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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-5, 9-10, 16-17, 20, 22-23, 28, 31, 33-34, 42-44, 46-48, and 72) in the reply filed on 4/29/2026 is acknowledged. Claim 57, Group II, has been cancelled in the claims filed 4/29/2026.
Additionally, claim 72 (drawn to a system (product)) was inadvertently grouped with Group I (drawn to a method). Claim 72 (Group III) lacks unity of invention with Groups I and II for the same reasons as presented in the Restriction/Election requirement of 3/2/2026 (shared technical features are not special technical features in light of the prior art). A call was made to Adrian Barker (Attorney of Record) on 5/13/2026 (summarized in the Interview Summary attached to this Office Action). Dr. Barker was asked if the Applicant elects for the method of claims 1-5, 9-10, 16-17, 20, 22-23, 28, 31, 33-34, 42-44, and 46-48 (amended Group I) or the product of claim 72 (Group III) to be examined. Applicant has elected for the method (claims 1-5, 9-10, 16-17, 20, 22-23, 28, 31, 33-34, 42-44, and 46-48) to be examined. Therefore, claim 72 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the phone call made on 5/13/2026.
Claims 1-5, 9-10, 16-17, 20, 22-23, 28, 31, 33-34, 42-44, and 46-48 are being examined on the merits.
Specification
The use of the terms “SMRT”, “MinION”, “GridION”, “PromethION” (paragraphs [0047, 0068]), “Nanobind” (paragraph [0059]), “KEGG”, “OMIM”, and “PharmGKB” (paragraph [00113]), which are trade names or marks used in commerce, have been noted in this application. These terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The examples above are not an exhaustive list of unmarked trade names or marks used in commerce throughout the specification. Please carefully read through and properly notate each instance.
Claim Objections
Claim 10 is objected to because of the following informalities: Claim 10, step (v), reads “third nucleotide sequence and said fourth nucleotide sequence” and should read “said third nucleotide sequence and said fourth nucleotide sequence” to remain consistent with the format of the rest of the claim. Appropriate correction is required.
Claim Rejections - 35 USC § 112b - Indefiniteness
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.
Claims 42-43 are 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 "said sequencing" in line 1. There is insufficient antecedent basis for this limitation in the claim. The indefiniteness of this claim could be resolved if claim 42 were to depend from claim 16.
Claim 43 depends from claim 42, inherits this deficiency, and is rejected on the same basis.
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.
Claims 1-5, 9-10, 16-17, 20, 22-23, 28, 31, 33-34, 42-44, and 46-48 are rejected under 35 U.S.C. 103 as being unpatentable over Ouellet (Ouellet et al., WO 2020/099675 A1; cited on IDS of 3/11/2025) in view of Shuber (US 2019/0071716 A1; cited on IDS of 5/23/2024).
Claim 1: Ouellet teaches a method of analyzing a genomic region of interest (“target region”) isolated from a sample comprising two steps of isolation of the genomic region of interest (pg 2-3, ln 32-35 and ln 1-19) followed by downstream analysis (pg 45, ln 17-18). Ouellet teaches a method of contacting genomic DNA comprising the genomic region of interest with a CRISPR-associated endonuclease and an outer pair of gRNAs, thereby generating a first excised fragment comprising the genomic region of interest (pg 37, ln 26-37-pg 38, ln 1-6 (step (a)) and Figure 1). Ouellet teaches contacting the nucleic acid fragment of the previous step with a CRISPR-associated endonuclease and an inner pair of gRNAs (pg 38, ln 12-22 and Figure 1).
Ouellet teaches that the CRISPR-associated endonucleases used in the methodology can be Class 2 Type V or Class 2 Type II Cas proteins (pg 37-38), and that said endonuclease is preferably Cas9 (pg 34, ln 19). Ouellet teaches that in a preferred embodiment of this method, that the CRISPR-associated endonuclease employed for the second isolation step is a catalytically dead version of Cas9, in order to ensure that the Cas protein “will have no impact on the structure of the ends of said nucleic acid molecule” (dCas9, pg 34, ln 22-23, Figure 1). However, there are other advantageous reasons for using catalytically active versus catalytically dead versions of CRISPR-associated endonucleases for target region isolation and analysis, as taught by Shuber.
