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 .
Status of the Claims
Claims 1-20, of record 30 May 2024, are pending. Therefore, prosecution on the merits commences for claims 1-20.
Priority
Applicant asserts that the instant application is a divisional under 35 USC § 121 of US Application No. 17/079097, filed 23 October 2020 (now US Patent 12,123,033 B2, filed 22 October 2024). However, the benefit claim as a divisional is inappropriate, as the instant application is not a proper divisional of US Application No. 17/079097. More specifically, the instant claims are not consonant with the restricted claims of parent Application No. 17/079097, as the programmable nuclease system in original claim 15 of the ‘097 application was only required to comprise “a modified double stranded DNA homology directed repair (HDR) donor, a programmable nuclease enzyme, and a gRNA, wherein the gRNA molecule is capable of targeting the programmable nuclease molecule to a target nucleic acid”. Therefore, since the instant claims incorporated all of the limitations of allowable claim 1 of the ‘097 application into instant claim 1, rather than amending the withdrawn claims within the parent application, the instant claims are not consonant with the original claims at the time of restriction within the parent application.
Furthermore, the addition of claims 12-20 within the instant application – wherein instant claim 12 is directed to a method for increasing homology directed repair (HDR) rates and reducing homology-independent integration in a programmable nuclease system and claims 13-16 are dependents thereof, while instant claim 17 is directed to a method for manufacturing a modified double stranded DNA HDR donor and claims 18-20 are dependents thereof – also renders the instant application an improper divisional of US Application No. 17/079097, as a divisional application may only comprise claims directed to the non-elected invention originally presented within the restriction requirement of the parent application. See MPEP § 201.06 and 802.
Therefore, the instant invention does not get the benefit of the “121 shield” that a proper divisional would. The instant application would be appropriate as a continuation under 35 USC § 120 of US Application No. 17/079097, filed 23 October 2020. To update the benefit claim, Applicant must request an updated filing receipt with the Office, as well as correct all references to the benefit claim within the instant disclosure.
In addition, acknowledgement is made of Applicant’s claim for benefit under 35 USC 119(e) to US Provisional Application No. 62/925366, all filed 24 October 2019. Therefore, the earliest priority date for the instant application is still 24 October 2019.
Specification
The substitute Specification filed 10 June 2024 is acknowledged and entered into the application file.
Claim Objections
Claims 1, 7-8, 12, and 17 are objected to because of the following informalities:
Regarding claim 1: The instant claim is objected to for misspelling “penultimate” in Line 12 of the claim.
Appropriate correction is required.
Regarding claim 7: The instant claim is objected to for reciting “greater 4 kb” in Lines 2-3 instead of “greater than 4kb”.
Appropriate correction is required.
Regarding claim 8: The instant claim is objected to for reciting “zinc fingers” with the associated acronym of “(ZFNs)” in Line 3, rather than “zinc finger[[s]] nucleases”.
Furthermore, the instant claim is objected to for reciting “or clustered, regularly interspaced, short palindromic repeat (CRISPR)” in Line 3 instead of “or a clustered, regularly interspaced, short palindromic repeat (CRISPR)” or “or clustered, regularly interspaced, short palindromic repeats (CRISPRs)”, or the like.
Appropriate correction is required.
Regarding claim 12: The instant claim is objected to for misspelling “penultimate” in Line 15 of the claim.
Furthermore, the instant claim is objected to for failing to end the claim with a period. See MPEP § 608.01(m).
Appropriate correction is required.
Regarding claim 17: The instant claim is objected to for misspelling “penultimate” in Line 17 of the claim.
Appropriate correction is required.
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 8 and 13-16 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.
Regarding claim 8: The instant claim recites the limitation “transcription activator-like effector nucleases (Taalense)” in Lines 2-3. The scope of the claim is rendered indefinite, as it is unclear if the recitation of “(Taalense)” is acting as exemplary language or attempting to serve as an acronym for “transcription activator-like effector nucleases” that is not well-known in the art. See MPEP § 2173.05(d). Therefore, the metes and bounds of the claim cannot be determined.
