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 .
Priority
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . This application is a Continuation of U.S. Application No. 17/226,044, now abandoned, which is a Continuation of U.S. Application No. 15/604,204, now abandoned, which is a Continuation-in-Part of U.S. Application No. 15/487,401, now U.S. Patent No. 10,886,006, which is a Continuation-in-Part of U.S. Application No. 15/361,280, now abandoned, which claims benefit of U.S. Provisional Application 62/339,317, filed 05/20/2016 and U.S. Provisional Application 62/259,913, filed 11/25/2015.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, U.S. Provisional Application 62/339,317, filed 05/20/2016 and U.S. Provisional Application 62/259,913, filed 11/25/2015 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The Provisional Application nos. 62/339,317 and 62/259,913 do not disclose the following subject matter recited as limitations of claim 14 of the instant Application No. 18/816,789.
“(ii) a sample nucleic acid comprising the target DNA sequence, wherein the target DNA sequence has been altered with a gene editing enzyme” (e.g. altered using CRISPR, Cas9, Cpf1: first disclosed in Application No. 15/361,280 filed 11/25/2016).
“hot start cleaving enzyme is thermostable and has reduced activity at lower temperatures” (e.g. a thermostable RNAse H2 e.g. thermostable Pyrococcus abyssi RNase H2: first disclosed in claims 11-13 of Application No. 15/361,280 filed 11/25/2016).
the “hot start cleaving enzyme comprising at least one amino acid substitution as compared to its wild type” (e.g. hot-start/thermostable G12A, P13T or G169A Pyrococcus abyssi RNase H2/ mutant RNase H2: first disclosed in para [0068], [0070], [0166]-[0167], [0174] of Application No. 15/604,204 filed 05/24/2017).
“hot start cleaving enzyme exhibiting mismatch discrimination” (first disclosed in para [0037] of Application No. 15/487,401 filed 04/13/2017).
The subject matters above are first disclosed in Application No. 15/604,204 filed 05/24/2017.
This applicant is construed as claiming to benefit from Application No. 15/604,204 filed 05/24/2017.
Status of the Claims
Claims 14, 16-24, 26-28, 30-51 and 53-54 are currently pending and under examination. Claims 1-13, 15, 25, 29 and 52 are canceled.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 42 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 42 recites the limitation “wherein sequencing is performed on the second extension product to determine the sequence of the target”. There is insufficient antecedent basis for “the second extension product” in the claim.
Claim 42 is also rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are:
providing a second oligonucleotide primer further comprises a tail domain comprising a second universal primer sequence; hybridizing universal primers to the second oligonucleotide primer and extending the second oligonucleotide primer to form a second extension product and sequencing the second extension product to determine the sequence of the target.
Method claims should recite positive, active process steps (see Ex parte Erlich 3 USPQ 2d 1011).
While minute details are not required in method claims, at least the basic steps must be recited in a positive, active fashion. See Ex parte Erlich, 3 USPQ2d, p. 1011 (Bd. Pat. App. Int. 1986). It is suggested that the claims be rewritten such that they set forth defined methods, such as by reciting "[a] method of . . . , comprising the steps of . . .", after which a series of active steps is recited, for example " the method of claim 32, further comprising sequencing the second extension product to determine the sequence of the target.".
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.
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.
Claims 14, 16-24, 26-28, 30-51 and 53-54 are rejected under 35 U.S.C. 103 as being unpatentable over Walder et al. (filed 04/30/2009, US2009/0325169) in view of Spier et al. (filed 01/13/2014, US2014/0329245), Behlke et al. (filed 11/14/2014, WO2015/073931A1) and Zhang et al. (filed 12/12/2013, WO2014/093622A2).
