DETAILED ACTION
The previous action mailed on 03/24/2026 is withdrawn. A new action is presented below.
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 .
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withdrawn.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Claims 63-65,68-70 and 72-74 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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
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 82 and 83 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.
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).
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 35, 43-45, 47-49, 53 and 80-83 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This rejection was made in the Office action mailed 09/10/2025 and has been rewritten to address the amendment to the claims in the reply filed 01/09/2026.
For the purposes of this rejection, claims 82 and 83 are being interpreted as if they depend from claim 49 (See the above rejection under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph).
Claims 44, 45, 48, 49 and 53 are drawn to a genus of Cas protein comprising a RuvC and a HNH domain less than 900 amino acids in length. The rejected claims thus comprise a genus of small Cas proteins or splitCas9 proteins that encompass the RuvC and HNH domain with an amino length of less than 900 amino acids.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification envisions split Cas9 proteins for the purpose of increased specificity and advantageous delivery of the Cas protein [0299]. The specification teaches that the split Cas can function as a nuclease or a dead-Cas, which is just for guide RNA targeting [0299]. The specification envisions the advantageous nature of using a split cas protein, however, the specification does not specifically explain how the Cas protein sequence is engineered to contain all required domains while retaining functionality and be less than 900 amino acid residues in the sequence. The specification describes the five naturally occurring Cas proteins listed in Table 12, such as Gammaproteobacteria bacterium AqS3, Deltaproteobacteria bacterium GWF2_42_12, JGI Metagenome: IMG 3300025323, Nitrospirae bacterium RBG_13_39_12, and Nitrospiraceae bacterium isolate UBA9935 [0997]. No description is provided of how the smallCas or SplitCas is created or what is removed from the Cas protein in order to create the Cas protein under 900 amino acids in length but retain the function of the Cas protein.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of the five exemplary small Type II-C Cas9 (Cas9-t) protein [0991]. The results are not necessarily predictive of the structure or necessary components for a small or splitCas that is able to retain the nuclease functions. Thus, it is impossible for one to extrapolate from the few examples described herein those smallCas or SplitCas that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of a functional mini/small/split Cas proteins. Ma et al (ACS Synth. Biol, 7, 978-985; 2018) teaches to bypass the AAV payload limit and deliver the Cas protein, the Cas9 is split and packaged into two separate AAVs along with a guide RNA expression unit, which allows functional reconstitution of the full-length SpCas9 in vivo (Page 978, Column 1). However, this does not limit the Cas protein to less than 900 amino acids.
Kim et al (Nat Commun 8, 14500, pgs. 1-12; 2017) Cas9 proteins, such as the SpCas9 and the SaCas proteins with 1368 and 1053 amino acids in length, respectively (Page 1, Column 1). Kim teaches the known ways to deliver the large Cas proteins include splitting the cas protein into two AAV vectors to create a split cas protein, however, the split cas is less active than the intact Cas protein as well as the co-delivery of two AAV vectors is less efficient than the delivery of a single AAV vector (Page 1, Column 1). Kim teaches its solution to the problem as a Cas9 protein derived from Campylobacter jejuni where the CjCas9 is efficient for genome editing and only 984 amino acids in length (Page 1, Column 1). However, the prior art demonstrates that in order for both efficient delivery and genome editing a specific length is required.
Claim 35 is drawn to a genus of nucleotide deaminase or catalytic domains that are modified to increase its activity against a DNA-RNA heteroduplex or to reduce off-target effects. The rejected claims thus comprise a genus of nucleotide deaminase or catalytic domains that encompass modified sequences to increase its activity against a DNA-RNA heteroduplex or to reduce off-target effects. This rejection was made in the Office action mailed 09/10/2025.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification envisions the use of a nucleotide deaminase with reduced off-target effects [0010]; however, no description is provided of how this nucleotide deaminase is able to increase its activity against a DNA-RNA heteroduplex. The disclosure cites Jordan L. Doman et al., Evaluation and minimization of Cas9-independent off-target DNA editing by cytosine base editors, Nat Biotechnol (2020). doi.org/10.1038/s41587-020-0414-6 at paragraph [0415]).
