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 .
Application Status
This action is written in response to applicant’s correspondence received on 10/11/2022. Claims 169-197 are pending. Claims 1-168 have been cancelled. All pending claims are currently under examination.
Election/Restrictions
Applicant’s election without traverse of the SOD1 mutation comprising A4V in the reply filed on 10/17/2025 is acknowledged. The Applicant’s election of the A4V mutation reads on claims 169-197.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO’s electronic filing system (see Section I.1 of the Legal Framework for EFS-Web or Patent Center (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via EFS-Web or Patent Center as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via EFS-Web or Patent Center as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above. In particular, the sequence incorporation statement entitled “Sequence Listing” in the specification refers to the sequence listing file in terms of “megabytes,” but must refer to the size of the file in terms of “bytes.” See MPEP 2422.03, section I, “ASCII Text File Submitted VIA EFS-Web.”
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The use of the terms ZYMOCLEAN (paragraphs [00801], [00803], [00804], [00805], [00807], [00808], [00810] and [00811]), QIAPREP (paragraphs [00801], [00803], [00804], [00805], [00806], [00807], [00808], [00809], [00810], [00811], [00818], [00844] and [00885]), GIBSON ASSEMBLY (paragraphs [00801], [00803], [00804], [00805], [00808], [00810] and [00811]), and LIPOFECTAMINE (paragraphs [00819], [00847], [00851], which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Drawings
The drawings are objected to because the figures are not properly labeled.
37 CFR 1.84 (u)(1) states “The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation "FIG." Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation "FIG." must not appear.”
The drawings are objected to because Figure 33 is improperly labeled. Figure 33 contains partial views on separate sheets. For example, Figure 33 spans multiple separate sheets and is labeled “Fig. 33” and “Fig. 33 (continued)” but should be labeled “Fig. 33A,” “Fig. 3B,” etc., for each new page of the drawing.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 171-173, 177, 179, 181-182, and 193 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 171, claim 171 recites “one or more mutations selected from mutations set forth in Table 1.” Claim 171 therefore makes reference to “Table 1” in the claim. Per MPEP 2173.05(s):
“[w]here possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience” (MPEP 2173.05(s)).
In the present case, it is improper to refer to Table 1 in the claim, as the individual mutations can be listed out in the claim, there being only 151 mutations.
Regarding claim 172, claim 172 lists a series of mutations in relation to SEQ ID NO: 100. For instance, claim 172 recites the mutation “A4S.” However, SEQ ID NO: 100 does not contain an “A” residue at position four. The mutations appear to be in reference to SEQ ID NO: 100, where the reference position is made without accounting for the initial methionine of the sequence, as stated at the bottom of Table 1 on page 22. Nonetheless, claim language indicating that the mutations are made with respect to SEQ ID NO: 100 absent the N-terminal methionine is not included in the claim. Thus, claim 172 is indefinite as it is unclear which amino acid residues are meant to be mutated with respect to SEQ ID NO:100.
Regarding claim 173, claim 173 suffers a similar 112(b) issue in that it recites a mutation such as “A4V” in reference to SEQ ID NO: 100; however, no “A” residue exists at position four. It is therefore unclear as to what specific mutations are being referred to in the claim.
Regarding claim 177, claim 177 recites “one improved characteristic.” Recitation of such a phrase renders the claim indefinite because the claim recites subjective terminology. It is unclear what is meant to be an improved characteristic regarding the recited RNP complex, as any individual practitioner could interpret such a phrase in a unique way. Furthermore, the specification at paragraph 186 recites that “improved characteristics” are not limited in anyway and only offers examples of what such characteristics could be. Thus, the term is not clearly defined in the specification.
Regarding claim 179, claim 179 recites that the CasX variant comprises an “improved characteristic” compared to a reference CasX. This claim language is subjective, as the term “improved characteristic” is unclear and could be interpreted to mean anything based upon an individual practitioner’s interpretation. Furthermore, the specification at paragraph 186 recites that “improved characteristics” are not limited in anyway and only offers examples of what such characteristics could be. Thus, the term is not clearly defined in the specification.
Regarding claim 181, claim 181 is directed to a gNA with a scaffold and targeting sequence, where “the targeting sequence is complementary to a superoxide dismutase 1 (SOD1) gene target nucleic acid sequence.” The final line of claim 181 further recites that “wherein the SOD1 gene comprises one or more mutations.” It is unclear how or if this additional limitation is meant to affect the structure of the gNA. For instance, the gNA is not recited to target the SOD1 mutation; it is unclear specifically how or if the presence of a SOD1 mutation is meant to affect the structure of the focus of the claim (i.e., a gNA).
Claim 182 depends from claim 181 and does not resolve this 112(b) issue and is therefore also rejected.
Regarding claim 193, claim 193 recites “A method of treating a SOD1-related disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the cells of claim 193.” Claim 193 therefore recites that it depends from itself. This claim language is unclear because it is unclear to which “cells” are being referred in the claim as recitation of “the cells of claim 193” lacks sufficient antecedent basis. Furthermore, it is unclear how the claim is meant to depend from itself, and what limitations are established by such a claim structure.
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 169-197 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Regents of the University of California v. Eli Lilly & Co, 119 F.3d at 1568, 43 USPQ2d at 1406.