Regarding claims 14 and 32, Walder et al. teach a method of detecting a variation in a target DNA Sequence and enriching the target, comprising:
(a) providing a reaction mixture comprising:
(i) an oligonucleotide primer having a cleavage domain positioned 5’ of a blocking group, the blocking group linked at or near the end of the 3’-end of the oligonucleotide primer wherein the blocking group prevents primer extension and/or inhibits the oligonucleotide primer from serving as a template for DNA synthesis (see paragraphs 0028-0035, 0116-0121,0133, 0146-0153);
(ii) a sample nucleic acid comprising the DNA target sequence, wherein the target sequence may or may not have the variation (paragraphs 0028-0035, 0133, 0146-0153);
(iii) a hot start cleaving enzyme comprising at least one amino acid substitution as compared to its wild type, wherein the hot start cleaving enzyme is thermostable and has reduced activity at lower temperatures, and wherein the hot start cleaving enzyme exhibits enhanced mismatch discrimination as compared to its wild type, and a polymerase (paragraphs 0028-0036, 0133, 0146-0153, para 0095, 0099, 0129);
and (iv) a polymerase (para 0384, exonuclease deficient mutant polymerase);
(b) hybridizing the oligonucleotide primer to the target DNA sequence to form a double-stranded substrate (paragraphs 0028-0035, 0133, 0146-0153);
(c) cleaving the oligonucleotide primer hybridized to the target DNA sequence, if the oligonucleotide primer is complementary at the variation, with the hot start cleaving enzyme at a point within or adjacent to the cleavage domain to remove the blocking group from the oligonucleotide primer (paragraphs 0028-0035, 0133, 0146-0153); and
(d) extending the oligonucleotide primer with the polymerase (paragraphs 0038-0035, 0095, 0099, 01290133, 0146-0153).
Walder et al. (claims 14, 28, 32-34, 37, 39)
Regarding claims 14, 28, 32-34, 39, Walder et al. suggests oligonucleotide primer having 5’tail sequence that comprises a universal primer sequence, wherein the tail is non-complementary to the target DNA sequence (see Fig. 35 and para [0475]: wherein Walder teach universal primer or acceptor nucleic acid is hybridized to the unknown nucleic acid. Attachment of a universal adaptor sequence on the end of the unknown sequence may be required to permit hybridization of the acceptor molecule, and this strategy permits use of the same acceptor nucleic acid for all reactions).
Regarding claim 37, Walder suggests the universal primers further comprise tailed sequences for addition of adapter sequences to the second extension product.
Walder et al. (claims 14, 16-17, 18-24, 32, 43-45, 46-51)
Regarding claims 14, 16-17, 23, 32, 43-44, Walder et al. teaches reaction mixture comprising a hot start (thermostable) cleaving enzyme is chemically modified and is Pyrococcus abyssi RNase H2 comprising:
(a) a G12A amino acid substitution;
(b) a P13T amino acid substitution;
(c) a G169A amino acid substitution; or
(d) a combination thereof (see pg 17, table 2, 0152, claim 4 , and see table 4 indicating accession number AJ248284 that comprises alanine at position 169).
The hot start cleaving enzyme of Walder exhibits enhanced mismatch discrimination as compared to its wild type.
Regarding claims 18 and 45, Walder et al. teach that the cleaving enzyme is a hot start cleaving enzyme that is reversibly inactivated through interaction with an antibody at lower temperatures, (paragraphs 0027, 0036, 0152).
Regarding claims 14, 19-24 and 46-51, Walder et al. teach that oligonucleotide primer having a cleaving domain that comprises at least one RNA base or one or more 2’-modified nucleosides or 2’-fluoronucleosides and the hot start cleaving enzyme cleaves between the position complementary to the variation and the RNA base or modified base (paragraphs 0032-0034, 0043-0044, 0103-0104, 0121-0122, 0140-0153).
Walder et al. (claims 33- 35, 37, 39)
Regarding claims 33-35, 37, 39, Walder teach steps (b) - (d) are performed 1-10 times (Fig. 22B, Fig. 32B, 0073-0076, 0475).
Omitted from Walder et al. (claims 14, 26-28, 30-32, 36-39 39-42, 53-54)
Regarding claims 28, 39, Walder does not teach the universal primer sequence comprises indexed P5/P7 universal primer sequences for next-generation sequencing (claims 28 and 39).
