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 .
Claim Status
Claims 25-31, 33-36, and 38 and 123 are currently pending in this application.
Election/Restrictions
Applicant’s election of the Cas12 protein species of SEQ ID NO:4 (Cas12p) is acknowledged from the submission filed Dec. 30, 2024. Thus, claims 28 and 30-31 are withdrawn pursuant to MPEP 821. Claims 25-27, 29, 33-36, 38 and 123 have been considered on the merits and all arguments have been fully considered.
Claim Objections
Claims 25-27 are objected to because of the following informalities:
Claim 25 recites a list of Cas12 variants separated by commas but in one such list the article “the” is repeated in an inconsistent manner prior to Cas12q (last line). Consistency throughout the claims is recommended.
Regarding claims 26-27, where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m). Appropriate correction is required.
Claim Interpretation
In the claims, the terms “Cas12a.1”, “Cas12p”, and “Cas12q” with regard to modifying the term “gRNA” are interpreted to require the gRNA be capable of forming a functional complex respectively with the respective Cas12a.1”, “Cas12p”, or “Cas12q” protein as defined by claim 25 or 123 so as to function to direct the complex to bind and align on a specific target DNA sequence.
In the claims the phrase direct repeats “capable of improving stem-loop stability” is interpreted to encompass any DNA or RNA sequence that is a direct repeat as this capability is presumed for this generic structure.
Status of Rejections
The previous claim rejections under 35 USC sections 101, 112(b) and 103 are withdrawn in view of the claim amendments.
Claim Rejections - 35 USC § 112(a), Written Description (modified)
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 25-27, 29, 33-36, and 38 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.
When claim 25 is analyzed in light of the specification, the instant invention is directed to a system comprising (a) a Cas12 protein selected from Cas12a.1, Cas12p, and Cas12q or, alternatively, a nucleic acid encoding the aforementioned; and (b) a cognate Cas12 gRNA or, alternatively, a nucleic acid encoding the aforementioned. While the sequence identity of the Cas12 protein is limited by the claim, the gRNA is only limited by functional limitations of: (1) not naturally occurring together with the Cas12 protein, (2) capable of hybridizing to a target sequence in a target DNA, and (3) capable of forming a complex with the Cas12 protein; and (4) the entire system must comprise non-naturally occurring direct repeat sequences. The target sequence is not structurally defined by merely limited functionally as being hybridizing with the gRNA and being comprised within a target DNA.
M.P.E.P. §2163 states “To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.”
In the instant case, claim 25 broadly comprises a genus of gRNAs defined only functionally as well as a genus of any target sequence in a target DNA bound by the gRNA. The claim is also broad in that the Cas12 protein may be catalytically active or dead (see dependent claims 36 and 38) while still being capable of cleaving a target DNA regardless of gRNA complex formation.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described.
The instant application lacks a single description of any species of Cas12 protein capable of cleaving a target DNA regardless of gRNA complex formation or of a Cas12 protein that is catalytically dead but yet capable of cleaving a target DNA.
Koonin teaches multiple Cas12 CRISPR/Cas systems (e.g., Cas12a-e) were already known and had been used to engineer sequence programmable induction of double-stranded DNA breaks (DSBs) with high efficiencies by forming complexes with synthetic gRNAs (Fig. 1, 3; pg. 71, left col., last para., to pg. 73, right col., 2nd para.). Koonin teaches specific Cas12 variants include Cas12a (Cpf1), Cas12b (C2c1), Cas12c, Cas12d, and Cas12e (Fig. 1, 3), with known protein sequences which cleave dsDNA via RuvC activity and sequence targeting by a spacer and complexed with a guide RNA (tracrRNA and/or crRNA) (Table 1; Fig. 1).
However in view of the above, the skilled artisan cannot envision which, or even how to identify which, Cas12a.1, Cas12p, and Cas12q proteins comprising one of the recited SEQ ID NOs satisfy the claim limitations of (1) both catalytically dead and (2) capable of cleaving a target DNA. Therefore, there is a lack of evidence in the instant specification as filed that the inventors were in possession of the entire scope of Cas12 engineered systems encompassed by the claims regarding both not catalytically active (claim 36) and capable of hybridizing/targeting/cleaving any target sequence.
Claims 25-27, 29, 33-36 and 38 encompasses a broad genus of gRNAs without structural limitation. Instead, the gRNA is defined only functionally as capable of (1) hybridizing to a “target” sequence in a “target DNA” and (2) forming a complex with the respective Cas12 protein. As the claims do not specify what constitutes a “target DNA” beyond it must comprise the target sequence, such as one in a genomic/mitochondrial DNA of a human, non-human primate, or associated with any bacteria or virus (claims 33-35), the target DNA could be as small as the target sequence alone (consisting of) or as large as over one million nucleotides (e.g., a human chromosome).
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350.
In the instant case, the gRNA genus is described and ordinarily understood as a Class 2 Type V guide RNA (gRNA) structurally comprising an unbranched RNA molecule comprising either (1) a crRNA and tracrRNA complex or (2) a single engineered fusion RNA comprising a crRNA/spacer of about 25-50 bases (nt) (e.g., variable targeting spacer sequence or entire crRNA) fused with a “mature scaffold” comprising a specific direct repeat (e.g., SEQ ID NO: 6-8, 19-21 or 26-42) or Cas12 protein binding sequence (e.g., a hairpin duplex or tracrRNA “handle”), wherein the spacer has a chosen/designed targeting sequence complementary to a “target” nucleic acid of at least about 60-99% over 23 contiguous bases at the 5’ terminus, perhaps based on in silico deductions ([00149]-[00159]; FIG. 38). Furthermore, each Cas12 protein is understood to inherently have its own PAM specificity (see [00167]; FIG. 8), which paired with the spacer sequence together determine Cas12 protein-gRNA complex binding to a target nucleic acid (see Mendoza and Trinh, Biotechnol J 13: e1700595 (2018) at pg. 1, right col.).
