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 with traverse of Group III (claims 9-12) in the reply filed on 5/30/25 is acknowledged. The traversal is on the ground(s) that a search of the prior art for the subject matter of group III would encompass the subject matter of group V and no additional burden would be incurred by searching and examining together group III and V in this application. This is not found persuasive because as stated in the restriction requirement mailed on 4/4/25 (pages 5-6), inventions III and V are related as intermediated-final product and the intermediate product can be used to make another final product and there is nothing of record to show groups III and V to be obvious variants. In addition, each invention has a different field of search due to class/subclass.
NOTE: applicant does not provide any arguments to address the restriction for groups I, II, and IV should be rejoined with group III.
The requirement is still deemed proper and is therefore made FINAL.
Claims 7 and 8 were cancelled; claim 9 was amended and new claims 20-22 were added in the amendment filed on 5/30/25.
Claims 1-6 and 13-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 5/30/25.
Applicant’s election of species (SEQ ID NO: 2 and SEQ ID NO: 14) in the reply filed on 5/30/25 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Upon further consideration, SEQ ID NO: 4 in claim 11 and SEQ ID NOs: 15-22 in claim 12 are rejoined with the elected species and examined.
SEQ ID NO: 3 in claim 11 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 5/30/25.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Interpretation
The claimed invention is directed to a single guide RNA (sgRNA) comprising an inactivation sequence in a region that would not interfere with the activity of the sgRNA (non-essential region), wherein the sequence is flanked by one or more endonuclease recognition sites (e.g., sites that are recognized by Cas 9). See Figure 3 of the specification. Also see Briner et al. (Molecular Cell 56, 333-359, 2014, Figure 1A) that teaches that sgRNA having this structure are well-known in the prior art. Briner teaches that several regions of sgRNA are tolerant to mutations, including the lower and upper stems (page 334). The hairpin has to be completely abolished to abolish cleavage in cell-based assays.
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The limitation “activatable” in the pre-amble of claim 9 does not add any structural limitations to the claimed sgRNA because it recites purpose or intended use. See MPEP 2111.02(I). The limitation ‘wherein the activatable sgRNA targets a transcribed strand of a nucleic acid molecule’ in claim 10 is directed to the use of the product and an intended usage does not have patentable weight over a product taught tin the prior art having the same structure but does not teach the intended usage. Also see MPEP 2111.04(I).
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 9-10 and 22 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Garreau de Loubresse (US 20190233806, priority date to 6/23/16, cited on an IDS).
’806 teaches a CRISPR/Cas system comprising a RNA-guided endonuclease (Cas9, Cpf1, C2c2) and an inactive sgRNA, wherein sgRNA comprises toehold switch system (an inactivation sequence) and the toehold switch system comprises at least one RNA-guided endonuclease recognition site (RNA-guided recognition site). See pages 8-22, 29-33 and Figures 1-19 and 31-32. Figures 14 and 15 tech targeting RNA. The instant claims could read on the sgRNA targeting either a RNA or DNA sequence. The limitation “activatable” in the pre-amble of claim 9 does not add any structural limitations to the claimed sgRNA because it recites purpose or intended use. See MPEP 2111.02(I). The limitation ‘wherein the activatable sgRNA targets a transcribed strand of a nucleic acid molecule’ in claim 10 is directed to the use of the product and an intended usage does not have patentable weight over a product taught tin the prior art having the same structure but does not teach the intended usage. Also see MPEP 2111.04(I) “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit to a particular structure.”
Claims 9-10 and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jacobson et al. (WO 2015168404, published on 11/5/15, cited on an IDS). ‘404 teaches a CRISPR/Cas system comprising a Cas endonuclease and a toehold-gated gRNA (thgRNA, an inactivation sequence) attached to the 3’ and/or 5’ end of a gRNA or within the scaffold of agRNA, wherein said thgRNA comprises at least one RNA-guided endonuclease recognition sites (Cas 9 recognition site). The scaffold domain of gRNA has a secondary structure that confers affinity to Cas9. See pages 3-19, 25-28, and 30- 32 and Figures 1-7. The thgRNA can detect RNA. The limitation “activatable” in the pre-amble of claim 9 does not add any structural limitations to the claimed sgRNA because it recites purpose or intended use. See MPEP 2111.02(I). The limitation ‘wherein the activatable sgRNA targets a transcribed strand of a nucleic acid molecule’ in claim 10 is directed to the use of the product and an intended usage does not have patentable weight over a product taught tin the prior art having the same structure but does not teach the intended usage. Also see MPEP 2111.04(I).