Regarding claim 36, Walder does not teach removing unextended oligonucleotide primers from the reaction and hybridizing universal primers to the extension product to form a second extension product.
Regarding claim 37, Walder suggests the universal primers further comprise tailed sequences for addition of adapter sequences to the second extension product.
Regarding claims 38 and 42, Walder does not teach wherein sequencing is performed on the second extension product to determine the sequence of the target.
Regarding claims 14, 26-27, 32 and 53-54, Walder does not teach a high discrimination polymerase that is a mutant H784Q Taq polymerase that is reversibly inactivated via chemical, aptamer, or antibody modification.
Regarding claims 14, 30-32, 40-41, Walder does not teach reaction mixture comprising a sample target DNA sequence treated with a gene editing enzyme, the enzyme being CRISPR enzyme that is a Cas9 or Cpf1 enzyme.
Zhang et al. WO2014/093622A2 (claims 14, 30-32, 40-41): Zhang et al. teach a routine matter of practice to use gene editing enzyme (e.g. cas9 or Cpf1 enzyme or CRISPR) to alter a target DNA sequence
Regarding claims 14, 30-32 and 40-41, Zhang et al. teach a method for targeted gene sequencing, the method comprising providing target nucleic acid treated or modified by CRISPR-Cas gene editing enzyme for preparing gene-edited target to minimize the degree of off-target cleavage and use of said modified targets for nuclease assays (paragraphs 0808-0829, 00935-00971).
Spier et al. US2014/0329245 (claims 14, 28, 32, 39)
Spier teaches methods and compositions for performing PCR with primers having blocked 3’-ends that are unblocked when the primers anneal to the template (see Abstract and paragraphs 13 and 14).
Specifically, regarding claims 14, 28, 32, 39, Spier further teaches that the primers may be tailed primers comprising a universal tag sequence (part a), a degenerate base region (part b), a target-specific region (part c), and a blocked 3’ end (part d), and may also comprise a cleavable site, wherein universal primers have a 3’ end that binds to the universal tag sequences of the tailed primers, and also comprise a 5’ end comprising P5/P7 sequencing tags (part f), and may also comprise index/sample bar codes (part g) (paragraph 42 and Figure 8).
In addition, Spier teaches that the blocked primers are used in a closed-tube PCR enrichment assay for next-generation sequencing, wherein after two cycles of amplification, the universal primers, present at a higher concentration than the tailed, blocked primers, are used in the amplification process to generate amplicons comprising the next-generation P5/P7 sequencing tags, wherein the sample indexes or barcodes of the universal primers may be used to identify each sample in a pool of samples (paragraph 63).
Behlke et al. WO2015/073931 (claims14, 26-27, 32, 53-54)
Regarding claims 14, 32, Behlke et al. teach a method of detecting a variation in a target DNA sequence, comprising:
(a) providing a reaction mixture comprising:
(i) an oligonucleotide primer having a cleavage domain positioned 5’ of a blocking group and 3’ of a position of variation, the blocking group linked at or near the end of the 3’-end of the oligonucleotide primer, wherein the blocking group prevents primer extension and/or inhibits the oligonucleotide primer from serving as a template for DNA synthesis (paragraphs 0125-0127, 0131, 0179-0185);
(ii) a sample nucleic acid comprising the target DNA sequence, wherein the target sequence may or may not have the variation (paragraphs 0125-0127, 0179-0185);
(iii) a cleaving enzyme (paragraphs 0125-0127, 0179-0185);
(iv) a high-discrimination mutant H784Q Taq polymerase (0125-0127, 0179-0185, 0195);
(b) hybridizing the oligonucleotide primer to the target DNA sequence to form a double-stranded substrate (paragraphs 0093, 0125, 0179-0185, 0309-0312);
(c) cleaving the oligonucleotide primer hybridized to the target DNA sequence, if the oligonucleotide primer is complementary at the variation, with the hot start cleaving enzyme at a point within or adjacent to the cleavage domain to remove the blocking group from the oligonucleotide primer (paragraphs 0093, 0125, 0179-0185); and
(d) extending the oligonucleotide primer with the high-discrimination polymerase (paragraphs 0093, 0125, 0179-0185).