Regarding claim 169, claim 169 is drawn to a composition comprising a CasX variant protein with 70% identity to SEQ ID NO: 126. Furthermore, the recited sequence is recited with the functionality of being a CasX protein, and therefore the claim requires functional limitations associated with the associated structure recited (the genus of proteins which are 70% identical to SEQ ID NO: 126 which also function as CasX proteins). This claim language is problematic because it recites the genus of proteins which are 70% identical to SEQ ID NO: 126 which are functionally CasX proteins. However, as discussed further below, the Applicant did not show possession commensurate in scope with what is being claimed, as it is known in the art that such large variations in uncharacterized Cas enzymes is known to cause unpredictable changes with regards to the protein’s functionality.
Regarding the specification, the Applicant has offered numerous examples of CasX constructs which were created. With regards to the present claim language which recites guide NAs which target SOD1, the Applicant offers Examples 10-19 which cover in vitro and theoretical in vivo testing of CasX proteins which target SOD1 using guide RNAs. The Applicant appears to have primarily focused on Cas variant “119,” which is represented by SEQ ID NO: 208). An alignment of SEQ ID NO: 126 and 208 is shown below, where ID NO: 208 is on top and SEQ ID NO: 126 is on the bottom:
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519
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Greyscale
As shown above, SEQ ID NO: 208 and 126 are approximately 93% identical. It appears that the Applicant has focused testing primarily on SEQ ID NO: 208, which reads on the instant claim language of CasX variant that is at least 70% identical to SEQ ID NO: 126. However, it does not appear that the Applicant has reduced to practice and tested the CasX variant of SEQ ID NO: 126 itself. Furthermore, the Applicant has offered CasX variants with different domain substitutions; however, the Applicant has not recited or elucidated any key structural-functional relationships between the recited genus of protein sequences and their ability to function as CasX proteins. For instance, the Applicant has not performed structural or mutagenesis studies to identify enzymatic domains which may be critical for functionality regarding the recited genus. For instance, the recited genus allows for proteins which have 30% of their amino acids deleted from the final protein structure; however, the Applicant has not identified such regions that are associated with the functionality of the CasX proteins.
Regarding the state of the art, it was known in the art at the time of filing that CasX proteins were novel Cas enzymes which had not been fully characterized. For instance, Yang (Yang H . Cell Res. 2019 May;29(5):345-346) – which was published the same year as the instantly filed invention and therefore is an accurate representation of the knowledge of the state of the art – teaches that CasX proteins were a novel class of enzyme discovered at the time of filing (Title, Abstract). Yang teaches that :
“CasX was identified by metagenomic analysis of bacteria from groundwater and characterized as an RNA-guided DNA nuclease. It recognizes a 5′-TTCN PAM and is capable of plasmid interference in E. coli when presenting sgRNA (covalently linked crRNA-tracrRNA). It shares no similarity to other reported Cas endonucleases except for a RuvC domain located at the C-terminus. The above features of CasX correlate with those of type V Cas12; however, the size of CasX (~980 aa) is smaller than those of reported Cas12 (~1200 aa),” (Intro, second paragraph).
Thus, Yang teaches that at the time of filing CasX was a novel enzyme which was not known to share similarity with other Cas enzymes (above). Yang further teaches that CasX is significantly smaller than other known Cas enzymes (above). Thus, at the time of filing, the structural domains were still in the stages of being elucidated as CasX was known to have a novel structure. Yang concludes by saying that further structural analysis with higher resolution is required to guide CasX engineering for future applications (final sentence). Thus, it was known in the art at the time of filing that CasX was a novel protein. Furthermore, the Applicant did not characterize CasX variants which are modified up to 30% from SEQ ID NO: 126, where such a genus includes mutations, deletions, substitutions, and other changes, where furthermore the recited genus is recited with functional language (i.e., such variants must be capable of acting as a CasX enzyme).
Claims 170-180 and 183-197 depend from claim 169 and do not resolve this 112(a) issue. Claims 170-180 and 183-197 are therefore also rejected.
Furthermore, claim 175 contains an additional 112(a) written description issue in that it recites a gNA with a scaffold sequence that is at least 70% identical to SEQ ID NO: 2238. Regarding this claim, the authors have not offered additional gNA scaffold structures tested with CasX variants with 70% identity to SEQ ID NO: 126 to show that such variants of both the CasX and scaffold are permitted. Recited together, the Applicant is reciting an enormous genus of CasX variant with 70% identity to SEQ ID NO: 126 and a gNA scaffold with 70% identity to SEQ ID NO: 2238, such that it is unknown which combinations of such scaffolds and CasX variants yield the functional requirements of the claims (i.e., that the molecules function as gNA scaffolds and CasX enzymes, where furthermore they function to “target” a SOD1 gene. For instance, Yang teaches that:
“The domain composition of CasX-sgRNA-DNA ternary complexes showed some similarity to that of Cas12; however, each structural element adopts distinct folds. They also made efforts at structure determination of apo CasX and CasX-sgRNA and obtained CasX-sgRNA maps at low resolution (7.5 Å). In combination with mass spectrometry data, they found that sgRNA assembly and DNA loading trigger domain rearrangements,” (page 345, right column, second paragraph).
Thus, Yang teaches that structural elements of the novel CasX-gRNA complex are unique, comprising unique folds, and that such structures must be elucidated empirically in order to determine functional structures. The Applicant has not characterized gNA scaffolds with up to 30% variation which can function as gNA with the similarly uncharacterized genus of CasX protein.
