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 .
Amendments
In the reply filed 5/1/2026, Applicant has amended Claims 1, 10, 11 and 15.
Claims 11-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable linking claim.
Claims 1-10 are under consideration.
Withdrawn Objection to Specification
The objection to the Specification as not conforming to sequence rules, requiring the use of “SEQ ID NO:” is withdrawn in light of Applicant’s amendment.
New Objection to Specification
The disclosure is objected to because of the following informalities: MPEP 608.01(p) states that simulated or predicted test results and prophetical examples (paper examples) are permitted in patent applications. However, paper examples should not be represented as work actually done. No results should be represented as actual results unless they have actually been achieved. Paper examples should not be described using the past tense. Hoffman-La Roche, Inc. v. Promega Corp., 323 F.3d 1354, 1367, 66 USPQ2d 1385, 1394 (Fed. Cir. 2003). For further guidance, see "Properly Presenting Prophetic and Working Examples in a Patent Application," 86 FR 35074 (July 1, 2021). In instant case, Applicant switches tense in Examples 1-16. For example, Example 10a indicates a vector “was” cloned, but the donor “is” driven, or Example 10b indicates the vector “was” cloned, but “is” transformed, or Example 11 indicates the vector “is” used”, but the seeds “has been” done. This is by no means an exhaustive list, and the Examiner suggests using a consistent tense for example that have actually been carried out versus those that are paper examples.
Appropriate correction is required.
New Claim Objections
Claim 10 is objected to because of the following informalities: instant claim uses the abbreviation “fuRNA”, which has not been spelled out upon first use. Although claims are allowed abbreviations, if an abbreviation is not spellout upon first use in a claim, MPEP §2429 states that Applicant only use abbreviations that are specifically defined in "WIPO Standard ST.25 (1998)" or that are well known and would be clear to someone who had not read the invention description.
Appropriate correction is required.
Withdrawn 35 USC § 112(b)
The prior rejection of Claim 10 under 35 U.S.C. § 112(b) pre-AIA 2nd paragraph as being indefinite is withdrawn in light of Applicant’s amendments of Claims 10 to describe the one or more cells.
Withdrawn 35 USC § 102
The prior rejection of Claims 1-10 under 35 U.S.C. 102(a)(2) as being anticipated by Cotta-Ramusino et al. (WO 2017/180711, published October 18, 2017 and having priority to April 13, 2016 based on US Provisional document 62/322,099, see IDS filed 9/16/2022) is withdrawn in light of Applicant’s amendment of Claim 1 to limit the homology arms to 50 or fewer nucleotides, which is a limitation Cotta-Ramusino does not anticipate.
New 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Potter et al. (WO2016/065364, filed 10/26/2015, published 4/28/2016, see IDS filed 9/16/2022)
[AltContent: textbox ([img-media_image1.png])]In regard to claim 1, Potter teaches methods for modifying a genomic target in cells comprising contacting the cell with a composition comprising steps (a)/(b) providing and contacting cells with a recombinant fusion nucleic acid molecule comprising a guide RNA covalently linked to a donor nucleic acid, and steps (b)/(c) introducing a Cas9 nuclease and allowing the cells to under homologous recombination ([0003-0004, 0047, 0098-0099, Claims 7-9 of Potter, see also excerpt from Fig. 9, adjacent).
With respect to the length of homology arms of the donor nucleic acid of claim 1(a), Potter teaches the donor nucleotide is as short as about 50 nt, and that homology arms are as short as 25 nt (p. 10, [0047], see also Claims 8 and 9 of Potter). Specifically, Potter provides a working example of a gRNA covalently attached to 80 bp ssDNA oligonucleotide (Example 1), wherein the homology arms of donor DNA for homologous recombination a the HPRT locus are about 27 nucleotides each (see p. 26, line 8).
With respect to the spacing of homology arms of the donor nucleic acid of claim 1(a), Potter teaches the method is very useful in DNA repair of single nucleotide polymorphisms (SNPs), wherein the donor DNA is designed with two homology regions that 25 nt in length and a single base pair correction (p. 10, [0047]), which would arrange the homology arms directly adjacent to each other since the single nucleotide is the wild-type sequence. Note that when the homology arms are greater than 15 nucleotides, instant claims allow as low as 60% complementary sequence in the homology arms with the target nucleic acid.
