Detailed Action
► The applicant's Preliminary Amendment filed 16 JUN 09 has been entered. Following the entry of the Preliminary Amendment, Claim(s) 1-20 is/are pending.
► The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 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 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.
Priority
► The instant application 17/366,643 is a CON of 15/813,974, filed 15 NOV 2017, now abandoned. 15/813,974 claims priority to Provisional USSN 62422341 filed 15 NOV 2016. Thus the priority date afforded the instant application is 15 NOV 2016.
35 U.S.C. 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 Objections
► Claim(s) 19 is objected to because it fails to recite the SEQ ID NOs associated with the probe ID recited (i.e a1, a2, S1… etc.).
Claim Rejection(s) under 35 U.S.C. 103
► Claim 1-5, 9-10, 13-14, 16-19 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Veres et al. [Cell Stem Cell 15 :27-30(JUL 2014) – hereinafter “Veres”] in view of Bensimon et al [US 2013/0130246 – hereinafter “Bensimon”] and Lu et al. [Applied Biochemistry and Biotechnology Vol. 136-140:: pgs 703-710 (2007) – hereinafter “Lu”].
Claim 1 is drawn to a method for distinguishing edited genomic DNA from unedited genomic DNA comprising:
editing a target sequence in an unedited genomic DNA,
molecularly combing the edited and unedited genomic DNA ;
contacting the combed edited and unedited genomic DNA with a set of genomic Morse code (“GMC”) probes under conditions suitable for hybridization of the probes to the edited and unedited genomic DNA, wherein said GMC probes bind to unedited genomic DNA in and around the target sequence in a known pattern and wherein differential binding of said GMC probes to the edited and unedited genomic DNA distinguishes between edited and unedited genomic DNA;
comparing the signals from bound GMC probes contacted with the edited genomic DNA with signals from bound GMC probes contacted with unedited genomic DNA, and
detecting the edited target sequence when a pattern of GMC probes produced on edited genomic DNA differs from the pattern produced on the unedited genomic DNA
Veres teach the mutagenesis and the genomic analysis of clones produced thereby using whole genome sequencing . In particular, Veres teach mutagenesis using two well known techniques [ i.e. the (CRISPR)-associated systems and TALEN) to perform their mutagenesis. Veres further teach the analysis of both edited and unedited (i.e. wild-type) genomes using whole genome sequencing. (hereinafter WGS), see the entire document., noting especially the para bridging on 29. Veres is silent as regards the exact technique(s) used to perform WGS. However, numerous methods of WGS were known. Consider at least Liang et al. [US 2015/012679 – hereinafter “Liang”] and/or Rava [US 2011/0230358 – hereinafter “Rava”] and/or Lam et al [Nature Biotechnology 30(1) : 78-83 (2012) – hereinafter “Lam”.
That said, Veres does not teach the use of Molecular Combing (hereinafter MC) and Genomic Morse Code probes (hereinafter GMC) to analyze mutagenized genomes. However, the use of MC and GMC probes to analyze modified genomes was known as evidenced by at least Bensimon, see the entire document noting especially paras Accordingly, absent an unexpected result it would have been prima facie obvious to the PHOSITA at the time of the invention to substitute the MC method of analyzing an edited genome(s) as taught by Bensimon for the analysis method (i.e. whole genome sequencing) of Verse. Please note that substitution of one known second method/reagent with known properties for a first known method/reagent with known properties would have been prima facie obvious to the ordinary artisan at the time of the invention in the absence of an unexpected result. As regards the motivation to make the substitution recited above, the motivation to combine arises from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. Support for making this obviousness rejection comes from the M.P.E.P. at 2144.07 and 2144.09, as well as, the SCOTUS decision in KSR International. Co. v. Teleflex, Inc., et al., 550 U.S.398 (2007).
As regards Claims 2-4, Where the general conditions of a claim are disclosed in the prior art, it is not inventive, in the absence of an unexpected result, to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Also as regards Claim 4,note that Bensimon teach the use probes having differently colored fluorophore labels, see at least para 158.
As regards Claim(s) 5 and 9-10, note that Verse teach CRISPR-Cas9, TALEN and NHEJ mutagenesis , see especially the para bridging the columns on pg. 27. As regards Claim 10 Veres makes clear that off-target mutagenic events can occur with both when the CRIPR-Cas9 and TALEN systems.
As regards Claim(s) 16, see Veres cited above.
As regards Claim(s) 13-14 and 17 note at least para 213 in Bensimon. Also note that Herrick et al. [Methods in Molecular Biology 521: 71-101(2009) – hereinafter Herrick teach quantifying chromosomal abnormalities using MC, See the para on pg. 94 which begins “Fully automating the combing procedure…”
As regards Claim(s) 18-20, see at least para 3 in Bensimon. Also note that Bensimon the use of target specific labeled probes (i.e. GMC probes).
► Claim 6-8 and 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Veres in view of Bensimon as applied above against Claims 1-5 and further in view of Silva et al. [Current Gene Therapy 11:11-27(2011) – hereinafter Silva”] and/or Stemmer [US5,605,793 – hereinafter “Stemmer”] and/or Holliger et al. [US 2004/0005594 – hereinafter “Hollinger”] and/or Duchateau et al. [US 2013/0117869 – hereinafter “Duchateau“] and/or Nakagawa et al. [Exp. Animals 63(1) :79-84(2014) – hereinafter “Nakagawa”].
