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 .
This action is in response to the amendment filed 01/09/2026, in which claims 1, 16, 27, 31, 34, 38, 45, 49, 53, 56 and 68 were amended; claims 8, 11, 14, 15, 29, 30, 35, 37, 43, 44, 47, 48, 59-61, 63-65, 69, 70 and 72-74 were previously presented; claims 2-7, 9, 10, 12, 13, 17-26, 28, 32, 33, 36, 39-42, 46, 50-52, 54, 55, 57, 58, 62, 66, 67 and 71 are currently listed as canceled; and claims 75-83 were newly added. Claims 1, 8, 11, 14-16, 27, 29-31, 34, 35, 37, 38, 43-45, 47-49, 53, 56, 59-61, 63-65, 68-70 and 72-83 are currently pending.
Applicant’s arguments have been thoroughly reviewed, but are not persuasive for the
reasons that follow. Any rejection and objections not reiterated in this action have been
withdrawn. This action is FINAL.
Election/Restriction
This restriction requirement was established in the previous Office Action.
Applicant’s election without traverse of Groups I, claims 1-2, 6, 8-9, 11, 14-16, 27, 29-31, 34-35, 37-38, 43-45, 47-49, 53, 56 and 59-61, as well as the election of the Cas Protein as Type II-C (Gamma proteobacterium AqS3), a functional domain having demethylase activity and glycogen storage disease in the reply filed on 07/08/2025 is acknowledged.
Claims 63-65,68-70 and 72-74 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/08/2025.
Claims 1-2, 6, 8-9, 11, 14-16, 27, 29-31, 34-35, 37-38, 43-45, 47-49, 53, 56, 59-61 and 75-83 are currently under examination.
Claim Rejections - 35 USC § 112
Claim 82 is dependent upon a canceled claim (i.e., claim 50) and is therefore “incomplete.” See MPEP § 608.01(n)(V).
Claim 83 is dependent upon a canceled claim (i.e., claim 51) and is therefore “incomplete.” See MPEP § 608.01(n)(V).
Claim Rejections - 35 USC § 112
The previous rejection of claims 1, 2, 8, 9, 11, 14-16, 27, 29-31, 34, 35, 37, 38, 43-45, 47-49, 53, 56 and 59-61 under 35 U.S.C. 112(a) has been withdrawn in view of Applicant’s amendments to the claims filed on 01/09/2026.
The previous rejection of claims 2, 6, 16, 27, 31, 38, 45, 49, 53 and 56 under 35 U.S.C. 112(b) has been withdrawn in view of Applicant’s amendments to the claims filed on 01/09/2026.
Claim Rejections - 35 USC § 101
The previous rejection of claims 1, 2, 6, 29 and 59-61 under 35 U.S.C. 101 has been withdrawn in view of Applicant’s amendments to the claims filed on 01/09/2026.
Response to Arguments - Claim Rejections - 35 USC § 102
The previous rejection of claims 1, 8, 11, 14-16, 27, 29, 31, 44, 48, 49, 53, 56, 59-61, 76 and 78 under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Wright et al (WO 2016/114972 A1) has been withdrawn in view of Applicant’s amendments to the claims filed on 01/09/2026.
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.
Claims 1, 8, 11, 14-16, 27, 29, 31, 38, 44, 48, 49, 53, 56, 59-61, 76, 78 and 81-83 are rejected under 35 U.S.C. 103 as being unpatentable by Wright et al (WO 2016/114972 A1) in view of Anantharaman et al (Nat Commun 7, 13219, pgs. 1-11; 2016) and Ge et al (Sci Rep 6, 32942, pgs. 1-10; 2016). This is a NEW REJECTION necessitated by the amendment filed on 01/09/2026.
The teachings of Wright are described above and applied as before.