The term “target sequence” is described broadly as encompassing any polynucleotide having 1-23 nucleotides, such as 8-25 nucleotides, with at least about 1-23 nucleotides having at least 60% sequence identity to a given gRNA spacer ([00150]-[00157]). Therefore, the Cas 12 gRNA structure of the claims encompasses over 250,000 variants (4^23) in the spacer sequence portion alone, and the target sequence variants include all possible 279,841 variants (4^23) of any 23 polynucleotide sequence complementary to the spacer sequence as anchored by having just 1-23 nucleotides with at least 60% sequence identity thereto (www.calculator.net/exponent-calculator).
Moreover, the prior art teaches not every sequence is targetable by CRISPR/Cas technology generally due to protospacer adjacent motif (PAM) limitations, and such was true for the subset of Cas12 variants of the instant claims as of the instant filing date (see e.g., Zhang, Trends Genet 36(8): 546-48 (2020) at pg. 546; Addgene, CRISPR Guide (2019) at pg. 2).
The written description requirement may be satisfied through 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 structure and function, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of any gRNA as functional defined to target virtually any DNA target. In the instant case, the specification fails to provide sufficient descriptive information. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed. 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 complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
As there is no established correlation between Cas12a.1, Cas12p or Cas12q gRNA functional abilities and its representative structures (nexus) in the instant specification or in the prior art as of the instant filing date, the instant written description fails to provide any additional species beyond the instant representative species disclosed. However Applicant is invited to provide evidence to the contrary. The target sequence can be any 23mer sequence at least 60% identical to any programmable spacer sequence but the description does not adequately describe the structure of a suitable Cas12 gRNA of the invention having any mature scaffold and crRNA of 25-50 bases, rather a few representative species are described but lacking a nexus to the full breadth of claims.
Amgen, Inc., v. Sanofi (2023)
“Amgen seeks to monopolize an entire class of things defined by their function”. “The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a ‘vast’ number of additional antibodies that it has not.” “It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claims encompass an enormously vast genus of gRNAs, structurally encompassing over 279,841 spacer sequence variations with at least 3 million (e.g., 434) theoretical structural variants of just the spacer/crRNA component chimerically paired with a given gRNA scaffold, e.g. comprising instant SEQ ID NO: 6-8, 19-21, 26-42, and/or 116-117 ([00154]; [00151]; www.calculator.net/exponent-calculator). These gRNAs function to hybridize to any target DNA comprising a bare minimum of sequence similarity to said 279,841 spacer sequences wherein the target DNA may comprise an additional, unlimited length of sequence, such as including the Cas12 complex cleavage site, or instead may merely consist of the exact complement to the 279,841 spacer sequences and be cleaved internally within. This is the entire universe of gRNAs only functionally limited to form a complex with the three recited Cas12 protein genera.
While it is true that gRNAs for various CRISPR enzymes (e.g., for Cpf1) in general were known in the prior art, the realm of possible Cas12a.1, Cas12p, and Cas12q gRNAs described in the instant application and known in the prior art at the instant filing date is very small. The instant disclosure provides no details about the genus of gRNAs in a target sequence unlimited way that bind to and function with Cas12a.1 comprising SEQ ID NO: 3, Cas12p comprising SEQ ID NO: 4 or 222, and Cas12q comprising SEQ ID NO: 5.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the enormously vast genus of gRNAs structurally unrecited and functionally undisclosed polynucleotides. Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph. All dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim.
Response to Arguments
Applicant’s remarks submitted 7/23/26 (pg. 9-13) were fully considered but not found persuasive. Applicant argues that the instant disclosure of gRNAs, e.g., targeting Hanta and SARS-CoV-2 targeting viral DNA sequences or other target sequences recited in Table 6g (or prophetic targets in Tables 6a-f without any disclosure of sequence) along with the skills of the ordinary artisan allow for identification and testing of novel gRNAs (and specific techniques disclosed in instant Examples 8 and 10) and that CRISPR-based technology was already predictably used with knowledge of designing gRNAs, including to target any DNA sequence citing prior art.
While a person of ordinary skill in the art would recognize applicant possessed the Cas12a.1, Cas12p and Cas12q recited any the claims and their cognate gRNAs as recited in claim 123, a person of ordinary skill would not recognize such over the full scope of claims 25-27, 29, 33-36, and 38.
Firstly, it is noted that the prior art mentioned in the response discloses nothing specific to Cas12a.1, Cas12p or Cas12q but rather discussed research on other Cas proteins, the only Cas12 protein of which is Cas12a (Cpf1), which quite unique from other Cas12 members, such as not requiring any tracrRNA. Thus, this cited prior art is silent to design teachings specific to any Cas12a.1, Cas12p or Cas12q protein. Second, it is technically incorrect to say any target DNA sequence can be targeted by CRISPR-based technologies as noted above because even after the instant filing date Cas9 and its many variants and engineered derivatives were not considered capable of targeting any DNA sequence.
Applicant also argues in response to 112(d) (pg. 14-15) that any Cas protein can be made catalytically dead, including just temporarily while maintaining the capability of cleaving a target DNA, such as due to a lack of availability of sufficient Mg2+ (e.g., in the microenvironment). This is not persuasive as the ordinary and customary meaning in the field for catalytically active/dead is never temporary nor due solely to ionic microenvironments but is rather a structural feature of the Cas protein, such as due to one or more point mutations in each the RuvC1 domain and HNH domains (i.e., nuclease dead or dCas9) (see e.g., Kampmann, ACS Chem Biol 13(2): 406-16 (2017) at Fig. 1; pg. 406, 412). Note, if applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term.
The functionally defined gRNA scope encompasses (1) paired crRNA and tracrRNA complexes as well as (2) single synthetic fusion RNA comprising a crRNA/spacer of about 25-50 bases fused with a mature scaffold comprising a specific direct repeat (e.g., SEQ ID NO: 6-8, 19-21 or 26-42) or Cas12 protein binding sequence (e.g., a hairpin duplex or tracrRNA “handle”). The disclosed structures are not representative of the breadth of the gRNA genus.
