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 .
Drawings
The drawings 1 and 7C are objected to because the refer to colors (“green” and “red”) but the drawings are not in color. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
Claims 1-13 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.
In claim 1(a) and 2(a) the phrase “the telomere repeat sequence” lacks proper antecedent basis because no repeat sequence is previously mentioned. While telomeres may have a main repeat sequence, they might also contain other repeats and are not always uniform throughout their entire length.
In claim 2(c) “the subtelomeric region” lacks proper antecedent basis because the claim does not recite or require the presence of a subtelomeric region in the genomic DNA that is contacted in step (a), and so it is not clear which region is “the subtelomeric region.”
In claim 6, the antecedent basis of “the fluorescently labeled sequences” is unclear, since sequences were labeled in part(b) and in part (d) and it is unclear which must be used as a barcode.
In claim 7, the antecedent basis of “the labeled DNA” is unclear since sequences were labeled in part(b) and in part (d) and it is unclear which must be labeled.
In claims 8 and 9, “the target sequence” lacks antecedent basis since claim 1 does not previously mention a target sequence.
Any claim not specifically mentioned is indefinite for the issue mentioned in claims 1 and 2. All other rejected claims depend from one of these.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-4, 6-8, 10, 12-15, and 17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by McCaffrey et al. (Nucleic Acids Research, published online 19 October 2015, vol. 44, No. 2, e11; 8 pages).
McCaffrey et al. teach a method of measuring telomere repeat length which includes contacting a gRNA specific for a telomere, first labeling the telomere with Cas9n fluorescent nick-labeling of red fluorescent nucleotides (claim 1, steps (a) and (b)), and then labeling DNA molecules with green nucleotides by Nt. BspQI nick-labeling (p. 6, first column; Figure 4B; claim 1 steps (c) and (d)). The reference teaches using sequence motif labeling over extended sub-telomere regions linked to Cas9n fluorescent nick labeling to identify the specific subtelomere (i.e. using the motif labeled nucleic acid as a barcode specific for the chromosome (p. 6, 2nd column)). Figure 4B shows the results from a method wherein genomic DNA was labeled by CAS9n fluorescent nick-labeling followed by motif labeleing with Nt. BspQ1. See also Figure 5 and related method description. Thus, McCaffery et al. anticipates claim 1. With regard to claim 14, the gRNA to a repetitive telomere sequence is a guide RNA having a portion complementary to a first target sequence that is a “motif sequence.”
With regard to claim 3, the reference teaches the length of the telomer is determined by comparing the intensity of the fluorescence to a standard (p. 6, first column, comparing to “known controls”).
With regard to claim 6, the fluorescently labeled sequences are used as a barcode to identify the chromosome (See figure 5 and description).
With regard to claim 7, the reference teaches ligating the labeled DNA with a ligase (p. 3, 1st column).
With regard to claims 8 and 15, the target telomere sequence labeled was 20 bases and is complementary to the telomere (Figure 4B).
With regard to claim 10, the guide RNA comprises a crRNA and a tracrRNA (p. 3, 2nd column).
With regard to claim 12, the guide RNA and the Cas9n form a complex prior to exposing to genomic DNA (p. 2, 2nd column).
With regard to claim 13, the Cas9 nickase is Cas9 D10A (title, throughout).
With regard to claim 17, the genomic DNA is mapped to find areas of high density of the target sequence (see Figure 4B).
McCaffery et al. teach contacting a genomic sample with a guide RNA (crRNA) specific for a telomeric repeat sequence and guide RNA for subtelomeric sequences and incubating these with Cas9n D10A (p. 2, 2nd column; p. 5, 1st column).
The reference teaches labeling nicked DNA with labeled nucleotides (p. 2, 2nd column; p. 5, 1st column; figure 3C).
The reference teaches detecting the length of the telomere by measuring the fluorescence of the first fluorescently nucleotide at the telomere repeat location (Figure 3C). Thus, the reference anticipates claim 2.
With regard to claim 4, the second guide RNA comprises multiple guide RNAs complementary to a different target sequence, detecting the fluorescent label, the pattern of which is a fluorescent barcode of the genomic DNA (p. 7, first column).