Regarding claims 1, 44 and 48, Wright teaches splitCas9 proteins comprising the RuvC and HNH domain with an amino acid sequence where the alpha-helical lobe was removed to minimize the distance between the RuvCI and RuvCII domains such that the amino acid sequence is approximately 713 resides long ([00540] and Page 194, Figure 1). Wright teaches the splitCas9 activity was dependent on complementarity between the sgRNA and target DNA [00506]. Wright teaches enriching a population of eukaryotic cells for cells in the G2/M transition of the cell cycle; and contacting the target DNA with a Cas9 targeting complex (e.g., via introducing into the target eukaryotic cell(s) at least one component of a Cas9 targeting complex) (e.g., contacting the target DNA with a split-Cas9, a Cas9 guide RNA, and a dimerizing agent [00525].
Wright does not teach the Cas protein is derived from specifically Gammaproteobacteria bacterium AqS3, Deltaproteobacteria bacterium GWF2_42_12, JGI Metagenome: IMG 3300025323, Nitrospirae bacterium RBG_13_39_12, or Nitrospiraceae bacterium isolate UBA9935.
Anantharaman teaches the genome sequence of deltaproteobacteria bacterium GWF2_42_12 (listed in Table 12 of the instant specification as SEQ ID NO: 62) where the genome sequence submitted for the deltaproteobacteria bacterium GWF2_42_12 is 100% identical to instant SEQ ID NO: 62 (See Appendix I).
Anantharaman does not teach the use of the deltaproteobacteria bacterium GWF2_42_12 in a CRISPR cas system.
Ge teaches using computational analysis to determine the direct repeats within the genome sequence for the guide sequence such as utilizing a de novo repeat detection program to find repeat copies within a range of sequence lengths, the repeats clustered into groups where weak DR copies were annotated by mapping the template DR onto the genome sequence (Page 2, Paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Wright to include the specific Cas protein derived from deltaproteobacteria bacterium GWF2_42_12 as taught by Anantharaman and Ge because Wright teaches it is within the ordinary skill in the art to use splitCas9 proteins comprising the RuvC and HNH domain with an amino acid sequence where the amino acid sequence is approximately 713 residues long and wherein the splitCas9 is regulatable by the sgRNA for genome-engineering application in cells, Anantharaman teaches the entire genome sequence of deltaproteobacteria bacterium GWF2_42_12 and Ge teaches it is within the skill of the art to determine the direct repeat for the guide sequence based on computational analysis of the genomic sequence.
One would have been motivated to make such a modification in order to receive the expected benefit of a Cas protein derived from the deltaproteobacteria bacterium GWF2_42_12 for targeted genome editing as taught by Anantharaman and Ge.
Regarding claims 8 and 29, Wright teaches the dual-guide RNA was composed of CRISPR RNA (crRNA and trans-activating crRNA (tracrRNA)) [00364 and 00366].
Regarding claim 11, Wright teaches the use of nuclear localization signals for the purpose of localizing the nucleic acid encoding the split-Cas9 protein to the nucleus of the cell [00128].
Regarding claim 14, Wright teaches the Cas9 heterodimer is enzymatically inactive
(Sometimes referred to as a "dead Cas9 heterodimer") [00275].
Regarding claim 15, Wright teaches the split-Cas9 (also referred to as a Cas9 heterodimer) can include nickase activity [00281].
Regarding claims 16, 31, 76 and 78, Wright teaches increased and decreased transcription by using transcription activator and transcription repressor domains (e.g., the Knippel associated
box (KRAB or SKD); the Mad mSIN3 interaction domain (SID); the ERF repressor domain
(ERD), etc) [00299]. Wright teaches that when specifically targeting ssRNA target nucleic acids, an adenosine deaminase can be used [00300].
Regarding claim 27, Wright teaches the use of a homologous template such that the homology-direct repair is supported [00469].
Regarding claim 38, Wright teaches the splitCas9 proteins for the method of modifying the target nucleic acid and wherein the method of binding a target nucleic acid (e.g., a single or double stranded target nucleic acid) can result in modification of the target nucleic acid [00289].