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of an exemplary small Type II-C Cas9 (Cas9-t) protein but provides no description of the deaminases or catalytic domains used in the small Type II-C Cas9 protein [0991]. Therefore, the results are not necessarily predictive of the structure or necessary components for a small or splitCas that contains a nucleotide deaminase or catalytic domain that would be capable to increase its activity against a DNA-RNA heteroduplex. Thus, it is impossible for one to extrapolate from the few examples described herein those nucleotide deaminase or catalytic domains that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of a functional nucleotide deaminase and/or catalytic domain capable of increasing its activity against a DNA-RNA heteroduplex. Cox et al (Science 385, Pages 1-9; 2017) teaches that although it is possible that ADAR could deaminate adenosine bases on the DNA strand in RNA-DNA heteroduplexes, it is unlikely to do so in this case because Cas13b does not bind DNA efficiently and because REPAIR is cytoplasmically localized (Page 8, Column 2). Given the difficulties expressed by Cox, one would have recognized that applicant was not in possession of deaminase variants with increased activity against DNA-RNA heteroduplex.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of a functional nucleotide deaminase and/or catalytic domain capable of reducing off-target effects. Doman et al (Nature Biotechnology Vol 38, Pgs 620-628; 2020) 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). Doman teaches a screening assay and provides, from the screening assay, variants of the CBEs (Page 624, Column 2 bridging Page 626, Column 1). However, variants are insufficient to describe a representative number of the species of the claimed genus.
Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”’).
Claims 43 and 47 are drawn to a genus of functional fragments of any reverse transcriptase. The rejected claims thus comprise a genus of reverse transcriptase that encompass functional reverse transcriptase activity. Claim 43 requires "a reverse transcriptase or functional fragment thereof." There is no limit as to how short the fragments may be. Thus, the claim reasonably encompassed fragments to two or more amino acids of any reverse transcriptase, where the fragments must be capable of providing reverse transcriptase function. This rejection was made in the Office action mailed 09/10/2025.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification envisions the use of a reverse transcriptase domain within the system [0260-0262]. The specification teaches the specific reverse transcriptases such as Human immunodeficiency virus (HIV) RT, Avian meyloblastosis virus (AMV) RT or Moloney murine leukemia virus (M- MLV) RT [0388]. Although the specification envisions the use of a reverse transcriptase, no description is provided of what “fragment” of a reverse transcriptase would be used as well as if the fragment of the reverse transcriptase would even be functional within the system.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of full-length reverse transcriptase. The results are not necessarily predictive of the structure or necessary components for fragments of a reverse transcriptase. Thus, it is impossible for one to extrapolate from the full-length protein those fragments of reverse transcriptases that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of a functional fragment of reverse transcriptase capable for use in the cas9 protein. Wohrl, Birgitta (Viruses Vol 11, No 7, 598, Pgs. 1-17; 2019) teaches that the structure of the reverse transcriptase is important to the way the reverse transcriptase functions, specifically the catalytic activity of the RNase H domain of retroviral RTs is essential during reverse transcription and mutations that inactivate the RNase H prevent virus propagation (Page 6, Paragraph 2). Wohrl teaches those specific domains within the reverse transcriptases are important for substrate binding and activity (Page 7, Paragraph 1). Therefore, it is unlikely and unpredictable that a fragment of a reverse transcriptase would be capable in functioning successfully.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 35, 43-45, 47-49 and 53.
Response to Amendments - Claim Rejections - 35 USC § 112
The previous rejection of claims 1, 2, 8, 9, 11, 14-16, 27, 29-31, 34, 37, 38, 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 35, 43-45, 47-49 and 53 under 35 U.S.C. 112(a) has been maintained and re-written to address Applicant’s amendments to the claims filed on 01/09/2026.
Applicant’s arguments have been fully considered but are not found to be persuasive. Applicant argues that the claims were amended to explicitly include the Cas protein having at least 95% sequence identity to specific SEQ ID NO: 62, 64, 66 or 68.
However, the amendment to claim 1 does not address the other written description rejections previously placed on the record as well as the claims that relied on addition independent claims that were not amended to include the new limitations, such as independent claims 44 and 48.
Specifically, claim 35 recites “The non-naturally occurring or engineered composition of claim 31, wherein 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” which would require both the increase of activity against a DNA-RNA heteroduplex and/or the reduction of off-target effects. It is stated above that, the use of a nucleotide deaminase with reduced off-target effects, however, no description is provided of how this nucleotide deaminase is able to increase its activity against a DNA-RNA heteroduplex.
Claims 44, 45, 48, 49 and 53 are drawn to a genus of Cas protein comprising a RuvC and a HNH domain less than 900 amino acids in length. The rejected claims thus comprise a genus of small Cas proteins or splitCas9 proteins that encompass the RuvC and HNH domain with an amino length of less than 900 amino acids. It is stated above, the specification envisions the advantageous nature of using a split cas protein, however, the specification does not specifically explain how the Cas protein sequence is engineered to contain all required domains while retaining functionality and be less than 900 amino acid residues in the sequence.