Claim(s) 14, 15 and 17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Church et al. (US 2018/0320226).
Church teaches a method in which a target DNA is nicked by providing a guide RNA that hybridizes to a portion of the genome and nicking the genome with a Cas9 nickase followed by extension initiated from the nick, a process which includes steps (a) and (b) of claim 14. The reference teaches that the primer extension is initiated from the nick to include a detectable label with the complementary strand serving as a template to detect the target. This feature of the disclosed invention can be used to include a detectable label in an extension product thereby detecting the target nucleic acid, where the reference teaches a detectable label includes a fluorescent label. See ¶3, 4, 15, 58, 94, 102, 110. The reference teaches the method can be used for enumerating repeat number, such as enumerating telomere sub-unit repeats, ¶0118. Regarding the requirement that the target sequence is a “motif” the specification does not provide a limiting definition of “motif.” It states that “a motif sequences” refers to a short DNA sequence, which generally recurs in the genome. See p. 13, lines 4-5. The broadest reasonable interpretation of “motif sequence” as set forth in the claim, therefore encompasses any “short” sequence, whether or not it recurs in the genome since the recurrence discussed in the specification does not put a limiting definition on the claim language. Furthermore, “short” is a relative term that is undefined. Thus, as guide RNA are “short”, relative to a chromosome, for example, it is inherent to the method of Church that the “target sequence” is a motif sequence found in genomic DNA.
Church teaches gRNA complementary to 20 nucleotides of target nucleic acid (¶0007).
The limitation of claim 17 states an outcome of practicing the steps of the method, but does not require any further action. Therefore, it follows that by practicing the step of claim 14, the genomic DNA is mapped. The recitation “to find areas of high density of the target sequence” is intended use.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Church et al. (US 2018/0320226) in view of WO2016/028843 (Cited in parent application).
The teachings of Church are given previously in this Office action and are fully incorporated here.
Church does not disclose that the guide RNA has one or two mismatches in the first 8 nucleotides of the target sequence.
WO2016/028843 teaches that a guide RNA could have one or two mismatches at the 5’ end of its sequence (p. 3, lines 4-6, and p. 71, lines 25-27).
It would have been obvious to one of ordinary skill in the art to modify Church with the teaching of WO2016/028843 for the purpose of allowing for mutation or polymorphism within the target sequence while still permitting Cas9 binding to the guide RNA.
Claim(s) 1, 3, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hastie et al. ((2013) PLoS ONE 8(2): e55864. doi:10.1371/journal.pone.0055864.) in view of Church et al. (US 2018/0320226).
Hastie et al. teach a method that includes contacting genomic DNA with a nickase to produce single-stranded break in the genomic DNA at a first target motif sequence, contacting the nicked DNA with a polymerase and a fluorescently labeled nucleotide, wherein the fluorescently labeled nucleotide is incorporated into the nicked DNA at the first target. Hastie et al. further teach repeating this step with a second round of labeling wherein a different target site is nicked with a different nickase. Hastie teaches that genome mapping on a nanochannel allows precise and accurate measurement of the distance between nick-labels on DNA molecules comprising a signature pattern (p. 2, 1st Column), and provide an improved method where a two color system is used to improve information density (p. 2, 1st column). Hastie includes steps of comparing the identified fluorescence maps to standards see figures 2, 5 and 7, for example.
Hastie teaches ligating labeled DNA with a ligase, p. 9, Col. 1.
The reference does not teach creating nicks using a guide RNA having a portion complementary to a first motif and a Cas9 nickase to produce the single stranded break. The reference does not teach detecting the length of a telomere.
Church teaches a method in which a target DNA is nicked by providing a guide RNA that hybridizes to a portion of the genome and nicking the genome with a Cas9 nickase followed by extension initiated from the nick. The reference teaches that the primer extension is initiated from the nick to include a detectable label with the complementary strand serving as a template to detect the target. This feature of the disclosed invention can be used to include a detectable label in an extension product thereby detecting the target nucleic acid. See ¶3,4, 15, 58, 94, 102, 110. The reference teaches one or multiple complexes can be detected at once and a pattern of complexes can be used to provide a map of the DNA molecule, ¶28. The reference teaches multiple sites of labeling can be used as a mapping tool, ¶94. The reference teaches the method can be used for enumerating repeat number, such as enumerating telomere sub-unit repeats, ¶0118.