Appropriate correction is required.
Regarding claims 13-16: The instant claims each recite the preamble of “[t]he method of claim 9”. The scope of the claim is rendered indefinite, as instant claim 9 is directed to a programmable nuclease and not a method. Therefore, the metes and bounds of the claim cannot be determined.
Appropriate correction is required.
For the sake of compact prosecution, each of instant claims 13-16 will be interpreted as being dependent upon the method of independent claim 12.
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.
Claims 1, 3-12, 14-17, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al (US 2019/0119701 A1, of record on IDS filed 28 October 2024).
Liang et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claim 1: Liang et al disclose methods, kits, and compositions for improving the efficiency of homologous recombination and downstream therapeutic applications, including evaluating proteins related to Parkinson’s disease (Abstract; Paragraphs [0003], [0487], [0492]).
As such, Liang et al disclose donor nucleic acid molecules designed for homologous recombination, wherein the molecules have at least three regions in the following order: (1) a first region of homology corresponding to nucleic acid at or near a target locus, (2) an insert region, and (3) a second region of homology corresponding to nucleic acid at or near a target locus (Paragraphs [0189], [0431]-[0455]; Figure 38). Liang et al further disclose that the donor nucleic acid molecules may be single-stranded or double-stranded and further comprise modifications at the 5' end, the 3' end, or the 5' and 3' ends, wherein the modifications comprise the addition of one or more nuclease resistant groups including 2′-O-methyl nucleotides, 2′-deoxy-2′-fluoro nucleotides, 2′-deoxy nucleotides, 5-C-methyl nucleotides, or a combination thereof (Paragraphs [0025], [0044], [0102], [0160], [0175], [0181], [0185], [0187], [0266], [0279], [0331], [0431]).
Liang et al further disclose that the donor nucleic acid can comprise a pair of outer primer sequences at the 5’ and 3’ ends (Paragraphs [0101], [0103], [0188], [0195][0485], [0487]; Figures 3A-B, 4A-B). Liang et al further disclose that, in some embodiments, the primer sequences can be universal primer sequences (Paragraph [0333]).
Liang et al further disclose that the donor nucleic acid molecules can be part of a system comprising a programmable nuclease and a gRNA that guides the programmable nuclease to a target nucleic acid (Paragraphs [0010], [0041], [0050], [0069]-[0076], [0175], [0237], [0308]-[0317]).
However, Liang et al do not exemplify or reduce to practice that universal primer sequences terminally flank the first homology arm region and the second homology arm region, as required by instant claim 1.
Therefore, it would have been prima facie obvious to have modified the donor nucleic acid molecule of Liang et al such that universal primer sequences terminally flank the first homology arm region and the second homology arm region of the donor nucleic acid molecule. One of ordinary skill in the art before the effective filing date of the invention would have recognized that the length and complexity of the primer terminally flanking the homology arms is not critical to the invention and can thereby be adjusted accordingly, and would have had a reasonable expectation of success given that Liang et al reasonably suggest terminally flanked primers and universal primer sequences within embodiments of their invention (Paragraphs [0195], [0333]-[0334]; Figures 3A-B, 4A-B). See MPEP § 2143(I)(G).
Consequently, Liang et al render obvious a programmable nuclease system comprising: a donor nucleic acid molecule that comprises universal primer sequences terminally flanking a first homology region and a second homology region, wherein the two regions of homology flank an insert region and are chemically modified to comprise a 2′-O-methyl nucleotide (2’-OME) at least at the 5’ end; a programmable nuclease enzyme; and a gRNA that guides the programmable nuclease to a target nucleic acid. As the 2’-OME modification within the donor nucleic acid molecule will inherently improve homology directed repair efficiency and reduce homology-independent integration, this therefore renders obvious the programmable nuclease system of the instant claim. See MPEP § 2112.01 and 2112.02, as well as the instant Specification at Page 9, Lines 22-28.