Claims 43 and 47 are drawn to a genus of functional fragments of any reverse transcriptase. The rejected claims thus comprise a genus of reverse transcriptase that encompass functional reverse transcriptase activity. Claim 43 requires "a reverse transcriptase or functional fragment thereof." There is no limit as to how short the fragments may be. Thus, the claim reasonably encompassed fragments to two or more amino acids of any reverse transcriptase, where the fragments must be capable of providing reverse transcriptase function. It is stated above, the specification envisions the use of a reverse transcriptase, no description is provided of what “fragment” of a reverse transcriptase would be used as well as if the fragment of the reverse transcriptase would even be functional within the system.
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
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 44 is rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception (i.e., a law of nature, nature phenomenon, or an abstract idea) without significantly more. The claims recite “a Cas protein that comprises a RuvC domain and a HNH domain and is less than 900 amino acids in size; and a guide sequence capable of forming a complex with the Cas protein and directing the complex to bind to a target sequence, which is a nature-based product. This rejection was made in the Office action mailed 09/10/2025.
Subject Matter Eligibility Test for Products and Processes - Claim 44
Step 1 – Is the claim to a Process, Machine, Manufacture or composition of Matter? YES
Claim 44 is directed to a complex comprising a Cas protein and guide sequence which is a composition of matter. The claims are directed to a statutory category.
Step 2A, Prong one – Does the claim recite an Abstract Idea, Law of Nature, or Natural Phenomenon? YES
Laws of nature and natural phenomena, as identified by the courts, include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature. MPEP 2106.04(c) outlines the markedly different characteristics analysis.
Claim 44 recites a Cas Protein comprising the RuvC and HNH domain and less than 900 amino acids in length. The Cas proteins can be designed to be small or split in order to efficiently deliver the cas protein to a cell. However, the specification teaches, in Table 12, a list of naturally occurring Cas proteins derived from naturally occurring bacteria [0997]. These are Cas proteins that are naturally less than 900 amino acids and naturally occurring in the bacteria. As shown in the GenBank Records, the Cas protein derived from the Gammaproteobacteria bacterium AqS3 shows the protein encoded by the genome is less than 900 amino acids long comprising the Cas protein (NCBI GenBank: MBF2755401.1, Pages 2/2; 2020). Organisms that express Cas proteins also express the cognate guide sequences capable of forming a complex with the Cas protein and directing the complex to bind to a target sequence as a mechanism of immunity (Hille et al. Phil. Trans. R. Soc. B 371:20150496, pgs. 1-12; 2016; Page 1 Abstract). Thus, clam 1 is not markedly different from the naturally-occurring counterpart, and recites a judicial exception without additional elements.
Step 2A, Prong Two – Does the claim recite additional elements that integrate the Judicial Exception into a Practical Application? NO
The Supreme Court has long distinguished between principles themselves, which are not patent eligible, and the integration of those principles into practical applications, which are patent eligible. The phrase "integration into a practical application" requires an additional element or a combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that it is more than a drafting effort designed to monopolize the exception.
In the instant case, claim 44 does not recite any elements in addition to the judicial exception (i.e., natural product) that would integrate the natural product into a practical application.
Step 2B – Does the Claim recite Additional Elements that amount to Significantly More than the Judicial Exception? NO
The Supreme Court has identified a number of considerations for determining whether a claim with additional elements amounts to "significantly more" than the judicial exception(s) itself. The claim as a whole is evaluated as to whether it amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim (MPEP 2106.05).
As stated above, claim 44 does not recite any elements in addition to the judicial exception (i.e., natural product). There are no additional elements to amount to significantly more than the judicial exception.
Dependent claims – Claim 47
Regarding claim 47, the claim requires the composition to further comprise a reverse transcriptase. In diverse bacteria, the cas1 gene is fused (or adjacent) to a gene encoding a reverse transcriptase (RT) related to group II intron RTs (Lambowitz et al. mBio 8:e00897-17 Vol. 8 Iss. 4, pgs. 1-16, 2017; Page 1, Abstract). 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 population of spacers contained within CRISPR arrays in a natural community of RT-Cas1-Carrying organisms is a potential “memory bank” of the pools of nucleic acids (Page 2, Paragraph 5). Lambowitz teaches phylogenetic analysis of the CRISPR-associated RTs demonstrates monophyly of the RT-Cas1 fusion, and coevolution of the RT and Cas1 domains (Page 1, Abstract).