35 USC § 112(a), Scope of Enablement (maintained)
Claims 25-27, 29, 33-36, and 38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because while the claims are enabled for wherein the Cas12 protein consists of SEQ ID NO: 3, 4, 5 or 222 and the gRNA comprises SEQ ID NO: 177-181, 225-226, 231-233, or 237-239, and when complexed the gRNA is capable of hybridizing to a target DNA sequence and the complex is capable of cleaving the target DNA; the specification does not enable any person skilled in the art to which it pertains or with which it is most nearly connected to make any engineered system comprising any Cas12a1 comprising SEQ ID NO: 3 paired with any Cas12a1 gRNA, any Cas12p protein comprising SEQ ID NO: 4 or 222 and paired with any Cas12p gRNA, or any Cas12q protein comprising SEQ ID NO: 5 and paired with any Cas12q gRNA. For example, wherein the Cas12 protein is both capable of cleaving a target DNA and catalytically dead in view of dependent claim 36 as encompassed by claims 25-27, 29, 33-35, and 38.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature and breadth of the invention:
The claims are directed to a system comprising (a) a Cas12 protein selected from Cas12a.1, Cas12p, and Cas12q or, alternatively, a nucleic acid encoding the aforementioned; and (b) a Cas12 gRNA or, alternatively, a nucleic acid encoding the aforementioned. The gRNA is only limited by functional limitations of: (1) not naturally occurring together with the Cas12 protein, (2) capable of hybridizing to a target sequence in a target DNA, and (3) capable of forming a complex with the Cas12 protein. The Cas12a.1, Cas12p, and Cas12q proteins are structurally limited to comprising a recited polypeptide sequence and functionally constrained to those capable of cleaving a target DNA substrate.
In Amgen, the Supreme Court, held that claims drawn to a genus of monoclonal antibodies were invalid due to lack of enablement wherein the genus was merely functionally claimed by their ability to bind to a specific protein as opposed to reciting a specific structure. MPEP 2164.01 explains "it may suffice to give an example (or a few examples) if the specification also discloses some general quality . . . running through the class that gives it a peculiar fitness for the particular purpose" and "disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. at 611 (internal quotations omitted). However, while the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class which included "a ‘vast’ number of additional antibodies" that Amgen had not described by their amino acid sequences. Id. at 613. The Court found that the patent owner sought to monopolize an entire class by their function, even though that class was much broader than the exemplary antibodies disclosed by their amino acid structure. Here, the gRNA described with a high level of generality in only functional terms resembles the situation in the Amgen case and as noted above may encompass millions of undescribed and unrecited gRNA structures.
Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas systems are naturally occurring in the genomes of bacteria and archaeal species as CRISPR arrays comprising repeating units interspersed with spacers and an adjacent Cas gene comprising conserved nuclease catalytic domains (Ishino et al., J Bacteriol 200: e00580-17 (2018) at pg. 8, Fig. 4). The prior art teaches scientists, predominantly via bioinformatics and then empirical validation, successfully identified at least thirty Cas proteins based on the foundational spCas9 by processes which overtime became increasingly more efficient (Ishino et al., (2018) at pg. 5, para. 3-4; pg. 6, para. , to pg. 9; Fig. 6; Murugan et al., Mol Cell 68(1): 15-25 (2017) at pg. 2, para. 2-4; pg. 3, last para., to pg. 7). For example, by 2018 scientists had identified multiple Cas protein families, including a dozen Cas9 proteins (e.g., NmCas9, SaCas9, CjCas9, etc.) along with Cas3, Cas14, and multiple Cas12 and Cas13 family members, such as Cas12a, Cas12b, Cas12c, and CasX, representing at least 2 classes, 6 types, and 22 subtypes (Cas1-Cas10) (see e.g., Li et al., Mol Cell 82: 333-47 (2022) at Suppl. table 1; Mendoza and Trinh (2018) at pg. 1, right col., 2nd para.). In particular, Cas12b (C2c1), Cas12c, Cas12(d) (CasY) and Cas12e (CasX) were discovered by computational prediction approaches and genomic sequence databases based on previously characterized Cas system sequences (Shmakov et al., Mol Cell 60: 385-97 (2015) at Fig. 1B, pg. 386; Burnstein2 (Burnstein et al., Nature 542: 237-41 (2017) at pg. 237, Fig. 1-2; Yan et al., Science 363: 88-91 (2019) at pg. 1, col. 1-2, Fig. 1).
The prior art teaches all gRNAs are small polyribonucleotides having a particular sequence, thusly all gRNAs are capable of hybridizing to certain “target” DNA molecules in certain situations, e.g., one comprising a reverse complementary sequence, which could be categorized as a “target” sequence. The prior art teaches that Cas endonuclease target recognition and nuclease activity both depend on the Cas protein and its cognate gRNA forming a complex as well efficient cleavage depending on the spacer region of the gRNA forming a heteroduplex with the target (Lim et al., Nat Commun 7: 13350 (2016) at abstract; Fig. 5). For example, Cas12 (Cpf1) can cleave DNA in certain situations in the absence of any RNA, but this cleavage is not sequence specific (Sundaresan et al., Cell Rep 21: 3728-39 (2017) at summary). Thus, there is no evidence in the prior art of a Cas12 protein capable of cleaving a target DNA without gRNA complex formation nor wherein the Cas12-gRNA complex cannot bind to its PAM/gRNA target sequence.
While the prior art reveals some structure-function correlations between Cas9 and gRNA functional abilities (Jiang and Doudna, Annu Rev Biophys 46: 505-29 (2017) at Fig. 3-5), the instant specification purports to have newly discovered three Cas12 proteins (Cas12a1, Cas12p and Cas12q) wherein such research couldn’t have existed before the effective filing date and, thus, any expansion/envisaging of gRNA structures beyond what is instantly taught relies on the data and species disclosed in the instant application, which are limited in number as detailed below.