Additionally, regarding claim 180, claim 180 recites that the protein is a chimeric CasX comprising domains from two or more CasX proteins. This claim language is further problematic owing to the 112(a) issues regarding claim 169 but also because, as Yang teaches, the genus of CasX proteins itself was novel and uncharacterized at the time of filing, where furthermore the structure and domains were novel and only overlapping in the RuvC domain with other known Cas proteins (page 345, left column, third paragraph). Thus, the genus of “CasX” domains was not shown to be in possession by the Applicant because the family of CasX proteins, as well as their novel domains, were not characterized either in the art or the application.
In addition, claims 177 and 179 contain another 112(a) issue in that they recite that the variants comprise an “improved characteristic” either to specific CasX proteins (claim 177) or any CasX protein (claim 179). The Applicant has not identified a structure-function relationship between CasX proteins with up to 30% modification which are also associated with an “improved characteristic.” Also, as discussed above, the family of CasX protein itself is novel and unpredictable; claim 179 is claiming that there is an improved characteristic relative to “a reference CasX protein.” However, the characteristics, and whether or not they have been improved upon, of the genus of “reference CasX” have not been shown to be in possession by the Applicant, as this class of protein is itself novel and not fully characterized. Thus, the Applicant can not show possession of “improved characteristics” relative to a wholly uncharacterized class of enzyme.
Additionally, the Applicant has not demonstrated possession of a method to treat a SOD1-related disease, as they have only offered a prophetic example of the compositions be tested in an animal model in the final Example (Example 19). Thus, given the unpredictability of the components of the method, which includes the highly unpredictable genus of CasX variants, the Applicant has not shown possession of any treatment method to treat a SOD1-associated disease, where furthermore they were not in possession of recited claim limitations such as a “therapeutically effective” amount (claims 193-194) or any improvement in a clinically relevant end-point (claim 196) because 1) the Applicant has not tested any such method and 2) the components which are unpredictable and uncharacterized (i.e., the genus of CasX variant with 70% identity to SEQ ID NO:126) have furthermore not been characterized in vivo to treat any subject. The uncertainty of the genus is thus compounded when recited to be capable of treating a disease.
Regarding claim 181, claim 181 recites the term “gNA,” where the gNA scaffold is 70% identical to SEQ ID NO: 2238. With regards to the specification, the specification offers guidance with respect to the definition of the term “gNA.” Per paragraph 108 of the specification:
“The present disclosure provides specifically-designed guide nucleic acids ("gNAs") with targeting sequences that are complementary to, and are therefore able to hybridize with either strand of the SODl gene as a component of the gene editing CasX:gNA systems,” (paragraph 108).
Thus, as defined by the specification at paragraph 108, “gNA” are guide nucleic acids which hybridize with the SOD1 gene and act as a component of gene editing CasX:gNA systems. Thus, by reciting the term “gNA” and because the term “gNA” is defined in the specification to mean a component of a CasX:gNA system which can target SOD1, the functional requirements are imparted onto recitation of “gNA” in claim 181, namely, that such gNAs can act as components of CasX/gNA systems to target SOD1 (per paragraph 108). Furthermore, paragraph 107 of the specification recites that such gNAs can be gRNA, but can also be DNA/RNA hybrids. However, SEQ ID NO: 2238 appears to be an RNA molecule.
Regarding the specification, it does not appear that the Applicant has offered examples of DNA/RNA and/or modified SEQ ID NO: 2238 scaffold proteins which are furthermore compatible in CasX gNA systems.
The prior art does not provide experimental evidence that DNA guide nucleic acid or DNA-RNA hybrid guide nucleic acid can be used with a CasX protein to provide a functional RNP complex. Thus, the state of the art is undeveloped.
Due to the underdeveloped nature of the CasX prior art, one would look to similar CRISPR systems to gauge the predictability of the invention. Yin (Nature Chemical Biology, Vol. 14, pages 311-316, page 1/1 of Online Methods, and pages 1/14-14/14 of Supplementary Information, January 29, 2018) teach that the crystal structure of Cas9-sgRNA complex was used to identify regions of the sgRNA that may be amenable to modification (e.g., paragraph bridging pages 311-312; page 315, left column, 1st full paragraph). Yin teach that the 3’ end of the sgRNA is essential for Cas9-sgRNA binding and recognition of targeted DNA (e.g., paragraph bridging pages 311-312). Based upon the analysis of the crystal structure, Yin hypothesized that partial replacement of RNA with DNA may be tolerated (e.g., paragraph bridging pages 311-312). Yin conducted experiments and found that replacing two, four, six, eight or ten RNA nucleotides with DNA nucleotides starting from the 5’ end of the 20 nucleotide targeting sequence generated similar levels of activity as sgRNA (e.g., paragraph bridging pages 311-312). In contrast, replacement with 12-nucleotide DNA generated significantly lower efficacy, and replacement with 14 or more DNA nucleotides reduced activity to background levels (e.g., paragraph bridging pages 311-312). With regard to the targeting sequence at the 3’ end of the sgRNA, Yin found that replacement of four RNA nucleotides with DNA at the 3’ end of the guide sequence resulted in a loss of guide function (e.g., page 312, right column, last paragraph; Fig. 2e,f). Yin teach that Cpf1 works with a guide RNA that has its crRNA at the 3’ end of the RNA, and an eight-nucleotide DNA replacement at the 3’ end was functional with Cpf1 (e.g., page 312, right column, 3rd full paragraph; Fig. 2d). Yin teach that the tail region of the guide RNA is more amenable to DNA replacement than the seed region (e.g., page 315, left column, 1st full paragraph). However, replacement of too many RNA nucleotides with DNA results in a loss of activity (e.g., page 315, left column, 1st full paragraph). Moon (Trends in Biotechnology, Vol. 37, No. 8, pages 870-881, March 4, 2019) state the following at page 874:
“The further incorporation of DNA into gRNA accordingly depends on the architecture of the gRNA-nuclease complex. Thus, a concomitant engineering of the effector protein, such as by directed protein evolution may provide an opportunity for an advanced hybrid or even a full DNA guide.”