Shuber teaches a method of negative enrichment of target nucleic acids in plasma samples using Cas endonucleases (Abstract). Shuber teaches that catalytically inactive Cas endonuclease fails to remain bound to targets in a plasma sample when exposed to exonucleases, therefore precluding negative enrichment (paragraph [0006]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Ouellet with that of Shuber to include catalytically active Cas proteins in the second isolation step. One would be motivated to do so given the assertion by Shuber that catalytically dead Cas proteins would not protect the target genomic region from the second exonuclease digestion step of Ouellet if said methodology was performed on particular types of samples such as plasma samples (paragraph [0006]). Shuber teaches that using catalytically active Cas endonucleases allows for isolation of target sequences from plasma samples without requiring significant preparation of said sample (paragraph [0044]). One would have a reasonable expectation of success given that Ouellet describes that the catalytically dead Cas9 protein is a preferred embodiment of their methodology, but that catalytically active Cas proteins could also be employed (pg 34). Usage of a catalytically active Cas protein in the second isolation step of Ouellet would create a “second” excised fragment containing the genomic region of interest.
Claim 2: Ouellet teaches that the CRISPR-associated endonuclease and said outer pair of gRNAs of a) associate with and block the 5’ and 3’ ends of said first excised fragment (pg 1, ln 26-28, pg 7, ln 21-29, Figure 1).
Claim 3: Ouellet teaches contacting the first excised fragment with one or more exonucleases, such that background genomic DNA is digested and said first excised fragment is not digested (pg 1, ln 26-28, pg 38, ln 7-8).
Claim 4: Ouellet teaches that the one or more exonucleases can be exonuclease I or exonuclease III.
Claim 5: Ouellet teaches that the outer pair of gRNAs comprises a first and second outer gRNA, with the first outer gRNA having a sequence complementary to a first nucleotide sequence and the second outer gRNA having a sequence complementary to a second nucleotide sequence, wherein the first and second nucleotide sequences are different and they flank the genomic region of interest (pg 7, ln 21-29 and Figure 1).
Claim 9: The phrase “up to about 100 kilobases” is being interpreted as meaning that either the first outer gRNA, the second outer gRNA, or both can be at most about 100 kilobases away from the genomic region of interest but there is no lower limit as to how close said outer gRNAs can be. Therefore, the teaching of Ouellet that the outer gRNAs are flanking (are “outside”) the genomic region of interest reads on the outer gRNAs not being more than 100 kilobases away from the genomic region of interest (pg 7, ln 21-29).
Claim 10: Ouellet teaches that the inner pair of gRNAs comprises a first and second inner gRNA, with the first inner gRNA having a sequence complementary to a third nucleotide sequence and the second inner gRNA having a sequence complementary to a fourth nucleotide sequence, wherein the third and fourth nucleotide sequences are different and they flank the genomic region of interest (pg 33, ln 9-12, pg 35, ln 17-23, pg 36, ln 4-5). The third and fourth sequences are preferably “nested between” saif first sequence and second sequence, meaning that the third sequence and the fourth sequence are at a base length close to the genomic region of interest than the first and second sequences (pg 35, ln 29-32), which in turn would excise a fragment smaller in base length than the first excised fragment (when the CRISPR-associated endonuclease is catalytically active in the second isolation step).
Claim 16: Ouellet teaches that the analyzing comprises sequencing the genomic region of interest that has been isolated (pg 45, ln 18).
Claim 17: Ouellet teaches performing the method on genomic DNA at an amount of 10ug (pg 61, ln 11).
Claim 20: Ouellet teaches that the method further comprises, prior to the second contacting step of the inner gRNA and CRISPR-associated endonuclease, isolating the first excised fragment (pg 61, ln 15-17).
Claims 22 and 44: Ouellet teaches that the method does not involve DNA amplification (pg 1, ln 31-32 and pg 29, ln 5-7).
Claim 23: Ouellet teaches, before downstream analysis, attaching one or more adapters to the ends of the second fragment (pg 5, ln 10-12).
Claim 28: Ouellet teaches that the CRISPR-associated endonuclease is Cas9 (pg 34, ln 19).
Claim 31: Ouellet teaches that the genomic DNA is not fragmented, digested, or sheared prior to a) (no fragmentation steps in the preferred methodology as described on pg 38-39). Ouellet teaches that fragmentation can occur, but that this is an optional supplementary step (pg 25).
Claim 33 and 34: Ouellet teaches that the genomic region of interest is a complex genomic region which comprises one or more repeat regions or duplications (pg 7, ln 35-36).
Claims 42 and 43: Ouellet teaches that the sequencing nanopore-based sequencing, which by definition is a type of long-read sequencing (pg 45, ln 30).
Claims 46-48: Ouellet teaches that the genomic DNA is obtained in a sample (pg 2, ln 33), specifically a biological sample (pg 5, ln 15). Ouellet teaches that the biological sample can be a bodily fluid or a solid tissue sample (pg 5, ln 23). Ouellet teaches that the nucleic acid isolation of the invention can be used for diagnostics, meaning that the samples employed would be diagnostic samples (pg 40, ln 2).