Regarding claims 49 and 81, Wright teaches the nucleotide sequence encoding first fusion polypeptide and the nucleotide sequence encoding the second fusion polypeptide are operably linked to two different transcriptional control elements (e.g., two different promoters) [00309].
Regarding claim 53, Wright teaches the split-Cas9 (nucleic acids encoding the split-Cas9) being introduced to a cell using an AAV vector [00471].
Regarding claim 56, Wright teaches the split-Cas9 (nucleic acids encoding the split-Cas9) being introduced to a cell using a liposome [00471].
Regarding claims 59-61, Wright teaches targeting the EMX1 locus in HEK293T cells by nucleofection using reconstituted splitCas9-sgRNA ribonucleoprotein (RNP) complexes [00580].
Regarding claims 82 and 83, the claims currently rely on canceled claims, however for the purpose of advancing prosecution, claim 82 will be interpreted as relying on claim 81 and claim 83 will be interpreted as relying on claim 82.
Wright teaches the use of a human U6 small nuclear promoter (U6) as the minimal promoter within the invention previously discussed [00321].
Claims 30, 34, 37, 38, 45 and 80 are rejected under 35 U.S.C. 103 as being unpatentable by Wright et al (WO 2016/114972 A1) in view of Anantharaman et al (Nat Commun 7, 13219, pgs. 1-11; 2016) and Ge et al (Sci Rep 6, 32942, pgs. 1-10; 2016), as applied to claims 1, 8, 11, 14-16, 27, 29, 31, 38, 44, 48, 49, 53, 56, 59-61, 76 and 78 above, and further in view of Cotta-Ramusino et al (WO 2017/180694 A1). This is a NEW REJECTION necessitated by the amendment filed on 01/09/2026.
The teachings of Wright, Anantharaman and Ge are described above and applied as before.
Regarding claim 30, Wright does not teach the Cas protein is a chimeric protein comprising a first fragment from a first Cas protein and a second fragment from a second Cas protein.
Cotta-Ramusino teaches a Cas9 fusion molecule is a chimeric protein comprising a Cas9 protein or a Cas9 polypeptide covalently linked to at least one template nucleic acid (Page 32, Lines 32-34). Cotta-Ramusino teaches a fragment of a Cas9 molecule of S. pyogenes comprising an N-terminal RuvC-like domain can be fused to a fragment of Cas9 molecule of a species other than S. pyogenes (e.g., S. thermophilus) comprising an HNH-like domain (Page 94, Lines 8-11). Cotta-Ramusino teaches a Cas9 molecule, e.g., a S. aureus or S. pyogenes Cas9 molecule, having a deletion is smaller, e.g., has reduced number of amino acids, than the corresponding naturally-occurring Cas9 molecule due to the smaller size of the Cas9 molecules, it allows increased flexibility for delivery methods, and thereby increases utility for genome-editing (Page 95, Lines 15-18). Cotta-Ramusino teaches the Cas protein is a Type II protein (Page 97, Lines 1-7 and Table 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Wright to include the Cas protein is a chimeric protein comprising a first fragment from a first Cas protein and a second fragment from a second Cas protein taught by Cotta-Ramusino because Wright teaches it is within the ordinary skill in the art to use splitCas9 proteins comprising the RuvC and HNH domain with an amino acid sequence where the amino acid sequence is approximately 713 resides long and wherein the splitCas9 is regulatable by the sgRNA for genome-engineering application in cells and Cotta-Ramusino teaches a fragment of a Cas9 molecule of S. pyogenes comprising an N-terminal RuvC-like domain can be fused to a fragment of Cas9 molecule of a species other than S. pyogenes (e.g., S. thermophilus) comprising an HNH-like domain.
One would have been motivated to make such a modification in order to receive the expected benefit of creating a splitCas9 polypeptide comprising both a RuvC domain and a HNH domain as taught by Cotta-Ramusino.