Claims 9 and 10 are rejected under 35 U.S.C. 102(a)(1) and (2) as being anticipated by Elling et al. (WO 2017/158153, published on 9/21/17 and priority date 3/17/16, cited on an IDS). ‘153 teaches an expression cassette comprising a Cas9-sgRNA complex comprising a sgRNA and a sequence flanked by at least a pair of recombinase recognition sites wherein recombinase activated recombination at the pair of recombinase recognition sites is capable of excising said flanked sequence, whereby either i) at least one of said recombinase recognition sites is located within the sgRNA sequence or ii) said flanked sequence is at least a part of the promoter or of the sgRNA (pages 2-5 and 67-71). The limitation “activatable” in the pre-amble of claim 9 does not add any structural limitations to the claimed sgRNA because it recites purpose or intended use. See MPEP 2111.02(I).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
MPEP 2141 II.C. Rationales to support rejections under 35 U.S.C. 103 recites, “Prior art is not limited to the references being applied, but includes the understanding of one of ordinary skill in the art.”
MPEP 2141. FACTORS TO CONSIDER IN DETERMINING LEVEL OF ORDINARY SKILL
The person of ordinary skill in the art is a hypothetical person who is presumed to have known the relevant art at the relevant time. Factors that may be considered in determining the level of ordinary skill in the art may include: (1) "type of problems encountered in the art;" (2) "prior art solutions to those problems;" (3) "rapidity with which innovations are made;" (4) "sophistication of the technology; and" (5) "educational level of active workers in the field." In re GPAC, 57 F.3d 1573, 1579, 35 USPQ2d 1116, 1121 (Fed. Cir. 1995). "In a given case, every factor may not be present, and one or more factors may predominate." Id. See also Custom Accessories, Inc. v. Jeffrey-Allan Indust., Inc., 807 F.2d 955, 962, 1 USPQ2d 1196, 1201 (Fed. Cir. 1986); Environmental Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696, 218 USPQ 865, 868 (Fed. Cir. 1983).
Claims 11 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Jacobson et al. (WO2015/168404, published on 11/5/15, cited on an IDS) as applied above to claims 9, 10 and 22 taken with Fulga (US 20190352634, priority date to 1/24/17) and Lu (US 20050257277), all of record.
The rejection of claims 9, 10, and 22 as being taught by ‘404 is incorporated herein.
‘404 does not specifically teach making the inactivation sequence comprises a cis-acting ribozyme encoded by a nucleic acid molecule of SEQ ID NO: 4.
However, Fulga teaches a CRISPR RNA comprising a spacer blocking element, a cleavable loop; and a CRISPR gRNA comprising a spacer element. See pages 2, 4, and 15-19 and Figure 15a-c. The cleavable loop element is one which is cleavable by a hammerhead ribozyme. Cleavage of the ribozyme helps dissociate the spacer-blocking element, rendering the sgRNA competent to target the target DNA.
In addition, Lu et al. teach a cis-acting ribozyme comprising instant SEQ ID NO: 4 recited in claim 11. Pages 5-6, 8-9, and 13-17 and SEQ ID NO: 1. Lu teaches that cleavage sites of ribozymes are well known in the art (page 6). A person of ordinary skill in the art would easily be able to choose the ribozyme and insert it into a nucleotide sequence which produces an RNA transcript including the ribozyme (page 6). Qy is SEQ ID NO: 4 and Db is SEQ ID NO: 1 of Lu.
