for the most part restricted to three small hypervariable regions in each chain (p. 383, Paragraph 2), including restriction endonuclease-based types for producing a sticky end in a working polynucleotide or target (p. 317, Paragraph 1), and a universal class of recombinase enzymes or primers which promote probe-target pairing reactions (p. 337, Paragraph 2). Further Short teaches that probe or nucleic acid generation in the array include outside sequences as vector sequences to minimize degeneracy (p. 347, Paragraph 1). Further, Short teaches the application of the sequence tag method or barcode into the previously described assembly, which involves generation of a large number of Expressed Sequence Tags ("ESTs") from cDNA libraries (each produced from a different tissue or sample) (p. 108, Paragraphs 5-6).
Additionally, Short teaches the application of the probe assembly system to 11-mer, which involves six nucleotides of interest (p. 83, Paragraphs 5-6). Short teaches that the involvement of additional probes or sequences of interest include preferred attached chemical substituents like cross-linking agents and nucleic acid cleavage agents, metal chelates,
topoisomerases, endonucleases (i.e., flap-endonucleases, XPG family (p. 345, Paragraph 2)), exonucleases, ligases, phosphodiesterases, photodynamic porphyrins, chemotherapeutic drugs, intercalating agents, labels, base-modification agents, agents which normally bind to nucleic acids such as labels or barcodes or tags, immunoglobulin chains, and oligonucleotides (p. 373-374).
Further, Short teaches that the previously described assembly method includes a
collection of selected complementarities determining regions ("CDRs") after the first round of affinity selection (p. 274, Paragraph 3) as part of shuffling of the DNA sequences to reduce error (p. 275, Paragraph 1-3). Short also teaches that CDR3 is used to increase diversity of the CDR regions (p. 721, Paragraph 2).
Further, Short teaches the application of this assembly for the generation and sorting of up to hundreds of nucleotides in length with high fidelity; however, these can be assembled, i.e. using overhangs or sticky ends, to form double-stranded nucleic acids of up to
thousands of base pairs, if not tens of thousands of base pairs, in length if so desired (p. 305, Paragraph 5).
Regarding claims 66-67, Short teaches the application of the previously described synthesizing method to a plurality of sequences (which may but do not necessarily overlap) which can be introduced into a terminal or variable region of an end-selectable polynucleotide by the use of an oligo in a polymerase-based reaction to provide a preferred 5' terminal region that is serviceable for topoisomerase I-based end-selection, which oligo is comprised of: a 1-10 base sequence that is convertible into a sticky end (preferably by a vaccinia topoisomerase I), a ribosome binding site (i.e. and "RBS", that is preferably serviceable for expression cloning), and optional linker sequence followed by an ATG start site and a template-specific or variant-specific sequence of about 100 bases (to facilitate annealment to the template in the polymerase-based reaction) (p. 317, Paragraph 3).
Further, Short teaches the application of a set of primers to a second set of synthesized variant regions, incorporating an additional 10-30 nucleotide long template or variant specific sequence in addition to the initial 100 bases of the first variant or template sequence, as described above (p. 319, Paragraphs 1-3).
Regarding claims 69 and 71, Short teaches that the involvement of additional probes or sequences of interest include preferred attached chemical substituents like cross-linking agents and nucleic acid cleavage agents, metal chelates, topoisomerases, endonucleases (i.e., flap-endonucleases, XPG family (p. 345, Paragraph 2)), exonucleases (i.e., exonuclease III for shuffling (Figure 1)), ligases, phosphodiesterases, photodynamic porphyrins, chemotherapeutic drugs, intercalating agents, labels, base-modification agents, agents which normally bind to nucleic acids such as labels or barcodes or tags, immunoglobulin chains, and oligonucleotides (p. 373-374).
Regarding claims 72-73, Short teaches that for assembly or cellular transformation, standard convention (5' to 3 ') is used herein to describe the sequence of double stranded polynucleotides via DNA polymerase generation (Figures 2 and 26; p. 59, Paragraph 2).
Regarding claim 74, Short teaches that the previously described de novo method of synthesis and assembly includes ligation, which refers to the process of forming phosphodiester bonds between two double stranded nucleic acid fragments and is accomplished using known buffers and conditions with 10 units ofT4 DNA ligase ("ligase") per 0.5 μg of approximately
equimolar amounts of the DNA fragments to be ligated (p. 54, Paragraph 2).
Regarding claims 75-76, Short teaches that the previously described de novo method of synthesis and assembly includes domain homology clamps or regions of fixed variability (20 to 100 nucleotides long) which are typically located at or near the 5' or 3' end, preferably domain homology clamps are internal or located at each end of the polynucleotide where it believed that the addition of recombinases permits efficient gene targeting with targeting polynucleotides having short (i.e., about 10 to 1000 basepairs long) segments of homology, as well as with targeting polynucleotides having longer segments of homology (p, 361, Paragraphs 1-2).
Short further teaches that a different 20-40 base sequence is amplified on an adjacent gene which contains the complementary strand of the initial or first sequence or site of fixed variability or interest (p. 479, Paragraph 1).
Regarding claim 77, Short teaches that the involvement of additional probes or sequences of interest include preferred attached chemical substituents like cross-linking agents and nucleic acid cleavage agents, metal chelates, topoisomerases, endonucleases (i.e., flap-endonucleases, XPG family, FEN1 (p. 345, Paragraph 2)), exonucleases (i.e., exonuclease III for shuffling (Figure 1)), ligases, phosphodiesterases, photodynamic porphyrins, chemotherapeutic drugs, intercalating agents, labels, base-modification agents, agents which normally bind to nucleic acids such as labels or barcodes or tags, immunoglobulin chains, and oligonucleotides (p. 373-374).