The amount of direction and guidance and working examples provided by Applicant:
The instant application provides no evidence of any Cas12 protein cleaving a DNA substrate in a targeted manner in the absence of an appropriate gRNA, i.e., a cognate gRNA, whereby a Cas12-gRNA complex forms that together binds and cleaves a target DNA in a sequence-specific manner.
The instant application provides a limited number of working examples of gRNA species (e.g., SEQ ID NO: 177-181, 225-226, 231-233, and 237-239), all of which comprise either a full or portion of a natural direct repeat sequence, optionally having two specific point mutations in the stem-loop region to improve stability (Table 2, 5a-b; Example 1, FIGs 5B, 5D, 5F, 7A-C). While one of skill in the art could use this information to design a great diversity of spacer sequences without undue experimentation, to extrapolate these species to the scope of undisclosed species encompassed by the claims would require undue experimentation (regarding non-spacer sequence structure variances); however, Applicant is invited to provide evidence to the contrary.
The instant disclosure fails to teach any general synthetic gRNA format for Cas12a.1, Cas12p, or Cas12q, e.g., regarding a generic scaffold and tracrRNA handle accommodating any spacer sequence. Nor does the instant disclosure teach how to change the PAM specificity.
Extensive experimentation would be required to determine the functional pairings over the scope of Cas12a1, Cas12p, or Cas12q protein comprising SEQ ID NO: 3, 222, or 5, respectively, with any gRNA defined only functionally and without structural limitation. As noted above there are over 20110 theoretical structural variants for each of Cas12a1, Cas12p, or Cas12q that may be tested for functionality.
In summary, claims 25-27, 29, and 33-39 are rejected under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement, to a person skilled in the art to which it pertains or with which it is most nearly connected to, to make and use the system comprising said Cas12 protein (or nucleic acid encoding it) and said gRNA (or nucleic acid encoding it). The limited guidance provided in the specification, the lack of guidance in the prior art regarding Cas12a.1, Cas12p and Cas12q, and the broad scope of the claims with regard to gRNA structure; undue and unreasonable experimentation would have been required for one skilled in the art to achieve targeted DNA cleavage across the entire scope of the claim terms: Cas12a.1, Cas12p, and Cas12q gRNA, which must work concordantly both in structure and function with respectively of the four recited Cas12 proteins for this functional achievement.
Response to Arguments
Applicant’s remarks submitted 7/23/26 were fully considered but not found persuasive. Applicant argues that the extensive prior art regarding gRNA design provides for making/using the full scope of the claimed invention without undue experimentation in view of the instant disclosure as gRNA design to targets of interest has already been standard practice in the field as mentioned in traversing the written description rejections above.
First, it is noted that claims 25-27, 29, 33-35, and 38 encompass wherein the Cas12 protein is both capable of cleaving a target DNA and catalytically “dead” in view of dependent claim 36, which is never described in the instant application by any working embodiment, and may never be achievable.
Also as noted in the rejection above, the disclosure is deemed insufficient across the full scope of any target and any gRNA structure without limits, especially in view of the Amgen holding. Applying that principle, the instant disclosure amounts to little more than an invitation for skilled artisans to engage in painstaking trial-and-error discovery across a functionally-defined genus that could include millions of candidates without a roadmap (e.g., Cas12a.1, Cas12p or Cas12q gRNA structure requirements for protein interaction/stability) that reliably led to the full scope claimed as where a genus is functionally defined and the field is unpredictable, a small number of worked examples plus a general research strategy can fail to meet the bar, particularly when the claimed genus is vast relative to what was actually disclosed. As noted for written description above, there are 279,841 spacer sequence variations with at least 3 million (e.g., 434) theoretical structural variants of just the spacer/crRNA component chimerically paired with a given gRNA scaffold.
Applicant argues that the instant disclosure (at Examples 8 and 10, [0120-[0126] and [0557], e.g., of gRNAs targeting specific DNA sequences or prophetic genomic targets in Tables 6a-f) along with the skills of the ordinary artisan allow for identification and testing of novel gRNAs without undue experimentation. While it is agreed that many different gRNAs binding many diverse target DNA sequences are enabled, the full scope claimed is not deemed herein to be enabled. The functionally defined gRNA scope encompasses any target DNA, which was not possible for any Cas protein at the instant filing date in view of the art. Also, a catalytically dead Cas12 protein capable of cleaving a target DNA is not enabled nor is an engineered system wherein the Cas12 and gRNA complex is not capable of hybridizing to a target DNA sequence and the complex is not capable of cleaving the target DNA.
Claim Rejections - 35 USC § 112(b) (new)
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 25-31, 33-36, and 38 is 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 pre-AIA the applicant regards as the invention.
Claim 25 recites the feature “non-naturally occurring direct repeats capable of improving stem-loop stability” as a required part of the engineered system; however this phrase is incoherent, ambiguous and unclear as to what, if any of the other components it is associated with, such as the nucleic acid encoding a Cas12 protein (e.g., a DNA or RNA), the Cas12 gRNA and/or the nucleic acid encoding said gRNA. As the invention components are claimed in the alternative, this phrase is logically not interpreted as requiring any specific alternative component, such as a Cas12 gRNA or a nucleic acid encoding the same. As this feature could be satisfied by an unrelated component (e.g., a DNA molecule of a cell of the system), one of ordinary skill in the art would not be reasonably appraised of the scope of this limitation (see MPEP 2173.02). Claims 26-31, 33-36, and 38 are included in this rejection for depending from indefinite claim 25.
Claim Rejections - 35 USC § 112(d) (maintained)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 36 and 38 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 36 further recites wherein the Cas12 protein of claim 25 is catalytically active; however, claim 25 requires the Cas12 protein be capable of cleaving the target DNA, which implies a catalytic activity. Thus, claim 36 fails to further limit the subject matter of a claim 25.