Regarding claim 3: Following the discussion of claim 1, Liang et al further disclose that the matched termini of the donor nucleic acid molecule share a sequence identity greater than or equal to 95% (Paragraph [0018]). Liang et al further disclose that the percentage of sequence identity is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions as compared to the reference sequence – which does not comprise additions or deletions – for optimal alignment of the two sequences. Furthermore, the percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity (Paragraph [0214]). Thus, since the donor nucleic acid molecule can have a sequence identity of 95%, there will be mismatches between the sequences. These mismatches therefore read on the non-template mismatches relative to the target DNA of the instant claim.
Regarding claims 4-5: Following the discussion of claim 1, Liang et al disclose that the matched termini on the 5′ and 3′ ends are 12 bp to 250 bp in length (Paragraph [0008]). Liang et al further broaden this disclosure, stating that the homology regions may be from about 20 bases to about 10,000 bases in total length, including from about 40 bases to about 100 bases (Paragraph [0438]).
Therefore, it would have been prima facie obvious for the matched termini – or homology regions – of the donor nucleic acid molecule to be either 40 to 150 bases – or nucleotides – in length (claim 4) or at least 100 nucleotides in length (claim 5), as homologous recombination efficiency increases with increased lengths and sequence identity of homology region. It is of note that the length of homology regions employed is often determined by factors such as the fragility of large nucleic acid molecules, transfection efficiency, and ease of generation of nucleic acid molecules containing homology regions (Paragraph [0437]). As such, one of ordinary skill in the art would have been motivated to increase the homologous recombination efficiency, and would have also arrived to these claimed ranges through a matter of experimental design. Furthermore, there is a reasonable expectation of success due to the protocols outlined in Liang et al. See MPEP § 2143(I)(G) and 2144.05(I).
Regarding claims 6-7: Following the discussion of claim 1, Liang et al further disclose that the insert region of donor nucleic acid molecules will be from about 1 to about 4,000 bases in length (Paragraph [0442]).
Therefore, it would have been prima facie obvious for the insert region of the donor nucleic acid molecule to be either greater than 100 bases in length (claim 6) or up to 4,000 bases in length (claim 7), as the insert region may be of a variety of lengths depending upon the application that it is intended for (Paragraph [0442]). As such, one of ordinary skill in the art would have been motivated to have an application-appropriate insert region size, and would have also arrived to these claimed ranges through a matter of experimental design. Furthermore, there is a reasonable expectation of success due to the protocols outlined in Liang et al. See MPEP § 2143(I)(G) and 2144.05(I).
Regarding claims 8-11: Following the discussion of claim 1, Liang et al further disclose that the programmable nuclease is a CRISPR-Cas9 nuclease system (claims 8-10) that further comprises a TAL-Buddy HDR enhancer (claim 11) (Paragraphs [0125], [0136], [0139], [0241], [0298], [0308]-[0317], [0391]). This therefore reads on the programmable nuclease system of the instant claims.
Regarding claim 12: Following the discussion of claim 1, Liang et al further disclose methods of using the nuclease system, wherein the HDR rates are increased and NHEJ is reduced (Abstract; Paragraphs [0048]-[0049], [0102], [0125], [0159]-[0160], [0164]-[0173], [0182], [0264], [0273]-[0274]). This therefore renders obvious the method of instant claim 12 for the same reasons as discussed in the rejection of instant claim 1.
Regarding claim 14: Following the discussion of claim 12, Liang et al further disclose that the programmable nuclease is a CRISPR-Cas9 nuclease system that further comprises a TAL-Buddy HDR enhancer (Paragraphs [0125], [0136], [0139], [0241], [0298], [0308]-[0317], [0391]). This therefore reads on the method of the instant claim.