Regarding claim 78, Short teaches that the previously described de novo method of synthesis and assembly can be formed of any number of individual capillaries, for example, a range from 100 to 4,000,000 capillaries, where each capillary applies to an individual nucleic acid (p. 238, Paragraph 2).
Short teaches each and every limitation of claims 61-64, 66-67, 69, and 71-78, and therefore Short anticipates claims 61-64, 66-67, 69, and 71-78.
Applicant’s Response: The Applicant argues that Short does not anticipate the claims because Short allegedly fails to disclose using a flap endonuclease as an enzymatic component in a nucleic acid assembly reaction. The Applicant further contents that Short merely references XPG family members as genetic targets or substrates for mutation, rather than as functional assembly enzymes, and therefore foes not teach the claimed reaction mixture comprising a flap endonuclease.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully and fully considered but are not found persuasive, as discussed below.
Firstly, anticipation does not require that a reference describe the claimed invention in the same words as used by the Applicant, nor does it require an express working example of every claimed step. A reference anticipates a claim when it discloses, either expressly or inherently, each and every limitation of the claim as arranged as in the claim. See MPEP 2131; In re Schreiber, 128 F. 3d 1473, 1477 (Fed. Cir. 1997).
Specifically, Short teaches a comprehensive de novo nucleic acid synthesis and assembly system that includes sequence design, synthesis, amplification, enzymatic processing, ligation, circularization, barcoding and large-scale assembly (p. 79, Paragraph 3; p. 82, Paragraph 3; p. 275, Paragraph 1; p. 337, Paragraph 2; p. 345, Paragraph 2; p. 373-374). Therefore, the overall process taught by Short corresponds directly to the method now recited in amended claim 61. Although the Applicant argues that Short does not anticipate the claims because Short allegedly fails to disclose use of a flap endonuclease in a nucleic acid assembly method. This argument is not persuasive. Short expressly teaches that the nucleic acid assembly process may include the use of endonucleases, including flap endonucleases of the XPG family, as part of the assemble and processing of nucleic acids (p. 345, Paragraph 2) among the enzymatic agents applicable to the disclosed assembly systems. A reference is not required to emphasize or single out a particular component for that component to be anticipatory. The identification of flap endonucleases as usable enzymatic agents within the disclosed assembly process is sufficient. See MPEP 2131.01; Upsher-Smith Labs Inc. v. Pamlab LLC, 412 F. 3d 1319 (Fed. Cir. 2005).
Further, the Applicant argues that Short discloses XPG family members as only genomic targets, rather than as enzymatic tools. This contention is not supported by the reference. Short repeatedly teaches enzymatic manipulation of nucleic acids during assembly, including cleavage, recombination, ligation, and shuffling. The inclusion of flap endonucleases, as part of the XPG family, among enzymatic agents usable during assembly demonstrates their functional role in processing nucleic acids within the disclosed method. Specifically, instant amended claim 61 recites contacting nucleic acids with a reaction mixture comprising an exonuclease, an endonuclease, a polymerase, and a ligase. Short teaches exonucleases (i.e., exonuclease III for shuffling), endonucleases (XPG family), DNA polymerases for synthesis and amplification, and ligases for joining nucleic acids ((p. 274, Paragraph 3; p. 275, Paragraph 1-3; p. 345, Paragraph 2; p. 721, Paragraph 2). The presence of these enzymes within Short’s assembly process satisfies the claimed reaction mixture. Anticipation does not require that the reference describe the reaction mixture in identical terms or specify a particular sequence of addition. See MPEP 2131.01 (V).
Therefore, the dependent claims are likewise anticipated. Short teaches variable and hypervariable regions, complementary determining regions (CDRs), polymerase activity in the 5’ to 3’ direction, ligation of nucleic acids, defined region lengths, specific enzyme classes including flap endonucleases and exonucleases, and large-scale parallel synthesis using capillary-based systems (Figures 1 and 2; p. 59, Paragraph 2; p. 274, Paragraph 3; p. 275, Paragraph 1-3; p. 305, Paragraph 5; p. 345, Paragraph 2; p. 721, Paragraph 2). Each limitation recited in claims 62-64, 66-67, 69, and 71-78 is disclosed by Short, either expressly or inherently, consistent with MPEP 2131.
Further, the Applicant’s arguments improperly attempt to narrow the claims by importing limitations relating to specific purposes, mechanisms, or preferred embodiments that are not recited in the claims. Claims must be given their broadest reasonable interpretation consistent with the Specification. See MPEP 2111. Under the proper interpretation, Short teaches all claimed limitations.
Accordingly, the Applicant’s arguments do not overcome the rejection. Short teaches each and every limitation of claims 61-64, 66-67, 69, and 71-78. Therefore, the rejections under 35 USC 102 (a)(1) and (a)(2) are maintained.
Conclusions
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELIZABETH ROSE LAFAVE whose telephone number is (703)756-4747. The examiner can normally be reached Compressed Bi-Week: M-F 7:30-4:30.
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/ELIZABETH ROSE LAFAVE/ Examiner, Art Unit 1684
/HEATHER CALAMITA/ Supervisory Patent Examiner, Art Unit 1684