Claim 38 further recites wherein the Cas12 protein of claim 25 is catalytically dead; however, claim 25 requires the Cas12 protein be capable of cleaving the target DNA, which implies a catalytic activity. Thus, claim 38 fails to include all the limitations of claim 25.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Arguments
Applicant’s remarks submitted 7/23/26 were fully considered but not found persuasive. Applicant also argues in response to 112(d) (pg. 14-15) that any Cas protein can be made catalytically dead, including just temporarily while maintaining the capability of cleaving a target DNA, such as due to a lack of availability of sufficient Mg2+ (e.g., in the microenvironment).
This is not persuasive as the ordinary and customary meaning in the field for catalytically active/dead is never temporary nor due solely to ionic microenvironments but is rather a structural feature of the Cas protein, such as due to one or more point mutations in each the RuvC1 domain and HNH domains (i.e., nuclease dead or dCas9) (see e.g., Kampmann, ACS Chem Biol 13(2): 406-16 (2017) at Fig. 1; pg. 406, 412). Note, if applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357 (Fed. Cir. 1999).
Claim Rejections - 35 USC § 103 (new)
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 25-27 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Koonin (Koonin et al., Curr Opin Microbiol 37:67-78 (2017); IDS ref.) in view of Murugan (Murugan et al., Mol Cell 68: 15-25 (2017)), Couvin (Couvin et al., Nucleic Acids Res 46: W246-51 (2018)) and Kocak (Kocak et al., Nat Biotechnol 37: 657-66 (2019), and as evidenced by KU516160 (NCBI GenBank Accession KU516160, submitted 08-MAR-2016) and KKQ38174 (NCBI GenBank Accession KKQ38174, submitted 07-MAY-2015).
The claims are interpreted as provided in a previous section.
Koonin teaches multiple Cas12 CRISPR/Cas systems (e.g., Cas12a-e) were already known and had been used to engineer sequence programmable induction of double-stranded DNA breaks (DSBs) with high efficiencies by forming complexes with synthetic gRNAs (Fig. 1, 3; pg. 71, left col., last para., to pg. 73, right col., 2nd para.). Koonin teaches specific Cas12 variants include Cas12a (Cpf1), Cas12b (C2c1), Cas12c, Cas12d, and Cas12e (Fig. 1, 3), with known protein sequences which cleave dsDNA via RuvC activity and sequence targeting by the gRNA’s spacer when complexed (Table 1; Fig. 1). Koonin teaches methods of searching databases to identify new Cas12 variants using in silico software analysis of prokaryotic genomic sequences anchored by the sequence of a known Cas gene(s) (pg. 71, left col., last para., to right col., 2nd para.).
Regarding claims 25-27 and 29, Koonin does not teach wherein the Cas12 protein comprises an amino acid sequence with any one of instant SEQ ID NOs: 3-5 or 222 nor wherein an engineered system thereof comprises nonnaturally occurring direct repeats capable of improving stem-loop stability.
However Murugan teaches a desire for new gene-editing Cas protein tools with different characteristics for use in creating new CRISPR/Cas engineering tools differentiated from ones already in use, such as characteristics regarding different PAM specificities or broader PAM tolerances and different nuclease activities, e.g., creation of directional sticky ends (pg. 2, 4th para., pg. 10-12; pg. 10, last two para.).
Couvin teaches the availability of CrisprCasFinder software, having parameter settings for finding Class 2 type V Cas sequences and/or those data sets including known Cas12 proteins (pg. W249). Moreover, websites of the U.S. National Center for Biotechnology Information (NCBI), e.g., UniRef and GenBank, taught genomes and genomic sequences of various prokaryotes encoding various Cas12 variants, such as Candidatus Micrarchaeota and Candidatus Peregrinibacteria as noted by instant Example 1.
It would have been prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing to identify new Cas12 protein variants, or a nucleic acid sequence encoding such variant, having any sequence readily searchable in an NCBI database publicly available before the instant filing date, such as a “Cas12p” comprising SEQ ID NO: 4, and then use laboratory tests to confirm DNA cleavage activity, such as in vitro, using routine assays comprising a naturally occurring gRNA of the same species as the Cas12 protein but retargeted with a spacer sequence matching a test DNA substrate sequence (e.g., a reporter). One of ordinary skill in the art would be motivated to search and screen for alternative Cas12 proteins to expand the diversity of CRISPR/Cas genomic editing tools. One would have a reasonable expectation of success to specifically find and create nucleic acids encoding a Cas12p consisting of SEQ ID NO: 4 based on known sequences of other Cas12 proteins, such as Cas12a (Cpf1, PDB:5B43), Cas12b (C2c1, PDB:5WQE, PDB:5NG6), Cas12c, Cas12d, and/or Cas12e discussed in Koonin and with searchable databases comprising genomic encoding sequences known respectively in Francisella cf. novicida (FnCas12a, FNFX1_1431-FNFX1_1428), Acidaminococcus sp. (AsCas12a), Alicyclobacillus acidoterrestris (Aac-Cas12b, N007_06525-N007_06535), Oleiphilus sp. (A3715_16885-A3715_16890), Bacterium CG09_39_24 (BK003_02070-BK003_02075), and Deltaproteobacteria sp. (A2Z89_08250-A2Z89_08265) (Fig. 1). Further, it would have been prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing to identify new Cas12 protein variants using available software tools for prior art purposes, including CrisprCasFinder taught by Couvin and/or methods taught by Koonin.
For example as evidenced by KU516160 or KKQ38174 before the earliest effective filing, a CRISPR/Cas system nucleic acid sequence of a metagenomic study comprising unidentified bacteria isolated from groundwater (KU516160) and the hypothetical Cas protein of Candidatus Roizmanbacteria bacterium (KKQ38174) were each known to relate to a Cas12 variant protein similar to instant SEQ ID NO: 4, i.e., with over 79% similarity and over 63% sequence identity.