Regarding claim 15: Following the discussion of claim 12, Liang et al disclose that the matched termini on the 5′ and 3′ ends are 12 bp to 250 bp in length (Paragraph [0008]). Liang et al further broaden this disclosure, stating that the homology regions may be from about 20 bases to about 10,000 bases in total length, including from about 40 bases to about 100 bases (Paragraph [0438]).
Therefore, it would have been prima facie obvious for the matched termini – or homology regions – of the donor nucleic acid molecule to be at least 100 nucleotides in length, as homologous recombination efficiency increases with increased lengths and sequence identity of homology region. It is of note that the length of homology regions employed is often determined by factors such as the fragility of large nucleic acid molecules, transfection efficiency, and ease of generation of nucleic acid molecules containing homology regions (Paragraph [0437]). As such, one of ordinary skill in the art would have been motivated to increase the homologous recombination efficiency, and would have also arrived to these claimed ranges through a matter of experimental design. Furthermore, there is a reasonable expectation of success due to the protocols outlined in Liang et al. See MPEP § 2143(I)(G) and 2144.05(I).
Regarding claim 16: Following the discussion of claim 12, Liang et al further disclose that the insert region of donor nucleic acid molecules will be from about 1 to about 4,000 bases in length (Paragraph [0442]).
Therefore, it would have been prima facie obvious for the insert region of the donor nucleic acid molecule to be either greater than 100 bases in length, as the insert region may be of a variety of lengths depending upon the application that it is intended for (Paragraph [0442]). As such, one of ordinary skill in the art would have been motivated to have an application-appropriate insert region size, and would have also arrived to these claimed ranges through a matter of experimental design. Furthermore, there is a reasonable expectation of success due to the protocols outlined in Liang et al. See MPEP § 2143(I)(G) and 2144.05(I).
Regarding claim 17: Following the discussion of claim 1, Liang et al further disclose that the donor nucleic acid molecules are manufactured by synthesizing and hybridizing complementary nucleic acid molecules, wherein a first nucleic acid molecule comprises the first region of homology, the insert region, and the second region of homology (Paragraphs [0186]-[0188], [0195], [0197], [0220]). This therefore renders obvious the method of instant claim 17 for the same reasons as discussed in the rejection of instant claim 1.
Regarding claim 19: Following the discussion of claim 17, Liang et al disclose that the matched termini on the 5′ and 3′ ends are 12 bp to 250 bp in length (Paragraph [0008]). Liang et al further broaden this disclosure, stating that the homology regions may be from about 20 bases to about 10,000 bases in total length, including from about 40 bases to about 100 bases (Paragraph [0438]).
Therefore, it would have been prima facie obvious for the matched termini – or homology regions – of the donor nucleic acid molecule to be at least 100 nucleotides in length, as homologous recombination efficiency increases with increased lengths and sequence identity of homology region. It is of note that the length of homology regions employed is often determined by factors such as the fragility of large nucleic acid molecules, transfection efficiency, and ease of generation of nucleic acid molecules containing homology regions (Paragraph [0437]). As such, one of ordinary skill in the art would have been motivated to increase the homologous recombination efficiency, and would have also arrived to these claimed ranges through a matter of experimental design. Furthermore, there is a reasonable expectation of success due to the protocols outlined in Liang et al. See MPEP § 2143(I)(G) and 2144.05(I).
Regarding claim 20: Following the discussion of claim 17, Liang et al further disclose that the insert region of donor nucleic acid molecules will be from about 1 to about 4,000 bases in length (Paragraph [0442]).
Therefore, it would have been prima facie obvious for the insert region of the donor nucleic acid molecule to be either greater than 100 bases in length, as the insert region may be of a variety of lengths depending upon the application that it is intended for (Paragraph [0442]). As such, one of ordinary skill in the art would have been motivated to have an application-appropriate insert region size, and would have also arrived to these claimed ranges through a matter of experimental design. Furthermore, there is a reasonable expectation of success due to the protocols outlined in Liang et al. See MPEP § 2143(I)(G) and 2144.05(I).