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It would have been prima facie obvious to a person of ordinary skill in the art before the time the effective filing date to combine the teaching of Jacobson taken with Fulga and Lu to make the system have a cis-acting ribozyme comprising SEQ ID NO: 4, namely to arrive at the claimed invention. lt would have been a simple substitution for a person of ordinary skill in the art to replace the toehold sequence with a nucleic acid sequence comprising a cis-acting ribozyme as the inactivation sequence and upon presence of a RNA guided endonuclease, the ribozyme undergoes structural changes that activates the ribozyme triggering cleavage of the gRNA. One of ordinary skill in the art would have been motivated to combine the teaching to study the function (efficiency or control) of the CRISPR/Cas system in a cell line. Jacobson and Fulga teach or make obvious a sgRNA comprises a spacer element, a lower stem, an upper stem, a bugle and a region which interacts with a Cas endonuclease; and at least one hairpin, wherein an activation sequence flanked by one or more Cas endonucleases is the upper stem or at least one hairpin of the sgRNA (for example see pages 3-4 and Figure 6A, 6D, 11A, 12, 15B and 16 of Fulga). Since a person of ordinary skill in the art would possess the knowledge that the lower and upper stem of the sgRNA are non-essential, it would have been obvious to insert the inactivation sequence into either of these regions.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Elling et al. (WO 2017/158153, published on 9/21/17 and priority date 3/17/16, cited on an IDS).
The rejection of claims 9 and 10 as being taught by ‘153 is incorporated herein.
‘153 teaches an expression cassette comprising a Cas9-sgRNA complex comprising a sgRNA and a sequence flanked by at least a pair of recombinase recognition sites wherein recombinase activated recombination at the pair of recombinase recognition sites is capable of excising said flanked sequence, whereby either i) at least one of said recombinase recognition sites is located within the sgRNA sequence or ii) said flanked sequence is at least a part of the promoter or of the sgRNA (pages 2-5 and 67-71). The limitation “activatable” in the pre-amble of claim 9 does not add any structural limitations to the claimed sgRNA because it recites a purpose or an intended use. See MPEP 2111.02(I). ‘153 teaches using either lox or frt recognition sites to flank the sequence (pages 5 and 11-12).
‘153 does not specifically teach using two different recognition sites to flank the sequence.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to use lox and frt sites to flank the sequence, namely to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to try making this sgRNA to control cleaving the site in the sequence depending on the recognition sequence. See MPEP 2143(I)F.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
NOTE: SEQ ID NOs: 14-22 in instant claim 12 appear to be free of the 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 9-12 and 20-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11788088. Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace an activatable single guide RNA (sgRNA) harboring an inactivation sequence in a non-essential region of the sgRNA, wherein said inactivation sequence comprises one or more endonuclease recognition sites, and the inactivation sequence is a cis-acting ribozyme encoded by a nucleic acid molecule of SEQ ID NO:2 or SEQ ID NO:3. In addition, both set of claims embrace an activatable sgRNA harboring an inactivation sequence in a non-essential region of the sgRNA, wherein said inactivation sequence comprises one or more RNA-guided endonuclease recognition sites, and the activatable sgRNA is encoded by a nucleic acid molecule of SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 or SEQ ID NO:22. With respect to the limitation in claim 9, a person of ordinary skill in the art would look for a definition for how to make the sgRNA and arrive at column 16, line 36- column 17, line 3 of the ‘088 disclosure. This section of the ‘088 disclosure indicates that the endoribonuclease recognition sites flank the inactivation sequence and the inactivation sequence is selected from one or more of the lower stem, upper stem or at least one hairpin. The sites are recognized and cleaved by Cas9. In addition, this section of the ‘088 disclosure indicates that the endoribonuclease sites can be two sites and a different type of endonuclease is used at each site. See MPEP 804(II)(B)(1) using the disclosure of a patent for a definition of a term.
Conclusion
Hu et al. (WO 2016196539, SEQ ID NO: 60, cited on an IDS) and Garreau de Loubresse (US 20190233806, SEQ ID NO: 30, cited on an IDS) teach a sequence comprising SEQ ID NO: 14 in instant claim 12, wherein nnxnn is defined as nucleotides within a region (tracRNA) of agRNA, but they do not teach or suggest inserting an inactivation sequence (ribozyme) at nucleotide 71 of the sequence. See Table 2 on page 33 of the as-filed specification.
See attached PTO-326 for disposition of claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian Whiteman whose telephone number is (571)272-0764. The examiner can normally be reached on Monday thru Friday; 6:00 AM to 3:00PM.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636