Regarding claims 34 and 37, Wright does not teach the complex comprising a nucleotide deaminase or a catalytic domain thereof wherein the nucleotide deaminase or catalytic domain thereof is covalently or non- covalently linked to the Cas protein or the guide sequence, or is adapted to link thereof after delivered to a cell and wherein the composition is capable of modifying one or more nucleotides in the target sequence.
Cotta-Ramusino teaches the endogenous homologous sequence comprises a domain, e.g., a catalytic domain, a domain that binds a target, a structural domain, found in the gene that comprises the target position (Page 103, Lines 26-28). Cotta-Ramusino teaches the composition is capable of modifying one or more nucleotides in the target sequence (Page 22, Lines 13-26).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Wright to include the complex comprising a nucleotide deaminase or a catalytic domain thereof wherein the nucleotide deaminase or catalytic domain thereof is covalently or non- covalently linked to the Cas protein or the guide sequence, or is adapted to link thereof after delivered to a cell and wherein the composition is capable of modifying one or more nucleotides in the target sequence taught by Cotta-Ramusino because Wright teaches it is within the ordinary skill in the art to use use splitCas9 proteins comprising the RuvC and HNH domain with an amino acid sequence where the amino acid sequence is approximately 713 resides long and wherein the splitCas9 is regulatable by the sgRNA for genome-engineering application in cells and Cotta-Ramusino teaches the composition is capable of modifying one or more nucleotides in the target sequence and the endogenous homologous sequence comprises a domain, e.g., a catalytic domain, a domain that binds a target, a structural domain, found in the gene that comprises the target position.
One would have been motivated to make such a modification in order to receive the expected benefit of targeting multiple regions of a target sequence for efficient genome modification as taught by Cotta-Ramusino.
Regarding claim 38, Wright does not teach the complex comprising a recombination template wherein modification of the one or more nucleotides in the target sequence remedies a disease caused by a G--A or C--T point mutation or a pathogenic SNP.
Cotta-Ramusino teaches a mutation in a target gene is corrected by homology directed repair (HDR) using an exogenously provided template nucleic acid (Page 102, Lines 25-30). Cotta-Ramusino teaches HDR-mediated sequence alteration is used to alter and/or correct (e.g., repair or edit) the sequence of one or more nucleotides in a genome (e.g., a point mutation in a target gene) (Page 102 bridging Page 103).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Wright to include the complex comprising a recombination template wherein modification of the one or more nucleotides in the target sequence remedies a disease caused by a G--A or C--T point mutation or a pathogenic SNP taught by Cotta-Ramusino because Wright teaches it is within the ordinary skill in the art to use splitCas9 proteins comprising the RuvC and HNH domain with an amino acid sequence where the amino acid sequence is approximately 713 resides long and wherein the splitCas9 is regulatable by the sgRNA for genome-engineering application in cells and Cotta-Ramusino teaches HDR-mediated sequence alteration is used to alter and/or correct (e.g., repair or edit) the sequence of one or more nucleotides in a genome (e.g., a point mutation in a target gene).
One would have been motivated to make such a modification in order to receive the expected benefit of correction of a point mutation caused by a disease using HDR as taught by Cotta-Ramusino.
Regarding claims 45 and 80, Wright does not teach the one or more polynucleotide sequences are codon optimized to express in a eukaryote, preferably wherein the one or more polynucleotide sequences is mRNA.
Cotta-Ramusino teaches the synthetic nucleic acid sequence can be codon optimized such as the synthetic nucleic acid can direct the synthesis of an optimized messenger mRNA, e.g., optimized for expression in a mammalian expression system (Page 96, Lines 18-22).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Wright to include the one or more polynucleotide sequences are codon optimized to express in a eukaryote, preferably wherein the one or more polynucleotide sequences is mRNA taught by Cotta-Ramusino because Wright teaches it is within the ordinary skill in the art to use splitCas9 proteins comprising the RuvC and HNH domain with an amino acid sequence where the amino acid sequence is approximately 713 resides long and wherein the splitCas9 is regulatable by the sgRNA for genome-engineering application in cells and Cotta-Ramusino teaches the synthetic nucleic acid sequence can be codon optimized such as the synthetic nucleic acid can direct the synthesis of an optimized messenger mRNA, e.g., optimized for expression in a mammalian expression system.