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 1-5, 9-10, 16-17, 20, 22-23, 28, 31, 33-34, 42-44, and 46-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 74-78, 81, 87, 90, 92-94, and 96-98 of copending Application No. 17/766,946 in view of Ouellet (Ouellet et al., WO 2020/099675 A1; cited on IDS of 3/11/2025) and Shuber (US 2019/0071716 A1; cited on IDS of 5/23/2024).
Although the claims are not identical, they are not patentably distinct from each other because both sets of claims are drawn to the same limitations. Any additional limitations of the ‘946 claims are encompassed by the open claim language “comprising” found in the instant claims.
Regarding claim 1: The method of claims ‘946 teach analyzing an excised fragment containing a complex genomic region using two or more gRNAs and a CRISPR-associated endonuclease that flank said complex genomic region.
The claims of ‘946 do not teach performing a second isolation step in which an inner pair of gRNAs and a CRISPR-associated endonuclease are contacted with the first excised fragment to generate a second excised fragment. However, performing multiple enrichment methods in succession is known in the art, as taught by Ouellet.
Ouellet teaches a method of analyzing a genomic region of interest (“target region”) isolated from a sample comprising two steps of isolation of the genomic region of interest (pg 2-3, ln 32-35 and ln 1-19) followed by downstream analysis (pg 45, ln 17-18). Ouellet teaches a method of contacting genomic DNA comprising the genomic region of interest with a CRISPR-associated endonuclease and an outer pair of gRNAs, thereby generating a first excised fragment comprising the genomic region of interest (pg 37, ln 26-37-pg 38, ln 1-6 (step (a)) and Figure 1). Ouellet teaches contacting the nucleic acid fragment of the previous step with a CRISPR-associated endonuclease and an inner pair of gRNAs (pg 38, ln 12-22 and Figure 1).
Ouellet teaches that the CRISPR-associated endonucleases used in the methodology can be Class 2 Type V or Class 2 Type II Cas proteins (pg 37-38), and that said endonuclease is preferably Cas9 (pg 34, ln 19). Ouellet teaches that in a preferred embodiment of this method, that the CRISPR-associated endonuclease employed for the second isolation step is a catalytically dead version of Cas9, in order to ensure that the Cas protein “will have no impact on the structure of the ends of said nucleic acid molecule” (dCas9, pg 34, ln 22-23, Figure 1). However, there are other advantageous reasons for using catalytically active versus catalytically dead versions of CRISPR-associated endonucleases for target region isolation and analysis, as taught by Shuber.
Shuber teaches a method of negative enrichment of target nucleic acids in plasma samples using Cas endonucleases (Abstract). Shuber teaches that catalytically inactive Cas endonuclease fails to remain bound to targets in a plasma sample when exposed to exonucleases, therefore precluding negative enrichment (paragraph [0006]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of ‘946 to include a second isolation step with an inner pair of gRNAs and a catalytically active CRISPR-associated endonuclease as taught by Ouellet and Shuber. One would be motivated to perform a second isolation step with an inner pair of gRNAs given the assertion by Ouellet that coupling one isolation method with a second downstream isolation method “the efficacy of isolation of a nucleic acid target region is improved” and “may be improved by at least 10,000-fold” (pg 3, ln 1-3). One would have a reasonable expectation of success given that the first round of isolation performed by Ouellet also employs a gRNA pair that flanks the genomic region of interest and forms a first excised fragment, similar to the methods used in the claims of ‘946. One would be motivated to use catalytically active CRISPR-associated endonuclease in the second isolation method of Ouellet given the assertion by Shuber that catalytically dead Cas proteins would not protect the target genomic region from the second exonuclease digestion step of Ouellet if said methodology was performed on particular types of samples such as plasma samples (paragraph [0006]). Shuber teaches that using catalytically active Cas endonucleases allows for isolation of target sequences from plasma samples without requiring significant preparation of said sample (paragraph [0044]). One would have a reasonable expectation of success given that Ouellet describes that the catalytically dead Cas9 protein is a preferred embodiment of their methodology, but that catalytically active Cas proteins could also be employed (pg 34). Usage of a catalytically active Cas protein in the second isolation step of Ouellet would create a “second” excised fragment containing the genomic region of interest.
Regarding claims 2-5, 9-10, and 17: The teachings of Ouellet in regards to claims 2-5, 9-10, and 17 are cited in the 103 rejection above.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILEY E CASH whose telephone number is (571)272-0971. The examiner can normally be reached Monday-Friday 8:30am-6pm ET.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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