Accordingly, one would have recognized the unpredictability of using a CasX guide nucleic acid that is anything other than an RNA guide molecule. The Applicant has not characterized the genus of recited gNA scaffolds comprising 70% identification with SEQ ID NO: 2238.
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 192-193 are rejected under 35 U.S.C. 101 because the claimed invention is directed to naturally occurring products and phenomenon of nature without significantly more.
Regarding claim 192, claim 192 recites a population of cells modified by the method of claim 186, where at least 70% of the cells do not express a detectable level of non-functional SOD1. Claim 192 therefore is broadly drawn to a population of cells, including embodiments where for instance 100% of the cell population does not express non-functional SOD1. Regarding Step 1 of the Subject Matter Eligibility Test (see MPEP 2106), the claim is drawn to a composition of matter. Regarding Step 2A, prong 1, the claim can most broadly be interpreted to recite a naturally occurring product of nature, namely, a wild-type cell. Note that, although claim 192 recites the method of claims 185-186, which include modifying a cell with non-natural CasX compositions, there is no requirement that these elements remain in the cell. Thus, the population of cells can most broadly be interpreted to be simply wild-type cells which do not express non-functional SOD1 genes, and therefore do not comprise markedly different characteristics compared with naturally occurring cells. Regarding Step 2A, prong 2, there are no other elements recited in the claim which integrate the judicial exception into a practical application. Regarding Step 2B, the claim does not recite additional elements which would transform the claim into significantly more than the judicial exception. Thus, claim 192 is not patent eligible.
Regarding claim 193, claim 193 is here being interpreted to depend from claim 192. Claim 193 recites a method of administering the cells of claim 192 to a subject in need thereof. However, given the interpretation above, that such cells can simply refer to the wild-type cells which exist in a healthy patient, claim 193 only appears to recite a naturally occurring phenomenon; namely, the existence of cells inside of a person’s body (step 2A, prong 1). Furthermore, the method step of “administering” does not add any significant weight to the claim, as such a term can broadly be interpreted to mean that the cells are supplied to a subject, where such cells are naturally occurring in the body (Step 2A, prong 2). Finally, no additional elements are recited which would transform the claim into significantly more than the judicial exception (Step 2B). Thus, claim 193 is not paten eligible.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 169-174, 176-179, and 183-197 are rejected under 35 U.S.C. 103 as being unpatentable over Doudna (WO 2018/064371 A1, published 5/4/2018; see the entire reference) in view of Ahlfors (WO 2017/216771 A2; see the entire reference), Kiskinis (Kiskinis E. . Cell Stem Cell. 2014 Jun 5;14(6):781-95), and Deng (Deng HX . Science. 1993 Aug 20;261(5124):1047-51, see entire reference).
Regarding claim 169, Doudna teach a composition comprising a CasX polypeptide, and a CasX guide RNA (e.g., paragraph 68). Doudna teach the Planctomycetes CasX polypeptide of SEQ ID NO: 2, and variants thereof (e.g., paragraphs 72, 74, and 198). SEQ ID NO: 2 of Doudna has a 93% identity, with 96% positives to instant SEQ ID NO: 126 (see alignment on page 1 of Doudna provided). Doudna teach that the guide RNA contains a “guide sequence” or “targeting sequence” that can be modified so that the CasX guide RNA can target a CasX protein to any desired sequence of any desired target nucleic acid, with the exception that the PAM sequence can be taken into account (e.g., paragraphs 147 and 150).
Doudna does not teach the composition where the guide RNA targets a sequence complementary to a superoxide dismutase 1 (SOD1) gene target nucleic acid sequence comprising one or more mutations.
Ahlfors teach a kit for genomic modification in a cell, where the kit comprises a repair template, a gRNA, and/or a Cas9 protein, or nucleic acids encoding them (e.g., paragraphs 70 and 157). Ahlfors teach the components for targeted genomic modification within a target genome region (TGR) in a mammalian cell of a patient, where the TGR comprises a disease-causing heterozygous mutation, and where the heterozygous mutation is a mutated SOD1 allele, and the system is capable of correcting the mutation, and where the modification is a higher specificity of genomic modification (e.g., paragraphs 13, 45, 61-62 and 66; Fig. 7). Ahlfors teach the target genomic DNA (gDNA) region may include an H46R mutation in the SOD1 gene (e.g., paragraphs 45, 79 and 234; Fig. 7). Ahlfors teach the gRNA comprises the sequence set forth in SEQ ID NO: 4 or 5, where SEQ ID NO: 4 is specific to the H46R mutation in the SOD1 gene (e.g., paragraphs 45 and 61; Table 2; Fig. 7E). Ahlfors teach the system comprises a Cas9 protein and a guide RNA (gRNA), where a gRNA is mutation-specific (e.g., paragraphs 18, 61-62 and 79; Fig. 7E). Ahlfors teach that the same methodology disclosed in Fig. 7 can be applied to treat similar gene mutations in other genes or in other locations in the genome (e.g., paragraphs 79 and 161). Ahlfors teach that the system is disclosed with regard to the type II Cas9 enzyme; however, any suitable Cas enzyme may be used (e.g., paragraph 162).