One would have been motivated to make such a modification in order to receive the expected benefit of optimized messenger mRNA for enhanced genome editing specific to the codon being targeted as taught by Cotta-Ramusino.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable by Wright et al (WO 2016/114972 A1) in view of Anantharaman et al (Nat Commun 7, 13219, pgs. 1-11; 2016) and Ge et al (Sci Rep 6, 32942, pgs. 1-10; 2016), as applied to claims 1, 8, 11, 14-16, 27, 29, 31, 38, 44, 48, 49, 53, 56, 59-61, 76 and 78 above, and further in view of Doman et al (Nature Biotechnology Vol 38, Pgs 620-628; 2020). This is a NEW REJECTION necessitated by the amendment filed on 01/09/2026.
The teachings of Wright, Anantharaman and Ge are described above and applied as before.
Regarding claim 35, Wright does not teach the nucleotide deaminase or catalytic domain thereof has been modified to increase its activity against a DNA-RNA heteroduplex or to reduce off-target effects.
Doman teaches of the CBEs identified as being especially promising for minimizing Cas9-independent editing, YE1-BE4 and R33A-BE4 offer the best balance between decreased off-target editing and robust on-target activity (Page 624, Column 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Wright to include the catalytic domain has been modified to reduce off-target effects taught by Doman because Wright teaches it is within the ordinary skill in the art to use use splitCas9 proteins comprising the RuvC and HNH domain with an amino acid sequence where the amino acid sequence is approximately 713 resides long and wherein the splitCas9 is regulatable by the sgRNA for genome-engineering application in cells and Doman teaches targeting domains with good orthogonality are selected to minimize off-target DNA cleavage.
One would have been motivated to make such a modification in order to receive the expected benefit of minimize off-targeting DNA cleavage events as taught by Doman.
Claims 43 and 47 are rejected under 35 U.S.C. 103 as being unpatentable by Wright et al (WO 2016/114972 A1) in view of Anantharaman et al (Nat Commun 7, 13219, pgs. 1-11; 2016) and Ge et al (Sci Rep 6, 32942, pgs. 1-10; 2016), as applied to claims 1, 8, 11, 14-16, 27, 29, 31, 38, 44, 48, 49, 53, 56, 59-61, 76 and 78 above, and further in view of Lambowitz et al (mBio 8:e00897-17 Vol. 8 Iss. 4, pgs. 1-16, 2017). This is a NEW REJECTION necessitated by the amendment filed on 01/09/2026.
The teachings of Wright, Anantharaman and Ge are described above and applied as before.
Regarding claims 43 and 47, Wright does not teach the composition further comprising a reverse transcriptase.
Lambowitz teaches that while the majority of CRISPR-Cas immune systems adapt to foreign genetic elements by capturing segments of invasive DNA, some systems carry reverse transcriptase (RTs) that enable adaptation of RNA molecules (Page 1, Paragraph 2). Lambowitz teaches the ability of the RT-Cas1 adaptation modules to acquire spacers from RNA, coupled with the ability of type III CRISPR-cas effector modules to target RNA, implies the potential to provide adaptive immunity against parasites with both RNA and DNA genomes (Page 2, Paragraph 4). Lambowitz teaches that the RT-mediated mechanism of spacer acquisition by CRISPR-Cas systems provide defense against transcriptionally active DNA-based parasites (Page 12, Paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Wright to include the reverse transcriptase as taught by Lambowitz because Wright teaches it is within the ordinary skill in the art to use splitCas9 proteins comprising the RuvC and HNH domain with an amino acid sequence where the amino acid sequence is approximately 713 resides long and wherein the splitCas9 is regulatable by the sgRNA for genome-engineering application in cells and Lambowitz teaches the RT-Cas1 CRISPR-cas system using the reverse transcriptase for spacer acquisition for immune defense.