Claims 48, 49 and 53 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception (i.e., a law of nature, nature phenomenon, or an abstract idea) without significantly more. The claims recite “a Cas protein that comprises a RuvC domain and a HNH domain and is less than 900 amino acids in size; and a guide sequence capable of forming a complex with the Cas protein and directing the complex to bind to a target sequence, which is a nature-based product. This rejection was made in the Office action mailed 09/10/2025.
Subject Matter Eligibility Test for Products and Processes - Claim 48
Step 1 – Is the claim to a Process, Machine, Manufacture or composition of Matter? YES
Claim 48 is directed to a complex comprising a Cas protein and guide sequence which is a composition of matter. The claims are directed to a statutory category.
Step 2A, Prong one – Does the claim recite an Abstract Idea, Law of Nature, or Natural Phenomenon? YES
Laws of nature and natural phenomena, as identified by the courts, include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature. MPEP 2106.04(c) outlines the markedly different characteristics analysis.
Claim 48 recites a Cas Protein comprising the RuvC and HNH domain and less than 900 amino acids in length. The Cas proteins can be designed to be small or split in order to efficiently deliver the cas protein to a cell. However, the specification teaches, in Table 12, a list of naturally occurring Cas proteins derived from naturally occurring bacteria [0997]. These are Cas proteins that are naturally less than 900 amino acids and naturally occurring in the bacteria. As shown in the GenBank Records, the Cas protein derived from the Gammaproteobacteria bacterium AqS3 shows the protein encoded by the genome is less than 900 amino acids long comprising the Cas protein (NCBI GenBank: MBF2755401.1, Pages 2/2; 2020). Organisms that express Cas proteins also express the cognate guide sequences capable of forming a complex with the Cas protein and directing the complex to bind to a target sequence as a mechanism of immunity (Hille et al. Phil. Trans. R. Soc. B 371:20150496, pgs. 1-12; 2016; Page 1 Abstract). Thus, clam 1 is not markedly different from the naturally-occurring counterpart, and recites a judicial exception without additional elements.
Step 2A, Prong Two – Does the claim recite additional elements that integrate the Judicial Exception into a Practical Application? NO
The Supreme Court has long distinguished between principles themselves, which are not patent eligible, and the integration of those principles into practical applications, which are patent eligible. The phrase "integration into a practical application" requires an additional element or a combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that it is more than a drafting effort designed to monopolize the exception.
In the instant case, claim 48 does not recite any elements in addition to the judicial exception (i.e., natural product) that would integrate the natural product into a practical application.
Step 2B – Does the Claim recite Additional Elements that amount to Significantly More than the Judicial Exception? NO
The Supreme Court has identified a number of considerations for determining whether a claim with additional elements amounts to "significantly more" than the judicial exception(s) itself. The claim as a whole is evaluated as to whether it amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim (MPEP 2106.05).
As stated above, claim 48 does not recite any elements in addition to the judicial exception (i.e., natural product). There are no additional elements to amount to significantly more than the judicial exception.
Dependent Claims – Claims 49 and 53
Regarding claim 49, the claim further requires a regulatory element operably linked to the first portion of the system, the Cas protein, and additionally a regulatory element operably linked to the second portion of the system, the guide sequence. Hille (Hille et al. Phil. Trans. R. Soc. B 371:20150496, pgs. 1-12; 2016) teaches promoter sequences were identified to lie within each repeat and some were able to initiate transcription leading to intermediate crRNA species (Page 3, Column 2).
Regarding claim 53, the claim further requires the composition be comprised within a vector. The instant specification envisions the “vector” as comprising one or more polynucleotides molecules encoding components of which have already been described [0152]. Therefore, if a naturally occurring cell or organism, such as a bacterium, comprises all the components listed in claim 1 then it is the cell or organism itself that is the vector.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 59, 60 and 61 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). The specification describes the administration of cells or population of cells, such as immune system cells, via implantation or transplantation [0792]. Therefore, the claimed invention reads on a human cell that would be transplanted or implanted into a human organism.
Response to Arguments - Claim Rejections - 35 USC § 101
The previous rejection of claims 1, 2, 6 and 29 under 35 U.S.C. 101 has been withdrawn in view of Applicant’s amendments to the claims filed on 01/09/2026.
The previous rejection of claims 59-61 under 35 U.S.C. 101 has been maintained in view of Applicant’s amendments to the claims filed on 01/09/2026.