Kiskinis teach combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing (RNA-seq) technologies to identify the transcriptional and functional changes induced by the SOD1 A4V mutation in human motoneurons (MNs) (e.g., page 783, left column, 2nd full paragraph). Kiskinis teach the use of a zinc finger nuclease (ZFN)-mediated gene targeting strategy to correct the A4V mutation in a patient-derived iPSC cell line and provide an isogenic control (e.g., pages 783-785, Gene Targeting and Correction of the SOD1A4V Mutation; page 793, Gene Targeting; Fig. 2A). Kiskinis teach that the A4V mutation is in Exon 1 of the SOD1 gene, and the double-strand break induced by the ZFN is upstream of exon 1 (e.g., Fig. 2A). Kiskinis teach that the modification of patient cells allows for hypotheses to be tested in human motoneurons with the patients’ unique genetic constellation (e.g., page 783, left column, 1st full paragraph).
Regarding Applicant’s elected species of an AV4 mutation, Deng teach the sequence of SOD1 protein with an AV4 mutation (e.g., Fig. 3). The A4V mutation of SOD1 protein is relative to instant SEQ ID NO: 100 without the N-terminal methionine. Deng teaches that such an AV4 mutation is known to be associated with familial amyotrophic lateral sclerosis (Figure 3 and caption); the AV4 is therefore a known pathogenic mutation per Deng (e.g., Figure 3 and caption).
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 composition of Doudna to include a guide sequence targeting the gene sequence encoding the SOD1 gene comprising one or more mutations such as the A4V mutation (Applicant’s elected species of mutation), because Doudna teach CasX guide RNA can target a CasX protein to any desired sequence of any desired target nucleic acid, and Ahlfors teach the design of a mutation-specific guide RNA to a mutation in a SOD1 gene to allow for correction of the mutated SOD1 gene. Further, Kiskinis teach the SOD1 A4V mutation as a target to be corrected, and Deng teach that the AV4 mutation is relative to instant SEQ ID NO: 100 without the N-terminal methionine. One would have had a reasonable expectation of success in designing the guide RNA of Doudna to bind to the mutated A4V sequence of the SOD1 gene, because Ahlfors teach that the guide nucleic acid can be adapted for a variety of mutations and a variety of Cas enzymes.
One would have been motivated to make such a modification in order to receive the expected benefit of modifying the composition of Doudna to specifically target a mutation in a SOD1 gene encoding a protein with an AV4 mutation in order to use patient-derived cells to study the disease with the patient’s unique genetic constellation as taught by Kiskinis , using a highly specific mutation-specific targeting of Ahlfors. Furthermore, such motivation exists to correct a known defective gene target site at a disease-specific mutation so as to ameliorate the effects of the disease as taught by such methods of Ahlfors.
Regarding claim 170, Kiskinis teaches that the AV4 mutation is in Exon 1 of the SOD1 gene (e.g., Figure 2A).
Regarding claims 171-173, as discussed above, Kiskinis and Deng teach the known AV4 pathogenic mutation and its association with ALS (see above).
Regarding claim 174, Doudna teaches the composition comprising a second guide RNA, where the second guide RNA has a targeting sequence complementary to a different sequence within the same target nucleic acid (e.g., paragraphs 198 and 231).
Regarding claim 176, Doudna teaches that the CasX protein can comprise an N-terminal NLS (e.g., paragraph 100, claim 31).
Regarding claim 177, Doudna teaches that the CasX variant is capable of forming an RNP complex with a guide RNA (paragraph 144). Regarding claim 177, this claim recites indefinite claim language; the broadest reasonable interpretation of the claim is simply that the CasX is capable of forming an RNP with a guide RNA. For instance, any such CasX/gRNA molecule may demonstrate an “one improved characteristic” relative to another sequence of CasX/gNA, where the improved characteristic is simply that editing efficiency data can be generated using any CasX/gRNA RNP complex, where obtaining such editing data can be viewed as an “improved characteristic.”
Regarding claim 178, Doudna teaches the composition further comprising a donor template nucleic acid (e.g., paragraph 198). Furthermore, Deng teaches that the AV4 mutation is in Exon 1 of the SOD1 gene (Figure 3).
Regarding claim 179, the broadest reasonable interpretation of claim 179 is that it is drawn to the claim limitations of claim 169, where a further subset of CasX variant recited can comprise “improved characteristics” relative to any other CasX protein. Such a broad genus of reference CasX proteins includes, for instance, catalytically inactivated CasX reference CasX proteins. Thus, broadly speaking, a functional version of the CasX protein recited by Doudna would show “improved chrematistics” relative to a reference CasX without enzymatic functionality.
Regarding claim 183, Doudna teaches that CasX variants can be encoded in an nucleic acid (e.g., claim 48).
Regarding claim 184, Doudna teaches that vectors such as AAV vectors can be used to deliver CasX variants (e.g., paragraph 72).
Regarding claim 185, Ahlfors teaches a method of treating ALS by introducing the components of their methods (CRISPR/Cas9 and gRNA) into a patient to repair mutations (paragraph 45). Such a repair strategy can reasonably be interpreted to occur within a cell of a patient, where furthermore the gene correction would result in at least 10% reduction/knockdown of the expression of a non-functional SOD1 gene, as Ahlfors teaches targeted gene repair for pathogenic mutations (e.g., paragraph 45).
Regarding claim 186, Ahlfors teaches that the cell can be a human cell (e.g., paragraph 44).
Regarding claim 187, Ahlfors teaches that the cell may be an embryonic stem cell (e.g., paragraph 44).