One would have been motivated to make such a modification in order to receive the expected benefit of improved immune defense to both DNA and RNA parasites as taught by Lambowitz.
Claims 75, 77 and 79 are rejected under 35 U.S.C. 103 as being unpatentable by Wright et al (WO 2016/114972 A1) in view of Anantharaman et al (Nat Commun 7, 13219, pgs. 1-11; 2016) and Ge et al (Sci Rep 6, 32942, pgs. 1-10; 2016), as applied to claims 1, 8, 11, 14-16, 27, 29, 31, 38, 44, 48, 49, 53, 56, 59-61, 76 and 78 above, and further in view of Geel et al (Phil. Trans. R. Soc. 8 373: 20170077, Pgs. 1-8; 2018). This is a NEW REJECTION necessitated by the amendment filed on 01/09/2026.
The teachings of Wright, Anantharaman and Ge are described above and applied as before.
Regarding claim 75, Wright teaches increased and decreased transcription by using transcription activator and transcription repressor domains (e.g., the Knippel associated box (KRAB or SKD); the Mad mSIN3 interaction domain (SID); the ERF repressor domain (ERD), etc) [00299].
Wright, Anantharaman and Ge do not specifically teach wherein the one or more transcriptional activation domains is VP64.
Geel teaches the split dCas9-VP64 as a chemically inducible system capable of activating endogenous loci (Page 6, Column 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the transcriptional activator of Wright for the VP64 transcriptional activator as taught by Geel because Wright teaches it is within the ordinary skill in the art to use splitCas9 proteins comprising the RuvC and HNH domain with an amino acid sequence where the amino acid sequence is approximately 713 resides long and wherein the splitCas9 is regulatable by the sgRNA for genome-engineering application in cells and Geel teaches the split dCas9-VP64 as a chemically inducible system capable of activating endogenous loci. One would have been motivated to make such a modification in order to receive the expected benefit of the chemically inducible system capable of activating endogenous loci as taught by Geel.
Regarding claim 77, Wright, Anantharaman and Ge do not specifically teach wherein the one or more nuclease domains is Fokl.
Geel teaches Fokl is often used nuclease that can induce double strand breaks upon dimerization: using Fokl as a DNA damage inducer thus requires two DNA-binding domains to target neighbouring sites, which has the added advantage of increasing specificity of the approach (Page 4, Column 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the nuclease domain of Wright for the Fok1 nuclease domain as taught by Geel because Wright teaches it is within the ordinary skill in the art to use splitCas9 proteins comprising the RuvC and HNH domain with an amino acid sequence where the amino acid sequence is approximately 713 resides long and wherein the splitCas9 is regulatable by the sgRNA for genome-engineering application in cells and Geel teaches Fokl is often used nuclease that can induce double strand breaks upon dimerization. One would have been motivated to make such a modification in order to receive the expected benefit of increasing specificity as taught by Geel.
Regarding claim 79, Wright, Anantharaman and Ge do not specifically teach wherein the disease is cancer, haemophilia, beta-thalassemia, Marfan syndrome, Wiskott-Aldrich syndrome, or a glycogen storage disease.
Geel teaches DNA targeting platforms (such as split dCas9), provide new avenues for Pompe's disease: correction of the genetic mutation or, for patients with residual activity, upregulation of CAA gene expression (Page 3, Column 2 and Page 6, Column 1). Geel teaches correcting the genetic defect in Pompe disease at an early stage in development could actually provide a cure for Pompe disease, while correcting the gene in secreting cells at later stage would contribute to a decrease in the current treatment costs (Page 3, Column 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Wright to include the treatment of Pompe’s disease (a glycogen storage disease) as taught by Geel because Wright teaches it is within the ordinary skill in the art to use splitCas9 proteins comprising the RuvC and HNH domain with an amino acid sequence where the amino acid sequence is approximately 713 resides long and wherein the splitCas9 is regulatable by the sgRNA for genome-engineering application in cells and Geel teaches gene therapy for the treatment of Pompe’s disease by methods known in the art.