Applicant’s arguments have been full considered but have not been found to be persuasive. Applicant argues Claim 59 recites "a cell comprising the composition of claim 1" such as an isolated cell containing the genome editing composition wherein an isolated cell is not an organism. Applicant continues to argue that the claim encompasses single eukaryotic cells including yeast, plant cells, and non-human animal cells and the USPTO has issued thousands of patents with claims to human cells and engineered human cells (e.g., CAR-T cells). Applicant argues Claims 60 and 61, which depend from claim 59, are similarly directed to isolated cells and cell products, not human organisms and therefore, the claimed composition is a non-naturally occurring, engineered composition with markedly different characteristics from anything in nature due to the synthetic guide sequence component designed to target user-selected sequences in eukaryotic genomes.
These arguments are not persuasive because claim 59 does not specify that the cell is isolated as well but rather recites “a cell comprising the composition of claim 1”. Claim 60 further requires that the eukaryotic cell be either a human cell, a non-human animal cell, a therapeutic T cell, an antibody producing B-cell, a stem cell or a plant cell. The human cell, the therapeutic T cell, the antibody producing B-cell and the stem cell all read on human. Claim 61 then further requires that a tissue, organ, organism, or cell product comprising the cell of claim 59 which clearly outlines that the cells previously stated in claim 60 would read on a human being. “Congress has excluded claims directed to or encompassing a human organism from eligibility”; See MPEP § 2105 (I). The specification describes the administration of cells or population of cells, such as immune system cells, via implantation or transplantation [0792]. Therefore, the claimed invention reads on a human cell that would be transplanted or implanted into a human organism. Given the broadest reasonable interpretation, the claimed cell reads on a human being.
The previous rejection of claims 44, 47-49 and 53 under 35 U.S.C. 101 has been maintained in view of Applicant’s amendments to the claims filed on 01/09/2026.
Applicant’s arguments have been fully considered but have not been found to be persuasive. Applicant argues that the claims were amended to explicitly include the Cas protein having at least 95% sequence identity to specific SEQ ID NO: 62, 64, 66 or 68 as well as the addition of the target sequence of interest being in a eukaryotic cell genome.
However, the amendment to claim 1 does not address the other 101 rejections previously placed on the record as well as the claims that relied on addition independent claims that were not amended to include the new limitations, such as independent claims 44 and 48. Independent claims 44 and 48 do not include the recited limitations that claim 1 was amended to include.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 44, 48, 49 and 53 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Wright et al (WO 2016/114972 A1). This rejection was made in the Office action mailed 09/10/2025 and has been rewritten to address the amendment to the claims in the reply filed 01/09/2026.
Regarding claims 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].
Regarding claim 49, 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].
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.
The previous rejection of claims 44, 48, 49 and 53 under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Wright et al (WO 2016/114972 A1) has been maintained and re-written to address Applicant’s amendments to the claims filed on 01/09/2026.
Applicant’s arguments have been fully considered but are not found to be persuasive. Applicant’s arguments have been fully considered but have not been found to be persuasive. Applicant argues that the claims were amended to explicitly include the Cas protein having at least 95% sequence identity to specific SEQ ID NO: 62, 64, 66 or 68 as well as the addition of the target sequence of interest being in a eukaryotic cell genome.
Applicant argues that 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), does 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 that the amended claims now explicitly recite a "composition for genome editing" comprising a "synthetic guide sequence" targeting "a target sequence of interest in a eukaryotic cell genome."; as well as Wright does not teach or suggest this specifically engineered, integrated genome editing composition targeting eukaryotic genomes using the specific compact Cas proteins of SEQ ID NOs: 62, 64, 66, or 68.
However, the amendment to claim 1 does not address the other 102 rejections previously placed on the record as well as the claims that relied on addition independent claims that were not amended to include the new limitations, such as independent claims 44 and 48. Independent claims 44 and 48 do not include the recited limitations that claim 1 was amended to include.
Applicant continues to argue that Wright's split-Cas9 system is fundamentally different from the claimed single- chain compact Cas protein architecture and Wright teaches splitting a conventional-sized Cas9 protein into two separate polypeptides for delivery purposes, while the claims require a single Cas protein of less than 850 amino acids. Applicant argues that the examiner's position that Wright's split components "collectively" meet the size limitation conflates two separate polypeptides with a single compact protein, which is not supported by claim construction principles
However, the current claim limitations, as well as the instant specification, does not include the detailed description of what is required to be removed to meet the limitation of the cas protein as well as does not include that the cas protein has to be a single protein, rather than a splitCas protein.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JENNIFER A DUNSTON can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
Prosecution Insights