As regards Claim(s) 6-8 and 11, Silva is a review article teaching several Targeted Genome Engineering (i.e. mutagenesis) systems including the use of Meganucleases including meganucleases of the LAGLIDADG family. Silva further teach for example I-CreI and/or I-SceI and Zinc Finger Protein - based systems for mutagenesis. Likewise the patent literature is rich with methods useful for Directed Evolution/mutagenesis/Targeted Genome Engineering. Consider at least for example Stemmer at Columns1-2; Holliger at least at para 305 and/or Duchateau, see at least para 4.
Absent an unexpected result it would have been prima facie obvious to the PHOSITA at the time of the invention to modify the method Verse in view of Bensimon wherein any known mutagenesis method(s) is used in place of the mutagenesis method(s) disclosed by Verse. Note that substitution of one known second method/reagent with known properties for a first known method/reagent with known properties would have been prima facie obvious to the ordinary artisan at the time of the invention in the absence of an unexpected result. As regards the motivation to make the substitution recited above, the motivation to combine arises from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. Support for making this obviousness rejection comes from the M.P.E.P. at 2144.07 and 2144.09, as well as, the SCOTUS decision in KSR International. Co. v. Teleflex, Inc., et al., 550 U.S.398 (2007).
Nakagawa teach knockout mutagenessis using TALEN mediated mutagenesis
► Claim(s) 11-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Veres in view of Bensimon as applied above against Claims 1 and further in view of Tesson et al. [Nature Protocols 29(8) :695-696 (2011) – hereinafter “Tesson”] and Qu et al. [Cancer Genetics 206:1-11(2013) – hereinafter Qu”].
As regards Claims 11-12, Tesson teach inducing genomic modifications (e.g. knockout mice via a TALEN-mediated mutagenesis system and screening for particular knockouts, see the entire document. Qu teach an in situ hybridization assay designed to detect particular known rearrangements (e.g. the TMPRSS2:ERG rearrangement). As such it would have been prima facie to the PHOSITA to modify the method suggested by Veres in view of Bensimon wherein MC assays for the detection of targeted modifications are designed and implemented.
► Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Veres in view of Bensimon as applied above against Claims 1 and further in view of Ran et al. [Nature 520: 186 (2015) – hereinafter “Ran”] and Amer [Molecular and Cellular Therapies 2 :27 (2014) -hereinafter “Amer”].
As regards Claim(s) 15, Ran teach in vivo genome editing using the CRISPR Cas9 system (i.e. gene therapy), see at least the abstract. In addition, other therapies (e.g. surgery, radiotherapy and/or chemotherapy) for the treatment of certain disease including cancer were known, see Amer. The selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results). In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946).
► Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Veres in view of Bensimon as applied above against Claims 1 and further in view of Wu [US 2014/0273226 – hereinafter “Wu”] and/or Kleinstiver et al. [ Nature 523:481 (JUL 2015) – hereinafter “Kleinstiver”].
As regards Claim 16 , Wu teach the use of an engineered nucleases (i.e. engineered CRISPR Cas9 nuclease(s), see at least para 3. See also, Kleinstiver.
► Claim 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Veres et al. [Cell Stem Cell 15 :27-30(JUL 2014) – hereinafter “Veres”] in view of Bensimon et al [US 2013/0130246 – hereinafter “Bensimon”] as applied above against Claim 1 and further in view of Lu et al. [Applied Biochemistry and Biotechnology Vol. 136-140:: pgs 703-710 (2007) – hereinafter “Lu”] and or Chari et al. [ Nature Methods 12(9) :823 (SEP 2015) – hereinafter Chari”] and/or Stemmer.
As regards Claim(s) 21, it was generally known to experimentally compare methods of preforming a given task. For example, it was known in the Genomic Engineering arts to compare method/protocols one to another in order to determine the simplest, cheapest and most efficient means for accomplishing a given task. For example, see at least Lu and/or Chari. Also note Stemmer who teach comparing the efficiency of their mutagenesis method (i.e. DNA shuffling) to a second mutagenesis method (i.e. Error Prone PCR and/or cassette mutagenesis), See at least Fig. 1 and Table 4.
Accordingly absent an unexpected result, it would have been prima facie obvious to the PHOSITA to use the Molecular Combing method of Bensimon to compare methods of genomic engineering (for example: TALEN mutagenesis vs. CRISPR mutagenesis). The legal standard for obviousness comprises determining if there was a motivation to combine the prior art elements, and if that combination would have produced a predictable outcome. If these conditions are met, the invention is likely obvious.
Conclusion
C. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Ethan Whisenant whose telephone number is (571) 272-0754. The examiner can normally be reached Monday-Friday from 8:30 am -5:30 pm EST or any time via voice mail. If repeated attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Anne Gussow, can be reached at (571) 272-6047.
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/ETHAN C WHISENANT/Primary Examiner, Art Unit 1683 ethan.whisenant@uspto.gov
EXAMINER SEARCH NOTES
15 AUG 2025 2022 - ECW
Databases searched: All available via PE2E SEARCH
CAplus, Medline and BIOSIS via STNext; and Google Scholar (note the search terms used below)
Reviewed the parent(s), if any, and any search(es) performed therein : see the BIB data sheet
Reviewed, the search(es), if any, performed by prior examiners including any international examiners.
Planned Search
Search terms:
All Inventor(s) e.g. Bensimon A?/au
Mutagenesis
DNA shuffling
genom$ enginer$
Molecular Combing
Probe$2 or Genomic Morse Code probe$2 or GMC probe$2
Label$ probe$2
Hybridization
Engineer$ nuclease$2
CRISPR
Cas9
Meganuclease$2
TALEN
► See the Examiner’s PE2E SEARCH notes/strategy in IFW