Regarding claims 26-27 and 53-54, Behlke et al. teach that the polymerase is a high discrimination polymerase, a mutant H784Q Taq polymerase that is reversibly inactivated via chemical, aptamer, or antibody modification (paragraphs 086-087, 0126-0133, 0183).
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 Walder, Zhang, Spier and Behlke since each reference teaches methods for improving nucleic acid amplification and reducing non-specific priming events, with Walder, Spier and Behlke particularly teaching the use of blocked primers that are unblocked after they anneal to their templates.
Walder and Behlke teach the use of hot start protocols, wherein a hot start RNase H2 that gains activity at higher temperatures is used to cleave a modified oligonucleotide primer when the primer hybridizes to a template to generate a functional 3’ end, wherein the ability of the RNase H2 enzyme to distinguish between base-pair match vs. mismatch at the RNA base cleavage site allows the protocol to be used for genotyping, including SNP discrimination, wherein the protocol is referred to as rhPCR (see paragraph 27 and Figures 18, 24 and 33 of Walder, and paragraph 179 of Behlke).
Behlke further teaches the use of high-discrimination DNA polymerases e.g. H784Q Taq polymerase that can improve the rhPCR assay since the modified polymerases can reduce priming efficiency when rare RNase H2 cleavage events occur at the 3’-side of the RNA base (see Behlke, paragraph 181, lines 1-12).
Spier teaches alternate means for cleaving the blocking moiety from a blocked primer, including the use of an endonuclease, a polymerase with a 3’-exonuclase activity or an RNase H enzyme, wherein the blocked primer may comprise an abasic site or an RNA base (see paragraphs 14, 25 and 30).
Walder suggest providing a tailed primer and Spier further teaches that the blocker primer may also be a tailed primer comprising a binding sequence for a universal primer, wherein universal primers are used to amplify the target sequence and incorporate P5/P7 next-generation sequencing tags and may also comprise index/sample bar codes (see Spier, paragraphs 42 and 63 and Figure 8).
Thus, an ordinary practitioner would have been motivated to combine the methods of Walder, Spier and Behlke since Spier teaches that blocked primers may also comprise a tail region comprising a binding site for a universal primer, wherein the universal primer may be used to add tag sequences and index/barcode sequences to the amplified target nucleic acid samples for use in next-generation sequencing protocols. Spier further teaches that combining the use of blocked primers and universal primers in a closed-tube amplification reaction is very useful for highly multiplexed reactions, since unblocked “primers form primer dimers that tend to dominate the amplification. Blocked primers are extremely resistant to primer dimer formation, thus enabling high multiplex PCR” (see Spier, paragraph 14). Furthermore, Behlke teaches a means to reduce the frequency of undesired mispriming following undesired 3’-cleavage events by RNase H2, therefore improving mismatch discrimination of the rhPCR assay, and therefore the use of the novel mutant DNA polymerases to improve specificity and SNP discrimination of rhPCR would have provided one of skill in the art a reasonable expectation of success using the mutant polymerases of Behlke in the hot start RNase H2 assays taught by Walder (see Behlke, paragraph 181, lines 12-22).
Walder, Zhang, Spier and Behlke together teach the limitations of claims, as discussed above.
It would also have been prima facie obvious to one of the ordinary person skilled in the art before the effective filing date of the invention to modify the methods of Walder, Spier and Behlke with the use of a target nucleic acid sequence treated with a gene editing enzyme as taught by Zhang et al. to develop an improved and sensitive method for detecting target DNA sequence variation and enrichment of the target nucleic acid for sequencing.