Church teaches gRNA complementary to 20 nucleotides of target nucleic acid (¶0007).
Church teaches guide RNA can comprise a crRNA and a tracrRNA or a or a fusion of these (single guide RNA) (¶0020).
The Cas9 and the guide RNA are complexed before being used to target DNA (¶27).
Church teaches the Cas9 nickase is a D10A mutation or a H840A mutant (¶0102). It would have been obvious to one having ordinary skill in the art to have modified the method taught by Hastie et al. so as to have substituted Cas9 nicking and labeling for one of the labeling steps taught in the reference OR to have simply added an additional step of nicking and labeling telomere sequences by employing a guide RNA for labeling telomere sub-unit repeat number. Labeling telomere subunit repeats within the method of Hastie et al. would provide greater density of information on genomic fragments that comprise telomeres and would support mapping these portions of the genome. One would have been motivated to make the modification because Church teaches that an advantage of using the Cas9 nickase approach is that the location where nicks are created is programmable via the use of the guide RNA, and multiple specific locations can be targeted (¶15), and the reference further specifically teaches that one such target region would be telomere repeats (¶118). Such an approach would have added to the genomic information that could be gathered and mapped, and further the analysis within the nanochannel taught by Hastie would include detecting the length of the telomere by measuring the number of repeats. It would have been obvious, following the method taught by Hastie et al. to use the fluorescently labeled motif sequences to identify the genomic sequence, that is to identify the chromosome. Furthermore, with regard to claim 5, it would have been obvious to carry out the labeling steps in any order as there is no evidence that any one labeling must occur before another in order to support the functionality of the method. Changing the order of steps was prima facie obvious. See MPEP 2144.04.
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hastie in view of Church as applied to claims 1, 3, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, and 17 above, and further in view of WO2016/028843.
The teachings of Hastie in view of Church are given previously and are incorporated here.
Hastie in view of Church does not disclose that the guide RNA has one or two mismatches in the first 8 nucleotides of the target sequence.
WO2016/028843 teaches that a guide RNA could have one or two mismatches at the 5’ end of its sequence (p. 3, lines 4-6, and p. 71, lines 25-27).
It would have been obvious to one of ordinary skill in the art to modify Church in view of Hastie with the teaching of WO2016/028843 for the purpose of allowing for mutation or polymorphism within the target sequence while still permitting Cas9 binding to the guide RNA.
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 14-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11761028. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the issued patent anticipate the instant claims.
The specification states that “a motif sequences” refers to a short DNA sequence, which generally recurs in the genome. The broadest reasonable interpretation of “motif sequence” as set forth in the claim, therefore encompasses any “short” sequence, whether or not it recurs in the genome since the recurrence discussed in the specification does not put a limiting definition on the claim language. Furthermore, “short” is a relative term that is undefined.
The issued claims teach contacting genomic DNA with a guide RNA having a portion complementary to a first sequence in the genomic DNA and with Cas9 nickase to produce a single-stranded break in the genomic DNA at the first target sequence, contacting the nicked DNA with a polymerase and a fluorescently labeled nucleotide, whine the fluorescently labeled nucleotide is incorporated into the nicked DNA at the first target sequence, wherein the target sequence is a motif sequences found in the genomic DNA. The “motif sequence” in this rejection is the “target genomic sequence,” which is “short” relative to the length of an entire chromosome, for example. See claims 1, 7, and 8. With regard to claim 17, this “wherein” clause does not require any further action that distinguishes the claim from the issued claim; it merely sets forth an intended outcome or use of the claimed method.
Claims 14 and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10640810. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the issued patent anticipate the instant claims.
The specification states that “a motif sequences” refers to a short DNA sequence, which generally recurs in the genome. The broadest reasonable interpretation of “motif sequence” as set forth in the claim, therefore encompasses any “short” sequence, whether or not it recurs in the genome since the recurrence discussed in the specification does not put a limiting definition on the claim language. Furthermore, “short” is a relative term that is undefined.