Regarding claim 188, Ahlfors teaches that the cells can be oligodendrocytes (e.g., claim 171).
Regarding claim 189, Doudna teaches that methods using their CasX systems and gRNA can be used in vitro in the context of treating a disease (paragraph 345). Furthermore, Ahlfors teaches that their Cas editing systems are introduced in vitro (e.g., paragraph 42).
Regarding claim 190, Ahlfors teaches that their methods of disease treatment and prevention can occur within a patient (paragraph 45), and further that such treatment methods can occur within a human cell (paragraph 44). Ahlfors further teaches that their methods of therapeutic treatments can occur in vivo (paragraph 66).
Regarding claim 191, Doudna teaches administering their CasX/gRNA compositions to subject in need of treatment of a disease by gene targeting (e.g., paragraph 323). Doudna teaches that CasX/gRNA can be introduced via an implantable device (i.e., a therapeutically effective dose, paragraph 286) and can be administered to treat a disease, where the route of implantation/administration is intraparenchymal (e.g., paragraph 289).
Regarding claim 192, Doudna teaches that their systems and methods can be used to “knock out” target cells (paragraph 345), where furthermore Ahlfors, Kiskinis, and Deng give ample motivation to target the pathogenic AV4 mutation. Thus, the combination of Doudna, Ahlfors, Kiskinis, and Deng, where Doudna teaches that such genes targets can be targeted for knock out (paragraph 345) reasonably includes a population of cells which do not express non-functional SOD1 protein. For instance, Doudna teaches that a single “host cell” can also include progeny cells (paragraph 53). Host cells targeted by the methods of Doudna, where SOD1 comprising an AV4 for knock out is targeted per the motivation provided by Ahlfors, Kisinis, and Deng, therefore include modified progeny cells (“a population of cells,” paragraph 53) which do not express non-functional SOD1 proteins.
Regarding claim 193, Ahlfors teaches treating ALS in a patient by targeting by targeting a genomic region within a cell of the patient (e.g., claim 205). Note that claim 193 is being interpreted to depend from claim 192 for the purposes of this rejection. Thus, Ahlfors teaches modifying ALS-disease state cells comprising SOD1 mutations using their genomic targeting strategies and administering such cells into a patient to treat ALS (claim 205 of Ahlfors).
Regarding claim 194, as discussed above, the combination of Doudna, Ahlfors, Kiskinis, and Deng renders obvious the use of Doudna’s CasX variants with the teachings of Ahlfors, Kiskinis, and Deng to target SOD1 mutations (see rejection of above claims). Furthermore, Doudna teaches that their compositions can be administered for therapeutic effect for disease (e.g., paragraph 345).
Regarding claim 195, Doudna teaches that the subject can be human (e.g., paragraph 367).
Regarding claim 196, as Ahlfors teaches that such targeted gene editing compositions and methods are used specifically for the treatment of ALS, it is reasonable to interpret the teachings of Ahlfors, who teaches the treatment of ALS, to include an improvement of a clinically relevant outcome such as time of death (e.g., Ahlfors, claim 205).
Regarding claim 197, Doudna teaches that the components of the composition can be in a kit with suitable container (e.g., claim 125 of Doudna).
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.
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Claims 169-184 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11,613,742 (‘742). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 169-184, claims 1-25 of ‘742 recite the same compositions, where ‘742 recites SEQ ID NO: 126 at a 90% identity and also a gNA with 70% sequence identity to SEQ ID NO: 2238 (e.g., claim 25). Each element of the recited claim elements of claims 169-184 are recited within the claim elements of claims 1-25 of ‘742; the claims are therefore not patentably distinct from each other, where the only distinction appears to be that SEQ ID NO:126 is recited at 90% identity compared with the instantly recited 70% identity. As such, claims 1-25 of ‘742 reasonably anticipate instant claims 169-184.
Claims 185-197 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11,613,742 (‘742) in view of Ahlfors (WO 2017/216771 A2; see the entire reference), Kiskinis (Kiskinis E. . Cell Stem Cell. 2014 Jun 5;14(6):781-95), and Deng (Deng HX . Science. 1993 Aug 20;261(5124):1047-51, see entire reference).
Regarding the instant claims, as discussed above, claims 1-25 of ‘742 recite the same compositions of the instantly recited claims, including the same CasX enzyme and gNA scaffold (e.g., claim 25). Furthermore, claim 18 of ‘742 recites that the gNA targets SOD1. Thus, the claims are directed to the same CasX and gNA of ‘742.
‘742, while reciting that the gNA targets SOD1, does not recite the methods of instant claims involving modifying target cells and treating SOD1-associated diseases (claims 185-197).
Ahlfors teach a kit for genomic modification in a cell, where the kit comprises a repair template, a gRNA, and/or a Cas9 protein, or nucleic acids encoding them (e.g., paragraphs 70 and 157). Ahlfors teach the components for targeted genomic modification within a target genome region (TGR) in a mammalian cell of a patient, where the TGR comprises a disease-causing heterozygous mutation, and where the heterozygous mutation is a mutated SOD1 allele, and the system is capable of correcting the mutation, and where the modification is a higher specificity of genomic modification (e.g., paragraphs 13, 45, 61-62 and 66; Fig. 7). Ahlfors teach the target genomic DNA (gDNA) region may include an H46R mutation in the SOD1 gene (e.g., paragraphs 45, 79 and 234; Fig. 7). Ahlfors teach the gRNA comprises the sequence set forth in SEQ ID NO: 4 or 5, where SEQ ID NO: 4 is specific to the H46R mutation in the SOD1 gene (e.g., paragraphs 45 and 61; Table 2; Fig. 7E). Ahlfors teach the system comprises a Cas9 protein and a guide RNA (gRNA), where a gRNA is mutation-specific (e.g., paragraphs 18, 61-62 and 79; Fig. 7E). Ahlfors teach that the same methodology disclosed in Fig. 7 can be applied to treat similar gene mutations in other genes or in other locations in the genome (e.g., paragraphs 79 and 161). Ahlfors teach that the system is disclosed with regard to the type II Cas9 enzyme; however, any suitable Cas enzyme may be used (e.g., paragraph 162).