However, Potter does not provide a preferred embodiment of modifying a cell for SNP with a gRNA covalently attached to 80 bp ssDNA oligonucleotide representing a wild-type sequence (i.e., the homology arms are adjacent to one another).
Nevertheless, it would have been obvious to one having ordinary skill in the art at the time the invention was filed to practice said method to modify a cell because each of the individual elements of the instant claims are independently presented by Potter as embodiments and are taught that they can be combined in various embodiments; therefore a combination of all the elements into a single embodiment would be apparent to an artisan skilled in cell modification in light of the Supreme Court’s KSR decision (see MPEP 2143 Exemplary Rationale (A)). Regarding the rationale for combining prior art elements according to known methods to yield predictable results, all of the claimed elements were known in the prior art and one skilled in the art could have combined the element as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of filing of the invention. Each of the elements (guide RNA fused to donor templates, Cas9 nucleases, transfection methods and formulations for modifying SNPs in a cell) are taught by Potter and further they are taught in various combinations and are shown to be used in a method for genetically modifying a cell. It would have been therefore predictably obvious to use a combination of these elements in said method.
In regard to claim 2, Potter teaches the cells after homologous recombination are identified by later sequencing of the target locus [0047], and claims obtaining cell that have undergone homologous recombination (see Claim 7, step (b) of Potter). Note that Applicant’s specification defines “isolated” as being removed by the hand of man and exists apart from its original, native environment.
In regard to claims 3 and 4, as stated supra, Potter teaches the guide RNA is RNA and the donor nucleic acid is a ssDNA.
In regard to claim 5 and 6, as stated supra, Potter teaches the homology arms are more than 15 consecutive bases in length and are at least 60% complementary to an area of the target nucleic acid.
In regard to claim 7 , Potter teaches the guide RNA comprises a spacer of at least 16 bases which are 100% complementary to at least 16 consecutive bases in the target sequence (Example 1, Methods, [0115]).
In regard to claim 8, Potter teaches the target site can be in a human cell (e.g., Jurkat T cell as in Example 1).
In regard to claim 9, Potter teaches that the Cas9 is a wild-type double stranded cutter (Example 1), but also teaches Cas9 can be a nickase [0006, 0031].
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 5/1/2026 are acknowledged.
Applicant argues that the preferred embodiments of Cotta-Ramusino use donor nucleic acids of 129 and 179 nucleotides in length, and are not explicit on the lengths of the homology arms but it would have been reasonable to assume that these lengths were about 64 or 89 nucleotides, respectively.
Applicant's arguments have been fully considered and they are found persuasive. Nevertheless, the amended claims necessitated a new rejection over Potter who makes predictably obvious a method of treating a genetic disease in an organism comprising a guide RNA fused to a donor nucleic acid with homology arms less than 50 nucleotides.
Claims 1-8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US2016/0208243, filed 12/18/2015, published 7/21/2016) in view of Potter et al. (WO2016/065364, filed 10/26/2015, published 4/28/2016, see IDS filed 9/16/2022)
Zhang teaches modifying a target RNA sequence in a cell comprising steps (a)/(b)/(c) providing and introducing to the cells the Type V CRISPR-Cas system comprising guide RNAs and donor RNA repair templates and a Cpf1 site directed nuclease, and step (d) of allowing homologous recombination to occur in said cell [0009, 0221-0226, 0448, 0903].
With respect to the length of homology arms of the donor nucleic acid of claim 1, Zhang teaches the lengths of the homology arms are at least 20 bp, for example about 50 bp [0222, 0635], which total template length being from about 40 to 100 bp [0634]. Zhang also teaches the lengths of the homology arms should be short to avoid repeat elements [0636]. Notably, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
With respect to the spacing of homology arms of the donor nucleic acid of claim 1, Zhang teaches the guide RNA and HDR template can target a single nucleotide to change it to a mutant allele to wild-type sequence [0632, 0857], which would arrange the homology arms directly adjacent to each other since the single nucleotide is the wild-type sequence. Note that when the homology arms are greater than 15 nucleotides, instant claims allow as low as 60% complementary sequence in the homology arms with the target nucleic acid.
With respect to covalent coupling of the donor nucleic acid of claim 1, although Zhang teaches the modification of the guide RNA to increase its activity, such as chemically modified guide RNAs, modified guide RNAs with attached functional domains, aptamers, added loops, etc. [0317-0321], they are silent to modification of the guide RNA to attach the donor nucleic acid.