Thus, an ordinary practitioner would have been motivated to combine the references to have a reasonable expectation of success that the combination would result in a sensitive detection of the target DNA sequence variation and enriching target nucleic acid because Walder, Spier and Behlke teach nuclease-based assays using blocked primers for detecting sequence variations, and Zhang et al. explicitly teaches that the target nucleic acid treated with CRISPR/Cas gene editing enzyme would minimize off-target cleavage, but would provide samples with on-target sequence alterations and enhance accurate detection of gene variation and sequence by the methods of Walder, Spier and Behlke (see Zhang, at least paragraphs 00820-00829) and such a modification is considered obvious over the cited prior art.
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 14, 16-24, 26-28, 30-51 and 53-54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16 and 21-41 of U.S. Patent No. 10,886,006B2 in view of Walder et al. (filed 04/30/2009, US2009/0325169).
Although the claims at issue are not identical, they are not patentably distinct from each other.
Similar to claims 16 and 21-41 of U.S. Patent No. 10,886,006, the instant detection methods and/or target enrichment of claims 14, 16-24, 26-28, 30-51 and 53-54 provide a reaction mixture comprising:
a high-discrimination polymerase,
a sample nucleic acid comprising the target DNA sequence, wherein the target DNA sequence has been altered with a gene editing enzyme, and where the target sequence may or may not have the variation,
an oligonucleotide primer containing a 5′ tail sequence that comprises a universal primer sequence and optionally a universal probe sequence, wherein the tail is non-complementary to the target DNA sequence, the oligonucleotide primer having a cleavage domain positioned 5' of a blocking group, the blocking group linked at or near the end of the 3'-end of the oligonucleotide primer wherein the blocking group prevents primer extension and/or inhibits the primer from serving as a template for DNA synthesis
a cleaving enzyme.
Omitted from claims 16 and 21-29, and 34-41 of U.S. Patent No. 10,886,006
Omitted from claims 16 and 21-29, and 34-41 of U.S. Patent No. 10,886,006 when compared to the instant claims 14, 16-24, 26-28, 30-51 and 53-54 are the limitations that the cleaving enzyme is a thermostable, hot start cleaving enzyme comprising at least one amino acid substitution as compared to its wild type, that has reduced activity at lower temperatures and the hot start cleaving enzyme exhibits enhanced mismatch discrimination as compared to its wild type.
Claims 22-23, 30-33, 40-41 of U.S. Patent No. 10,886,006 vs. the instant claims 26-27, the instant claims 30-31, and the instant claims 14, 16-24,26-28, 30-51 and 53-54)
Claims 22-23 of U.S. Patent No. 10,886,006 recite the gene editing enzyme consisting a CRISPR enzyme, OR Cas9 or Cpf1.
Claims 30-33 of U.S. Patent No. 10,886,006 are directed to a hot start cleaving enzyme which is thermostable and has reduced activity at lower temperatures (claim 30, claim 33), the thermostable start cleaving enzyme that has reduced activity at lower temperatures is RNase H2 enzyme (claim 31), or is Pyrococcus abyssi RNase H2 enzyme (claim 32) respectively.
Claims 40-41 of U.S. Patent No. 10,886,006 recite the high discriminating polymerase is a mutant H784Q Taq polymerase.
Omitted from claims 16 and 21-29, and 30-41 of U.S. Patent No. 10,886,006
Accordingly, claims 16 and 21-29, and 30-41 of U.S. Patent No. 10,886,006 do not teach a hot start cleaving enzyme comprises at least one amino acid substitution as compared to its wild type, exhibiting enhanced mismatch discrimination as compared to its wild type.
Walder et al. (US2009/0325169)
Walder et al. teaches a similar method for detecting a variation in a target nucleic acid using as the hot start cleaving enzyme, mutant Pyrococcus abyssi RNase H2 having amino acid having the G169A amino acid substitution (see entire document, see para [0152]-[0153], Tables 1-4, and table 4 indicating mutant Pyrococcus abyssi RNase H2 with accession number AJ248284 that comprises alanine at position 169).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of U.S. Patent No. 10,886,006 with the teaching of Walder to use a modified cleaving enzyme to develop an improved and sensitive method for detecting a target DNA sequence variation and enriching the target nucleic acid for sequencing.