One would have been motivated to make such a modification in order to receive the expected benefit of correcting the genetic defect in Pompe disease at an early stage in development could actually provide a cure for Pompe disease, while correcting the gene in secreting cells at later stage would contribute to a decrease in the current treatment costs as taught by Geel.
Response to Arguments - Claim Rejections - 35 USC § 103
The previous rejection of claim 6 under 35 U.S.C. 103 as being unpatentable over Wright et al (WO 2016/114972 A1) in view of Anantharaman et al (Nat Commun 7, 13219, pgs. 1-11; 2016) and Ge et al (Sci Rep 6, 32942, pgs. 1-10; 2016) has been withdrawn in view of applicant’s cancelation of the claim filed in 01/09/2026. However, a new rejection was made of claims 1, 8, 11, 14-16, 27, 29, 31, 38, 44, 48, 49, 53, 56, 59-61, 76, 78 and 81-83 under 35 U.S.C. 103 as being unpatentable over Wright et al (WO 2016/114972 A1) in view of Anantharaman et al (Nat Commun 7, 13219, pgs. 1-11; 2016) and Ge et al (Sci Rep 6, 32942, pgs. 1-10; 2016) including the scope of cancelled claim 6. Therefore, Applicant’s arguments were fully considered but not found to be persuasive,
Applicant argues the proposed combination fails to establish a prima facie case of obviousness because the recited references, Wright et al (WO 2016/114972 A1) in view of Anantharaman et al (Nat Commun 7, 13219, pgs. 1-11; 2016) and Ge et al (Sci Rep 6, 32942, pgs. 1-10; 2016), do not teach or suggest amended claim 1’s requirements such as the cas protein having “at least 95% sequence identity to SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66 or SEQ ID NO: 68”. Applicant continues to argue Anantharaman and Ge do not teach the limitations of claim 1 nor fix the deficiencies that Wright does not teach.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Wright to include the specific Cas protein derived from deltaproteobacteria bacterium GWF2_42_12 as taught by Anantharaman and Ge because Wright teaches it is within the ordinary skill in the art to use splitCas9 proteins comprising the RuvC and HNH domain with an amino acid sequence where the amino acid sequence is approximately 713 resides long and wherein the splitCas9 is regulatable by the sgRNA for genome-engineering application in cells, Anantharaman teaches the entire genome sequence of deltaproteobacteria bacterium GWF2_42_12 and Ge teaches it is within the skill of the art to determine the direct repeat for the guide sequence based on computational analysis of the genomic sequence. One would have been motivated to make such a modification in order to receive the expected benefit of a Cas protein derived from the deltaproteobacteria bacterium GWF2_42_12 for targeted genome editing as taught by Anantharaman and Ge.