Although Koonin, Murugan and Couvin does not teach wherein the engineered system comprises a non-naturally occurring direct repeat sequence capable of improving stem loop stability, Kocak teaches adding a synthetic hairpin secondary structure onto the spacer region of single guide RNAs (hp-sgRNAs) improves CRISPR/Cas specificity in engineered systems (abstract, Fig. 1). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing to design the Cas12p gRNA to comprise such an artificial stem loop (i.e., a non-naturally occurring direct repeat capable of improving stem-loop stability). One of ordinary skill in the art would be motivated by Kocak teaching synthetic gRNA stem loops increase CRISPR/Cas specificity, including for Cas12a nucleases (pg. 660-662).
Claims 25-27, 29, 33-34, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Koonin, Murugan, Couvin and Kocak as applied above, and further in view of Tu (Tu et al., Nucleic Acids Res 45: 11295-304 (2017)).
Regarding claims 33-34, although Koonin does not specifically teach wherein the target sequence is a sequence of a human, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to program the gRNA in the Cas12 systems taught by the combination of Koonin, Murugan and an NCBI database to target a sequence for gene editing of a gene of any mammal of interest (e.g., in a mammalian cell), especially in view of the references cited therein.
Furthermore in view of Tu specifically, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing use a Cas12 system taught by Koonin, Murugan, Couvin and an NCBI database to target a human gene for editing because Tu teaches engineered Cas12 system using Cas12 gRNAs targeting human DNA sequences (e.g., DNMT1) (Fig. 3). One of ordinary skill in the art with the goal of editing the genome of a human or nonhuman primate cell would be motivated to use a Cas12a-related system because Tu teaches Cas12a nucleases have equivalent editing efficiency to Cas9 but may have better specificity (pg. 11300, right col., last para., to pg. 11300, right col., 1st para.), especially in human cells (pg. 11296, left col., 2nd para.).
Regarding claim 36, Tu teaches using a catalytically active Cas12 variant which has dsDNA nuclease activity (Fig. 1; pg. 11296, right col., last para., to pg. 11299, left col., 1st para.; Fig. 2-3).
Regarding claim 37, Tu teaches Cas12a proteins cleave at sites distal to their target sequence (Fig. 3).
Claims 25-27, 29, 33-34, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Koonin, Murugan, Couvin and Kocak as applied above, and further in view of Liu (Liu et al., Nat Commun 8: 2095 (2017)).
Regarding claims 33-34, although Koonin does not specifically teach wherein the target sequence is a sequence of a human, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to program the gRNA in a Cas12 system taught by Koonin, Murugan and an NCBI database to target a sequence for gene editing in any mammal, especially in view of the references cited therein.
Furthermore in view of Liu specifically, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to use a Cas12 system taught by Koonin, Murugan and Couvin to target a human gene for editing because Liu teaches engineered Cas12 system using Cas12 gRNAs targeting human DNA sequences (e.g., DNMT1) (Fig. 1-4). One of ordinary skill in the art with the goal of editing the genome of a human or nonhuman primate cell would be motivated to use a Cas12 system because Liu teaches Cas12-based systems can overcome some issues with Cas9-based systems, which suffer from in vivo delivery inefficiencies and large sizes (pg. 2, left col., last para., to right col., 1st para.).
Regarding claim 38, Koonin does not specifically teach using a catalytically active Cas12 variant.
However Liu teaches a catalytically inactive Cas12a-based (dAsCpf1-D908A) gene expression tuning system for use in human cells that overcomes some issues with dCas9-based systems, which suffer from in vivo delivery inefficiencies and large sizes (pg. 2, left col., last para., to right col., 1st para.), such as for engineering customized human cell signaling circuits and studying human cell biology (Abstract). Liu teaches using a Cas12a fused to a transcription repressor domain (KRAB) or a synthetic transcriptional activator domain (VPR) to program target gene expression with the benefit of lower mismatch tolerance than Cas9 and is more suitable for targeting AT rich promoters (id.; pg. 3, left col., last para., to pg. 5, left col., Fig. 1-2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to program a Cas12 system taught by Koonin, Murugan, Couvin and an NCBI database to target a sequence for transcription regulation in a human cell using a catalytically inactive Cas12 variant. One of ordinary skill in the art with the goal of editing the genome of a human genomic molecule would be motivated to use such a Cas12 system because Liu teaches it has advantages over traditional Cas9 systems, e.g., in terms of size, specificity, and targetable sequences.
Claims 25-27, 29, and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Koonin, Murugan, Couvin, and Kocak as applied above, and further in view of Swarts (Swarts et al., Mol Cell 66: 221-33 (2017)).
Regarding claims 35-36, although Koonin does not specifically teach wherein the target sequence is a sequence of a bacteria, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to program the gRNA in a Cas12 system taught by Koonin, Murugan, Couvin and an NCBI database to target a bacterial sequence in view of Swarts teaching using Cas12a systems to target DNA sequences from bacteria (e.g., found in Francisella cf. novicida), such as a catalytically active Cas12 protein which cleaves at a site distal to the target sequence as does a wild-type Cas12a (Table S1; pg. e2, 3rd para.; Fig. 1, 3).
Thus, the claimed invention as a whole is prima facie obvious before the earliest effective filing date in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Jul. 23, 2026 have been fully considered (pg. 15-20) but not found persuasive regarding the current obviousness rejection.
As laid out above, the prior art Koonin teaches searching databases to identify new Cas12 variants using in silico software analysis of prokaryotic genomic sequences anchored by sequences of known Cas genes or Cas12 proteins and multiple Cas12 CRISPR/Cas systems (e.g., Cas12a-e) were already known and had been used to engineer sequence programmable induction of DSBs with high efficiencies by forming complexes with synthetic gRNAs having inverted repeated sequences. Motivations to find new Type V Cas12 variants provided in the prior art include the desire for new gene-editing tools with different characteristics, such as, inter alia, a different PAM specificity to increase the range of targets compared to already characterized Cas proteins for use in creating new CRISPR/Cas engineering tools as taught by Murugan (pg. 10, para. 4-5). This same general logic could be applied to Cas9 or any other known Cas protein to choose as an anchor sequence in an in silico computational analysis and subsequent validation by DNA cleavage assay. The whole entirety of public availably, searchable prokaryotic genomic databases in the prior art available for the obviousness analysis and these contain instant SEQ ID NO: 4 as admitted in the instant application.