The ordinary person skilled in the art would have motivated to combine the claims with a modified cleaving enzyme as taught by Walder et al. to have a reasonable expectation of success that the combination would result in a sensitive detection of the target DNA sequence variation and enriching target nucleic acid because Walder et al. explicitly teaches the use of a modified cleaving enzyme in improved cleavage of the target at the discriminating nucleotide in the target (see at least para 0218 and table 4) and such a modification is considered obvious over the claims of U.S. Patent No. 10,886,006.
Claims 14, 16-24, 32 and 43-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-17 of U.S. Patent No. 11,926,866B2 in view of Walder et al. (filed 04/30/2009, US2009/0325169).
Although the claims at issue are not identical, they are not patentably distinct from each other.
Similar to claims 16-17 of U.S. Patent No. 11,926,866B2, the instant detection methods of claims 14, 16-24, 32, 43-51 provide a reaction mixture comprising:
a high-discrimination polymerase,
a sample nucleic acid comprising the target DNA sequence, wherein the target DNA sequence has been altered with a gene editing enzyme,
an on-target oligonucleotide primer containing a 5′ tail sequence that comprises a universal primer sequence, wherein the tail is non-complementary to the target DNA sequence, said on-target oligonucleotide primer having a cleavage domain positioned 5' of a blocking group, the blocking group linked at or near the end of the 3'-end of the oligonucleotide primer wherein the blocking group prevents primer extension and/or inhibits the primer from serving as a template for DNA synthesis, AND/OR
one or more off-target oligonucleotide primers containing a 5′ tail sequence that comprises a universal primer sequence, wherein the tail is non-complementary to the target DNA sequence,
said one or more off-target oligonucleotide primers having a cleavage domain position 5′ of a blocking group and a complementary region flanking one or more predicted off-target genome edited loci, wherein the blocking group prevents primer extension and/or inhibits the oligonucleotide primer from serving as a template for DNA synthesis,
a cleaving enzyme.
Omitted from claims 16-17 of U.S. Patent No. 11,926,866
Omitted from claims 16-17 of U.S. Patent No. 11,926,866B2 when compared to the instant claims 14, 16-24, 32, 43-51 are the limitations that the cleaving enzyme is a thermostable, hot start cleaving enzyme comprising at least one amino acid substitution as compared to its wild type, that has reduced activity at lower temperatures and the hot start cleaving enzyme exhibits enhanced mismatch discrimination as compared to its wild type.
Walder et al. (US2009/0325169) (claims 14, 16-24, 32, 43-51)
Walder et al. teaches a similar method for detecting a variation in a target nucleic acid using as the hot start cleaving enzyme, mutant Pyrococcus abyssi RNase H2 having amino acid having the G169A amino acid substitution (see entire document, see para [0152]-[0153], Tables 1-4, and table 4 indicating mutant Pyrococcus abyssi RNase H2 with accession number AJ248284 that comprises alanine at position 169).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of U.S. Patent No. 11,926,866B2 with the teaching of Walder to use a modified cleaving enzyme to develop an improved and sensitive method for detecting a target DNA sequence variation and enriching the target nucleic acid for sequencing.
The ordinary person skilled in the art would have motivated to combine the claims with a modified cleaving enzyme as taught by Walder et al. to have a reasonable expectation of success that the combination would result in a sensitive detection of the target DNA sequence variation and enriching target nucleic acid because Walder et al. explicitly teaches the use of a modified cleaving enzyme in improved cleavage of the target at the discriminating nucleotide in the target (see at least para 0218 and table 4) and such a modification is considered obvious over the claims of U.S. Patent No. 11,926,866B2.
Conclusion
No claims are currently allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OLAYINKA A OYEYEMI whose telephone number is (571)270-5956. The examiner can normally be reached Monday -Thursday: 9:00 am - 5:00 pm, EST.
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OLAYINKA A. OYEYEMI
Examiner
Art Unit 1681
/OLAYINKA A OYEYEMI/Examiner, Art Unit 1681 /GARY BENZION/Supervisory Patent Examiner, Art Unit 1681