Applicant argues the amended claims explicitly recite a “composition for genome editing” comprising a “synthetic guide sequence” targeting “a target sequence of interest in a eukaryotic cell genome” – none of which is taught by the combination of Wright, Anantharaman and Ge.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “composition for genome editing comprising a synthetic guide sequence”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). As previously stated above, Wright teaches splitCas9 proteins comprising the RuvC and HNH domain with an amino acid sequence where the alpha-helical lobe was removed to minimize the distance between the RuvCI and RuvCII domains such that the amino acid sequence is approximately 713 resides long ([00540] and Page 194, Figure 1); as well as Wright teaches enriching a population of eukaryotic cells for cells in the G2/M transition of the cell cycle; and contacting the target DNA with a Cas9 targeting complex (e.g., via introducing into the target eukaryotic cell(s) at least one component of a Cas9 targeting complex) (e.g., contacting the target DNA with a split-Cas9, a Cas9 guide RNA, and a dimerizing agent [00525]. While, Anantharaman teaches the genome sequence of deltaproteobacteria bacterium GWF2_42_12 (listed in Table 12 of the instant specification as SEQ ID NO: 62) where the genome sequence submitted for the deltaproteobacteria bacterium GWF2_42_12 is 100% identical to instant SEQ ID NO: 62 and Ge teaches using computational analysis to determine the direct repeats within the genome sequence for the guide sequence such as utilizing a de novo repeat detection program to find repeat copies within a range of sequence lengths, the repeats clustered into groups where weak DR copies were annotated by mapping the template DR onto the genome sequence. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Wright to include the specific Cas protein derived from deltaproteobacteria bacterium GWF2_42_12 as taught by Anantharaman and Ge because Wright teaches it is within the ordinary skill in the art to use splitCas9 proteins comprising the RuvC and HNH domain with an amino acid sequence where the amino acid sequence is approximately 713 resides long and wherein the splitCas9 is regulatable by the sgRNA for genome-engineering application in cells, Anantharaman teaches the entire genome sequence of deltaproteobacteria bacterium GWF2_42_12 and Ge teaches it is within the skill of the art to determine the direct repeat for the guide sequence based on computational analysis of the genomic sequence. One would have been motivated to make such a modification in order to receive the expected benefit of a Cas protein derived from the deltaproteobacteria bacterium GWF2_42_12 for targeted genome editing as taught by Anantharaman and Ge.
The previous rejection of claims 30, 34, 37, 38 and 45 under 35 U.S.C. 103 as being unpatentable by Wright et al (WO 2016/114972 A1) in view of Cotta-Ramusino et al (WO 2017/180694 A1) has been withdrawn in view of applicant’s cancelation of the claim filed in 01/09/2026.
The previous rejection of Claim 35 under 35 U.S.C. 103 as being unpatentable by Wright et al (WO 2016/114972 A1) in view of Doman et al (Nature Biotechnology Vol 38, Pgs 620-628; 2020) has been withdrawn in view of applicant’s cancelation of the claim filed in 01/09/2026.
The previous rejection of Claims 43 and 47 under 35 U.S.C. 103 as being unpatentable by Wright et al (WO 2016/114972 A1) in view of Lambowitz et al (mBio 8:e00897-17 Vol. 8 Iss. 4, pgs. 1-16, 2017) has been withdrawn in view of applicant’s cancelation of the claim filed in 01/09/2026.
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, 14 and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of 1 and 13-15 copending Application No. 17/612,504 (referred herein as ‘504. Although the claims at issue are not identical, they are not patentably distinct from each other because the subject matter disclosed in the patented claims anticipate the limitations recited in claims 1, 14 and 15. Claim 1 of ‘504 recites “An engineered Cas protein comprising an HNH and/or a RuvC nuclease domain, between 600-800 amino acids in size…”. Claim 13 of ‘504 recites “The engineered Cas protein of claim 1, wherein the cas protein is a class 2, Type II CRISPR-Cas protein”. Claim 14 of ‘504 recites “The engineered Cas protein of claim 1, further comprising an additional nuclease domain, wherein one or both nuclease domains are catalytically inactive or modified to be catalytically inactive, or wherein the Cas protein is a nickase”. Claim 15 of ‘504 recites “The engineered Cas protein of claim 14, wherein both nuclease domains are catalytically inactive”.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments - Double Patenting
The previous rejection of claims 1, 14 and 15 provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims of 1 and 13-15 copending Application No. 17/612,504 has been maintained and re-written to address claim amendments filed on 01/09/2026. Applicant’s arguments have been fully considered but have not been found persuasive.
Applicant argues the issue of whether there is indeed double patenting is contingent upon whether the remarks herein are considered and entered as well as if the Examiner believes that there is overlap with the amended claims.
As stated above, there is currently a double patenting rejection of the amended claims 1, 14 and 15 provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims of 1 and 13-15 copending Application No. 17/612,504.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm EST.
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/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/CELINE X QIAN/Primary Examiner, Art Unit 1637