While there is no specific motivation identified to find a naturally occurring Cas12 protein consisting of instant SEQ ID NO: 4 from the database, the prior art KU516160 and KKQ38174 teach Cas protein sequence useful in in anchoring Cas12 variant searches in silico taught by Koonin and, based on sequence similarity, would identify instant SEQ ID NO: 4, among others. Thus, the opinion of this office action is all such Cas12 variants are prima facie obvious as equivalents in prior art databases absent evidence to the contrary, such as regarding unexpected property/function or a lack of public availability before the instant filing date. Further, a Cas variant comprising SEQ ID NO: 4 is considered a natural variant merely pulled out of a publicly available database. Once identified in natural source (e.g., bacterium), some gRNA structures having a non-natural direct repeat would be straightforward to design from the CRISPR genomic sequence (specific Cas12 array) and knowledge in the prior art among skilled artisans using CRISPR-based technology (pg. 11 of response).
Applicant traverses the previous obviousness rejection by arguing that there is no disclosure in the prior art of the claimed Cas12 proteins (SEQ ID NO: 3-5 and 222) and the logic of the rejection is merely a motivation for possible research and/or obvious to try rationale lacking a predictable or targeted result at arriving at the claimed invention, such as due to a finite set of Cas12 variants taught by the prior art.
The basis of the obviousness rejection is from instant Example 1 (see [0429]): “Metagenome sequences were obtained from NCBI,” and “CRISPR arrays were identified using CrisprCasFinder software.” “The criteria of filtering were putative Class II type II and V effectors >500 aa, which were adjacent to cas genes and CRISPR arrays. Sequences were aligned with Clustal Omega using HMM profiles” to find novel Cas12a.1, Cas12p and Cas12q proteins. Nothing in this description is outside the skills of artisan before the instant filing date and Koonin in view of Murugan and Couvin as evidenced by KU16160 and KKQ38174 are used in detail to establish this further. The claimed proteins appear to be obvious variants of a known genus (similar structure, properties and predictability to other Cas12 variants known in the prior art (e.g., Cas12b (C2c1), Cas12c, Cas12(d) (CasY) etc.)); however, nonobviousness may be shown by secondary indicia of unexpectedly advantageous or superior properties over known Cas12 variants.
Regarding Tu, Applicant traverses arguing the cited prior art does not specifically teach wherein the target DNA sequence is human; however as discussed above teaches using Cas12 gRNAs targeting the human DNMT1 gene. Regarding Liu, Applicant traverses arguing the cited prior art does not specifically teach wherein the target DNA sequence is of a mammal of interest; however it similar obvious to target human DNMT1 as nonhuman primate DNMT1 in a primate cell. Regarding Swarts, Applicant traverses arguing the cited prior art does not specifically teach wherein the target DNA sequence is bacterial; however as discussed above, Swarts teaches targets in the bacterium Francisella cf. novicida.
The logic of the obviousness rejection above is the skilled artisan possessed both the necessary methods and the publicly available databases possessed the necessary sequences to arrive at the instantly claimed Cas12 inventions with a reasonable expectation of success, given the motivation to find any such variants of known Cas12 proteins by sequence homology/phylogenetics. While it may have been time-consuming, arduous and/or improbable to arrive at exactly instant SEQ ID NO: 4, this just represents one of many obvious species in the opinion of this office action absent any secondary indicium of nonobviousness or evidence of failures of prior art methods at obtaining SEQ ID NO: 4 and the like.
Note, the invention of claim 123 appears to be free of the prior art.
Double Patenting (maintained)
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 25-26, 29-30, and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11 of copending Application No. 17/772,960 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 11 of the reference application discloses a CRISPR/Cas complex comprising a Cas12 protein (SEQ ID NO: 6) comprising instant SEQ ID NO: 4 and 222 (as shown below) and a functional guide RNA (gRNA).