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al (US 2019/0119701 A1) in view of Scoles et al (Neurol Genet, 2019, of record on IDS filed 28 October 2024).
The discussion of Liang et al regarding claims 1, 12, and 17 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Liang et al render obvious claims 1, 3-12, 14-17, and 19-20. Scoles is considered prior art under 35 USC 102(a)(1).
Regarding claims 2, 13, and 18: As aforementioned in the discussion of claims 1, 12, and 17 above, Liang et al disclose double-stranded donor nucleic acid molecules that comprise two regions of homology, wherein the homology regions are chemically modified to comprise a 2′-O-methyl nucleotide (2’-OME) at the 5’ end.
Liang et al further disclose methods and compositions comprising the double-stranded donor nucleic acid molecules for improving the efficiency of homologous recombination and downstream therapeutic applications, including evaluating proteins related to Parkinson’s disease (Abstract; Paragraphs [0003], [0487], [0492]).
Liang et al do not disclose a double-stranded DNA donor wherein the chemical modification is 2’-O-methoxylethyl (2′-MOE), as required by instant claims 2, 13, and 16.
Scoles et al, however, disclose various types of antisense oligonucleotides (ASOs), how they are used therapeutically, and the present efforts to develop new ASO therapies that will contribute to a forthcoming toolkit for treating multiple neurodegenerative diseases including Parkinson’s disease (Abstract).
As such, Scoles et al disclose that natural – or unmodified – nucleic acids are susceptible to nuclease degradation and have poor protein binding, thereby having inefficient tissue uptake precluding their use as drugs. However, multiple types of modifications made to nucleotides and their linkages improve various properties thus increasing the suitability of ASO as drugs (Page 2, Oligonucleotide chemistry). One such chemical modification is 2’-O-methoxyethyl (MOE), which Scoles et al disclose enhances binding affinity to the target mRNA and is considerably less toxic than the 2’-O methyl (OMe) modification. In addition, MOE is sufficiently nuclease resistant (Pages 2-3, Methoxyethyl oligonucleotides).
Therefore, it would have been prima facie obvious to have modified the donor nucleic acid of Liang et al such that the homology regions are modified at the 5’ terminus to comprise a 2’-MOE, as detailed in Scoles et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to include this modification, as it is considerably less toxic than the 2’-OME modification while also being nuclease resistant (Scoles et al, Pages 2-3, Methoxyethyl oligonucleotides), and would have had a reasonable expectation of success due to the disclosure of Scoles et al (Pages 2-3) coupled with the disclosure and protocols expanded upon in Liang et al (Paragraphs [0025], [0331], [0360]-[0363], [0431]). It is of note that the ASO of Scoles et al reads on an embodiment of the donor nucleic acid molecule detailed in Liang et al. See MPEP § 2143(I)(G).
Consequently, Liang et al as modified by Scoles et al render obvious a donor nucleic acid molecule comprising two regions of homology flanking an insert region, wherein the homology regions are chemically modified to comprise a 2′-O-methoxylethyl nucleotide (2’-MOE) at least at the 5’ end. This therefore renders obvious the programmable nuclease system (claim 2) and methods (claims 13, 18) of the instant claims.
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 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 12,123,033 B2 in view of Liang et al (US 2019/0119701 A1, of record on IDS filed 28 October 2024). It is of note that the instant application is being treated as a CONTINUATION of the parent Application 17/079197, which is now U.S. Patent No. 12,123,033 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims either anticipate or render obvious the instant claims. More specifically, when applicable, the patent claims are not identical because no single patent claim discloses all of the limitations of any of the instant claims; however, each of the limitations of the instant claims are rendered obvious by the accompanying prior art.