The issued claims teach contacting genomic DNA with a guide RNA having a portion complementary to a first sequence in the genomic DNA and with Cas9 nickase to produce a single-stranded break in the genomic DNA at the first target sequence, contacting the nicked DNA with a polymerase and a fluorescently labeled nucleotide, whine the fluorescently labeled nucleotide is incorporated into the nicked DNA at the first target sequence, wherein the target sequence is a motif sequences found in the genomic DNA. The “motif sequence” in this rejection is the “target sequence in the genomic DNA,” which is “short” relative to the length of an entire chromosome, and which issued claim 11 teaches is a repeated sequence. See claims 1, 11, and 19. With regard to claim 17, this “wherein” clause does not require any further action that distinguishes the claim from the issued claim; it merely sets forth an intended outcome or use of the claimed method.
Claims 1, 3, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10640810 in view of Church et al. (US 2018/0320226).
The issued claims teach a method that is generic to instant claim 1 but does not teach the method of claim 1 wherein the guide RNA has complementary to a telomere repeat sequence.
Church teaches a method in which a target DNA is nicked by providing a guide RNA that hybridizes to a portion of the genome and nicking the genome with a Cas9 nickase followed by extension initiated from the nick. The reference teaches that the primer extension is initiated from the nick to include a detectable label with the complementary strand serving as a template to detect the target. This feature of the disclosed invention can be used to include a detectable label in an extension product thereby detecting the target nucleic acid. See ¶3,4, 15, 58, 94, 102, 110. The reference teaches one or multiple complexes can be detected at once and a pattern of complexes can be used to provide a map of the DNA molecule, ¶28. The reference teaches multiple sites of labeling can be used as a mapping tool, ¶94. The reference teaches the method can be used for enumerating repeat number, such as enumerating telomere sub-unit repeats, ¶0118.
Church teaches gRNA complementary to 20 nucleotides of target nucleic acid (¶0007).
Church teaches guide RNA can comprise a crRNA and a tracrRNA or a or a fusion of these (single guide RNA) (¶0020).
The Cas9 and the guide RNA are complexed before being used to target DNA (¶27).
Church teaches the Cas9 nickase is a D10A mutation or a H840A mutant (¶0102). It would have been obvious to one having ordinary skill in the art to have modified the method taught by the issued so as to have substituted Cas9 nicking and labeling for one of the labeling steps taught in the reference OR to have simply added an additional step of nicking and labeling telomere sequences by employing a guide RNA for labeling telomere sub-unit repeat number. Labeling telomere subunit repeats within the method of the issued patent would provide greater density of information on genomic fragments that comprise telomeres and would support mapping these portions of the genome. One would have been motivated to make the modification because the Church teaches that an advantage of using the Cas9 nickase approach is that the location where nicks are created is programmable via the use of the guide RNA, and multiple specific locations can be targeted (¶15), and the reference further specifically teaches that one such target region would be telomere repeats (¶118). Such an approach would have added to the genomic information that could be gathered and mapped, and further the analysis within the nanochannel taught by the issued patent would include detecting the length of the telomere by measuring the number of repeats. It would have been obvious, following the method taught by the claims of the issued patent to use the fluorescently labeled motif sequences to identify the genomic sequence, that is to identify the chromosome. Furthermore, with regard to claim 5, it would have been obvious to carry out the labeling steps in any order as there is no evidence that any one labeling must occur before another in order to support the functionality of the method. Changing the order of steps was prima facie obvious. See MPEP 2144.04.
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10640810 in view of Church and WO2016/028843.
Claim 16 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10640810 in view of WO2016/028843.
The issued patent and Church do not disclose that the guide RNA has one or two mismatches in the first 8 nucleotides of the target sequence.
WO2016/028843 teaches that a guide RNA could have one or two mismatches at the 5’ end of its sequence (p. 3, lines 4-6, and p. 71, lines 25-27).
It would have been obvious to one of ordinary skill in the art to modify the issued patent or the issued patent in view of Church with the teaching of WO2016/028843 for the purpose of allowing for mutation or polymorphism within the target sequence while still permitting Cas9 binding to the guide RNA.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682