In regard to claim 1, Potter teaches methods for modifying a nucleic acid in cells comprising contacting the cell with a composition comprising a recombinant fusion nucleic acid molecule comprising a guide RNA covalently linked to a donor nucleic acid (Example 1, Claims 7-9 of Potter, see Fig. 9).
Accordingly, it would have been obvious to practice methods for modifying a cell comprising the CRISPR-Cas system comprising a guide RNA and a donor nucleic acid as taught by Zhang and to attach the guide RNA to the donor nucleic acid as taught by Potter with a reasonable expectation of success. One of ordinary skill would have been motivated to do so as taught by Potter because doing so enhances homologous recombination by increasing the concentration of donor nucleic at or in close proximity to the junction of a break in a nucleic acid molecule resident in a cell [0004]. In regard to the reasonable expectation of success in doing so, Potter teaches click-chemistry used for the ligation of RNA molecules is particularly advantageous because it is fast, modular, efficient, does not produce waste products, done in water, and can be stereospecific [0082].
In regard to claim 2, Zhang teaches the cells after homologous recombination are re-introduced into an animal [0223], thereby indicating they were isolated. Note that Applicant’s specification defines “isolated” as being removed by the hand of man and exists apart from its original, native environment.
In regard to claims 3 and 4, as stated supra, Zhang teaches the guide RNA is RNA and the donor nucleic acid is a RNA.
In regard to claim 5 and 6, as stated supra, Zhang teaches the homology arms are more than 15 consecutive bases in lengthand are at least 60% complementary to an area of the target nucleic acid.
In regard to claim 7 , Zhang teaches the guide RNA comprises a spacer of 23-25 nucleotides which are 100% complementary to at least 16 consecutive bases in the target sequence [0226].
In regard to claim 8, Zhang teaches the target RNA can be in a human cell [0223, 0448].
In regard to claim 10, as stated supra, Zhang teaches the guide RNA is RNA and the donor nucleic acid is a RNA, and can be delivered to the cells via liposomes or nanoparticles [0655-0656]
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 5/1/2026 are acknowledged and have been addressed supra.
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1-10 are rejected on the grounds of nonstatutory double patenting over claims 1-20 of U.S. Patent No. 11,608,499 (Neuteboom et al., Patented 3/21/2023), in view of Li et al. (Metabolic Eng, 2015, 31:13-21, prior art of record).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for modification of a target nucleic acid in a cell comprising a guide nucleic acid covalently linked to donor nucleic acid makes obvious the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant claims are more specific with respect to the donor nucleic acid comprising homology arms that are 50 or less nucleotides and are directly adjacent.
[AltContent: textbox ([img-media_image2.png])]Nevertheless, Li teaches that homology arms are to be directly adjacent in the 89 nucleotide donor template when deleting a target sequence during genome editing using CRISPR-Cas9 based system (see Fig.1 excerpt, adjacent).
Accordingly it would have been obvious to claim the method comprising a donor nucleic acid of cited patent and to claim a donor with left and right homology arms 50 nucleotides or less and directly adjacent for the purposes of deleting a genomic sequence as taught by Li with a reasonable expectation of success. One of ordinary skill would have been motivated to do so because targeted deletions from the taught donor would have been immediately envisioned as one from a limited number of options for gene modification.
Since the instant application claims are obvious over cited patent claims in view of Li, said claims are not patentably distinct.
Provisional nonstatutory double patenting
Claims 1, 3-10 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-6, 8-9, 11-13, 15-19 of copending Application No. 17/933,023. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the method for modification of a target nucleic acid in a subject comprising a guide nucleic acid covalently linked to donor nucleic acid anticipates the method of instant application. It is clear that elements of the cited application claims are to be found in instant claims. The difference between the cited application claims and the instant claims lies in the fact that the cited application claims are more specific with respect to the method being in vivo. Thus the invention of said claims of the cited application are in effect “species” of the “generic” invention of the instant claim. It has been held that the generic invention is “anticipated” by the “species”. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
Since the instant application claims are anticipated by cited application claims, said claims are not patentably distinct.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 5/01/2026 are acknowledged and ask that the double patenting rejections be held in abeyance until allowable subject matter has been identified.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Doug Schultz can be reached on 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ARTHUR S LEONARD/Examiner, Art Unit 1631
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