Patent claim 1 is directed to a double stranded DNA homology directed repair (HDR) donor comprising:
a first homology arm region,
an insert region,
a second homology arm region; and
universal primer sequences terminally flanking the first homology arm region and the second homology arm region;
wherein:
the first homology arm region and the second homology arm region comprise one or more 2′-OME, 2′-MOE, 2′-F, or 2′-oxygen-4′-carbon methylene (Locked Nucleic Acid) modifications of the 5′-terminal nucleotide, the 5′-penultimate nucleotide, the 5′-antepenultimate (third) nucleotide, or a combination of the nucleotides at or near the 5′-terminus of the first homology arm region and the second homology arm region;
the 2′-OME and 2′-MOE modifications improve homology directed repair efficiency and reduce homology-independent integration; and
the Locked Nucleic Acid and 2′-F modifications improve homology directed repair efficiency and increase homology-independent integration.
Patent claim 1 does not disclose a programmable nuclease system comprising the double stranded DNA HDR donor, as required by instant claim 1.
Liang et al, however, disclose donor nucleic acid molecules designed for homologous recombination, wherein the molecules have at least three regions in the following order: (1) a first region of homology corresponding to nucleic acid at or near a target locus, (2) an insert region, and (3) a second region of homology corresponding to nucleic acid at or near a target locus. Furthermore, donor nucleic acid molecules may be single-stranded or double-stranded and further comprise modifications at
the 5' end, the 3' end, or the 5' and 3' ends (Paragraphs [0003], [0025], [0431] [0487], [0492]). These modifications at the 5' end, the 3' end, or the 5' and 3' ends comprise the addition of one or more nuclease resistant groups in at least one strand of at least one terminus, wherein the nuclease resistant groups comprise one or more phosphorothioate groups, one or more amine groups, 2′-O-methyl nucleotides, 2′-deoxy-2′-fluoro nucleotides, 2′-deoxy nucleotides, 5-C-methyl nucleotides, or a combination thereof (Paragraphs [0025], [0331]; Figure 38).
Liang et al further disclose that the donor nucleic acid molecules are manufactured by synthesizing and hybridizing complementary nucleic acid molecules, wherein a first nucleic acid molecule comprises the first region of homology, the insert region, and the second region of homology (Paragraphs [0186]-[0188], [0195], [0197], [0220]).
Liang et al further disclose that the donor nucleic acid molecules can be part of a system comprising a programmable nuclease and a gRNA that guides the programmable nuclease to a target nucleic acid (Paragraphs [0010], [0041], [0050], [0069]-[0076], [0175], [0237], [0308]-[0317]).
Liang et al further disclose methods of using the system, wherein the HDR rates are increased and homology-independent integration is reduced (Abstract; Paragraphs [0102], [0125], [0159]-[0160], [0164]-[0173], [0273]-[0274]).
It therefore would have been prima facie obvious to have modified the double stranded DNA HDR donor such that it is comprised within a programmable nuclease system, as detailed in Liang et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to utilize the double stranded DNA HDR donor within a programmable nuclease system such that the double stranded DNA HDR donor is inserted into a target genome, and would have had a reasonable expectation of success based on the procedures outlined in Liang et al. See MPEP § 2143(I)(G).
This therefore renders obvious the programmable nuclease system of instant claim 1, and corresponding methods of instant claims 12 and 17.
With that, instant claims 2-11, 13-16, and 18-20 are known from the patent or prior art and can be further incorporated into the method rendered obvious by patent claim 1 as modified by Liang et al:
Patent claims 2-7 teach the limitations recited in instant claims 2-7, 13-16, and 18-20.
Liang et al teach the limitations recited in instant claims 8-11.
Examiner’s Comment
The double-stranded DNA HDR donor claimed within parent application 17/079097, now US Patent 12,123,033 B2, was found allowable due to considerations presented within the Declaration under 37 CFR 1.132 filed 19 September 2023 by co-Inventor Jessica Woodley. The Examiner would like to note that declarations are not imported from the parent application, and must be refiled within the instant application to be considered. See MPEP § 716.
Conclusion
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/ALYSSA G WESTON/Examiner, Art Unit 1633
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