Kiskinis teach combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing (RNA-seq) technologies to identify the transcriptional and functional changes induced by the SOD1 A4V mutation in human motoneurons (MNs) (e.g., page 783, left column, 2nd full paragraph). Kiskinis teach the use of a zinc finger nuclease (ZFN)-mediated gene targeting strategy to correct the A4V mutation in a patient-derived iPSC cell line and provide an isogenic control (e.g., pages 783-785, Gene Targeting and Correction of the SOD1A4V Mutation; page 793, Gene Targeting; Fig. 2A). Kiskinis teach that the A4V mutation is in Exon 1 of the SOD1 gene, and the double-strand break induced by the ZFN is upstream of exon 1 (e.g., Fig. 2A). Kiskinis teach that the modification of patient cells allows for hypotheses to be tested in human motoneurons with the patients’ unique genetic constellation (e.g., page 783, left column, 1st full paragraph).
Regarding Applicant’s elected species of an AV4 mutation, Deng teach the sequence of SOD1 protein with an AV4 mutation (e.g., Fig. 3). The A4V mutation of SOD1 protein is relative to instant SEQ ID NO: 100 without the N-terminal methionine. Deng teaches that such an AV4 mutation is known to be associated with familial amyotrophic lateral sclerosis (Figure 3 and caption); the AV4 is therefore a known pathogenic mutation per Deng (e.g., Figure 3 and caption).
Therefore, given that ‘742 recites that the gNA targets SOD1, and furthermore that known targets exist for targeting SOD1 mutations for gene corrective therapy, the Ahlfors, Kisinis, and Deng supply ample motivation to use the compositions of ‘742 to target SOD1 in cells and to treat SOD1-associated diseases.
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 composition of ‘742 to include a guide sequence targeting the gene sequence encoding the SOD1 gene comprising one or more mutations such as the A4V mutation (Applicant’s elected species of mutation), because Ahlfors teach the design of a mutation-specific guide RNA to a mutation in a SOD1 gene to allow for correction of the mutated SOD1 gene. Further, Kiskinis teach the SOD1 A4V mutation as a target to be corrected, and Deng teach that the AV4 mutation is relative to instant SEQ ID NO: 100 without the N-terminal methionine. One would have had a reasonable expectation of success in designing the guide RNA of ‘742 to bind to the mutated A4V sequence of the SOD1 gene, because Ahlfors teach that the guide nucleic acid can be adapted for a variety of mutations and a variety of Cas enzymes.
One would have been motivated to make such a modification in order to receive the expected benefit of modifying the composition of ‘742 to specifically target a mutation in a SOD1 gene encoding a protein with an AV4 mutation in order to use patient-derived cells to study the disease with the patient’s unique genetic constellation as taught by Kiskinis , using a highly specific mutation-specific targeting of Ahlfors. Furthermore, such motivation exists to correct a known defective gene target site at a disease-specific mutation so as to ameliorate the effects of the disease as taught by such methods of Ahlfors.
Claims 169-174, 176-180, 183-197 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25 of U.S. Patent No. 11,560,555 (‘555) in view of Doudna (WO 2018/064371 A1,) and Eggan (US Patent Application Publication No. 2015/0301028 A1), Ahlfors (WO 2017/216771 A2; see the entire reference), Kiskinis (Kiskinis E. . Cell Stem Cell. 2014 Jun 5;14(6):781-95), and Deng (Deng HX . Science. 1993 Aug 20;261(5124):1047-51, see entire reference).
Regarding claim 169, claim 25 of ‘555 recites a protein consisting of a sequence at least 70% identical to SEQ ID NO: 3548. SEQ ID NOs 3548 (‘555) is aligned with 126 (instant) below:
PNG
media_image2.png
765
503
media_image2.png
Greyscale
As seen above, SEQ ID NOs 3548 and instant 126 are identical.
Claim 245 of ‘555 does not require a guide nucleic acid. The claims of ‘555 do not specify that the guide nucleic acid comprises a targeting sequence complementary to a superoxide dismutase 1 (SOD1) gene target nucleic acid sequence comprising one or more mutations, and the elements of the dependent claims.
The teachings of Doudna regarding the 103 rejection are herein incorporated. Briefly, Doudna teach a composition comprising a CasX polypeptide, and a CasX guide RNA (e.g., paragraph [0068]). Doudna teach that the guide RNA contains a “guide sequence” or “targeting sequence” that can be modified so that the CasX guide RNA can target a CasX protein to any desired sequence of any desired target nucleic acid, with the exception that the PAM sequence can be taken into account (e.g., paragraphs [00147] and [00150]). Doudna teach the composition where the guide RNA is a single-molecule guide RNA (e.g., paragraph [00148]). Doudna teach the composition comprising a second guide RNA, where the second guide RNA has a targeting sequence complementary to a different sequence within the same target nucleic acid (e.g., paragraphs [00198] and [00231]). Doudna teach the composition where the CasX protein comprises one to ten nuclear localization signal (NLS) sequences (e.g., paragraphs [00133]-[00134]). Doudna teach the composition further comprising a donor template nucleic acid (e.g., paragraph [00198]).
Furthermore, Eggan teach that it is within the skill of the art to design a guide nucleic acid to a sequence complementary to a SOD1 gene target nucleic acid comprising one or more mutations, such as an A4V mutation (e.g., paragraphs [0095]-[0100]). Eggan teach that the provision of a CRISPR nuclease and single molecule guide RNA allows for the production of patient cells that contain a mutation and a cell line that is isogenic with the test cell line in which the mutation has been corrected (e.g., paragraph [0096]).
In addition, the teachings of Kisinis, Deng, and Ahlfors are herein incorporated from the 103 rejection. Briefly, Kisinis, Deng, and Ahlfors teach additional motivation to target SOD1 mutations using methods for treatment such as using CRISPR Cas enzymes.
It would have been obvious to one of ordinary skill in the art to modify the guide nucleic acid of the ‘555 patent to target the mutation in the SOD1 gene encoding the AV4 mutation in order to provide a composition capable of correcting the mutation in patient cell lines and to use such a method in combination with the instantly recited CasX also taught by ‘555 in a method to treat SOD1-associated diseases as already taught and known by Eggan.
This is a provisional nonstatutory double patenting rejection.
Claims 169-197 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 39, 71, 103, 120 and 160 of copending Application No. 17/542,219 (hereinafter the ‘219 application) in view of Doudna (WO 2018/064371 A1), Eggan (US Patent Application Publication No. 2015/0301028 A1), Ahlfors (WO 2017/216771 A2; see the entire reference), Kiskinis (Kiskinis E. . Cell Stem Cell. 2014 Jun 5;14(6):781-95), and Deng (Deng HX . Science. 1993 Aug 20;261(5124):1047-51, see entire reference).
Claim 71 of the ‘219 application is drawn to a CasX variant comprising the sequence of SEQ ID NO: 336. SEQ ID N O: 336 of the ‘219 application is identical to instant SEQ ID NO: 126. Claim 120 of the ‘219 application is drawn to a gene editing pair comprising a variant CasX protein and a guide nucleic acid comprising a variant of a reference guide nucleic acid scaffold capable of binding the reference CasX protein or the CasX variant, and wherein the guide nucleic acid comprises a targeting sequence complementary to a target DNA sequence. The claims of the ‘219 application do not specify that the guide nucleic acid comprises a targeting sequence complementary to a superoxide dismutase 1 (SOD1) gene target nucleic acid sequence comprising one or more mutations, and the elements of the dependent claims. However, Doudna teach a composition comprising a CasX polypeptide, and a CasX guide RNA (e.g., paragraph [0068]). Doudna teach that the guide RNA contains a “guide sequence” or “targeting sequence” that can be modified so that the CasX guide RNA can target a CasX protein to any desired sequence of any desired target nucleic acid, with the exception that the PAM sequence can be taken into account (e.g., paragraphs [00147] and [00150]). Doudna teach the composition where the guide RNA is a single-molecule guide RNA (e.g., paragraph [00148]). Doudna teach the composition comprising a second guide RNA, where the second guide RNA has a targeting sequence complementary to a different sequence within the same target nucleic acid (e.g., paragraphs [00198] and [00231]). Doudna teach the composition where the CasX protein comprises one to ten nuclear localization signal (NLS) sequences (e.g., paragraphs [00133]-[00134]). Doudna teach the composition further comprising a donor template nucleic acid (e.g., paragraph [00198]).
Furthermore, Eggan teach that it is within the skill of the art to design a guide nucleic acid to a sequence complementary to a SOD1 gene target nucleic acid comprising one or more mutations, such as an A4V mutation (e.g., paragraphs [0095]-[0100]). Eggan teach that the provision of a CRISPR nuclease and single molecule guide RNA allows for the production of patient cells that contain a mutation and a cell line that is isogenic with the test cell line in which the mutation has been corrected (e.g., paragraph [0096]).
In addition, the teachings of Kisinis, Deng, and Ahlfors are herein incorporated from the 103 rejection. Briefly, Kisinis, Deng, and Ahlfors teach additional motivation to target SOD1 mutations using methods for treatment such as using CRISPR Cas enzymes (pertaining to instant claims 193-196).
It would have been obvious to one of ordinary skill in the art to modify the guide nucleic acid of the ‘219 application to target the mutation in the SOD1 gene encoding the AV4 mutation in order to provide a composition capable of correcting the mutation in patient cell lines. Thus, instant claims 169-174, 176-180, 183-197 are not patentably distinct from the claims of the ‘219 application.
Claim 103 of the ‘219 application is drawn to a guide nucleic (gNA) acid variant, wherein the scaffold of the gNA variant sequence comprises a sequence selected from the group consisting of SEQ ID NOS: 2101-2280, or having at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% identity thereto. SEQ ID NO: 2238 of the ‘219 application is identical to instant SEQ ID NO: 2238.
It would have been obvious to make a composition comprising the CasX variant protein and suitable guide nucleic acid of claim 103. Accordingly, instant claims 175 and 181-182 are not patentably distinct for this reason, and for the reasons set forth with regard to instant claims above.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/D.C.R./Examiner, Art Unit 1635
/KIMBERLY CHONG/Primary Examiner, Art Unit 1636