100.0% identity in 1281 residues overlap; Score: 6717.0; Gap frequency: 0.0%
Sequence4 1 MKKSIFDQFVNQYALSKTLRFELKPVGETGRMLEEAKVFAKDETIKKKYEATKPFFNKLH
Sequence6 1 MKKSIFDQFVNQYALSKTLRFELKPVGETGRMLEEAKVFAKDETIKKKYEATKPFFNKLH
************************************************************
Sequence4 61 REFVEEALNEVELAGLPEYFEIFKYWKRYKKKFEKDLQKKEKELRKSVVGFFNAQAKEWA
Sequence6 61 REFVEEALNEVELAGLPEYFEIFKYWKRYKKKFEKDLQKKEKELRKSVVGFFNAQAKEWA
************************************************************
Sequence4 121 KKYETLGVKKKDVGLLFEENVFAILKERYGNEEGSQIVDESTGKDVSIFDSWKGFTGYFI
Sequence6 121 KKYETLGVKKKDVGLLFEENVFAILKERYGNEEGSQIVDESTGKDVSIFDSWKGFTGYFI
************************************************************
Sequence4 181 KFQETRKNFYKDDGTATALATRIIDQNLKRFCDNLLIFESIRDKIDFSEVEQTMGNSIDK
Sequence6 181 KFQETRKNFYKDDGTATALATRIIDQNLKRFCDNLLIFESIRDKIDFSEVEQTMGNSIDK
************************************************************
Sequence4 241 VFSVIFYSSCLLQEGIDFYNCVLGGETLPNGEKRQGINELINLYRQKTSEKVPFLKLLDK
Sequence6 241 VFSVIFYSSCLLQEGIDFYNCVLGGETLPNGEKRQGINELINLYRQKTSEKVPFLKLLDK
************************************************************
Sequence4 301 QILSEKEKFMDEIENDEALLDTLKIFRKSAEEKTTLLKNIFGDFVMNQGKYDLAQIYISR
Sequence6 301 QILSEKEKFMDEIENDEALLDTLKIFRKSAEEKTTLLKNIFGDFVMNQGKYDLAQIYISR
************************************************************
Sequence4 361 ESLNTISRKWTSETDIFEDSLYEVLKKSKIVSASVKKKDGGYAFPEFIALIYVKSALEQI
Sequence6 361 ESLNTISRKWTSETDIFEDSLYEVLKKSKIVSASVKKKDGGYAFPEFIALIYVKSALEQI
************************************************************
Sequence4 421 PTEKFWKERYYKNIGDVLNKGFLNGKEGVWLQFLLIFDFEFNSLFEREIIDENGDKKVAG
Sequence6 421 PTEKFWKERYYKNIGDVLNKGFLNGKEGVWLQFLLIFDFEFNSLFEREIIDENGDKKVAG
************************************************************
Sequence4 481 YNLFAKGFDDLLNNFKYDQKAKVVIKDFADEVLHIYQMGKYFAIEKKRSWLADYDIDSFY
Sequence6 481 YNLFAKGFDDLLNNFKYDQKAKVVIKDFADEVLHIYQMGKYFAIEKKRSWLADYDIDSFY
************************************************************
Sequence4 541 TDPEKGYLKFYENAYEEIIQVYNKLRNYLTKKPYSEDKWKLNFENPTLADGWDKNKEADN
Sequence6 541 TDPEKGYLKFYENAYEEIIQVYNKLRNYLTKKPYSEDKWKLNFENPTLADGWDKNKEADN
************************************************************
Sequence4 601 STVILKKDGRYYLGLMARGRNKLFDDRNLPKILEGVENGKYEKVVYKYFPDQAKMFPKVC
Sequence6 601 STVILKKDGRYYLGLMARGRNKLFDDRNLPKILEGVENGKYEKVVYKYFPDQAKMFPKVC
************************************************************
Sequence4 661 FSTKGLEFFQPSEEVITIYKNSEFKKGYTFNVRSMQRLIDFYKDCLVRYEGWQCYDFRNL
Sequence6 661 FSTKGLEFFQPSEEVITIYKNSEFKKGYTFNVRSMQRLIDFYKDCLVRYEGWQCYDFRNL
************************************************************
Sequence4 721 RKTEDYRKNIEEFFSDVAMDGYKISFQDVSESYIKEKNQNGDLYLFEIKNKDWNEGANGK
Sequence6 721 RKTEDYRKNIEEFFSDVAMDGYKISFQDVSESYIKEKNQNGDLYLFEIKNKDWNEGANGK
************************************************************
Sequence4 781 KNLHTIYFESLFSADNIAMNFPVKLNGQAEIFYRPRTEGLEKERIITKKGNVLEKGDKAF
Sequence6 781 KNLHTIYFESLFSADNIAMNFPVKLNGQAEIFYRPRTEGLEKERIITKKGNVLEKGDKAF
************************************************************
Sequence4 841 HKRRYTENKVFFHVPITLNRTKKNPFQFNAKINDFLAKNSDINVIGVDRGEKQLAYFSVI
Sequence6 841 HKRRYTENKVFFHVPITLNRTKKNPFQFNAKINDFLAKNSDINVIGVDRGEKQLAYFSVI
************************************************************
Sequence4 901 SQRGKILDRGSLNVINGVNYAEKLEEKARGREQARKDWQQIEGIKDLKKGYISQVVRKLA
Sequence6 901 SQRGKILDRGSLNVINGVNYAEKLEEKARGREQARKDWQQIEGIKDLKKGYISQVVRKLA
************************************************************
Sequence4 961 DLAIQYNAIIVFEDLNMRFKQIRGGIEKSVYQQLEKALIDKLTFLVEKEEKDVEKAGHLL
Sequence6 961 DLAIQYNAIIVFEDLNMRFKQIRGGIEKSVYQQLEKALIDKLTFLVEKEEKDVEKAGHLL
************************************************************
Sequence4 1021 KAYQLAAPFETFQKMGKQTGIVFYTQAAYTSRIDPVTGWRPHLYLKYSSAEKAKADLLKF
Sequence6 1021 KAYQLAAPFETFQKMGKQTGIVFYTQAAYTSRIDPVTGWRPHLYLKYSSAEKAKADLLKF
************************************************************
Sequence4 1081 KKIKFVDGRFEFTYDIKSFREQKEHPKATVWTVCSCVERFRWNRYLNSNKGGYDHYSDVT
Sequence6 1081 KKIKFVDGRFEFTYDIKSFREQKEHPKATVWTVCSCVERFRWNRYLNSNKGGYDHYSDVT
************************************************************
Sequence4 1141 KFLVELFQEYGIDFERGDIVGQIEVLETKGNEKFFKNFVFFFNLICQIRNTNASELAKKD
Sequence6 1141 KFLVELFQEYGIDFERGDIVGQIEVLETKGNEKFFKNFVFFFNLICQIRNTNASELAKKD
************************************************************
Sequence4 1201 GKDDFILSPVEPFFDSRNSEKFGEDLPKNGDDNGAFNIARKGLVIMDKITKFADENGGCE
Sequence6 1201 GKDDFILSPVEPFFDSRNSEKFGEDLPKNGDDNGAFNIARKGLVIMDKITKFADENGGCE
************************************************************
Sequence4 1261 KMKWGDLYVSNVEWDNFVANK
Sequence6 1261 KMKWGDLYVSNVEWDNFVANK
*********************
Regarding instant claims 36-37 and 39, the CRISPR/Cas complex of reference claim 11 is implicitly and inherently catalytically active and also inherently cleaves (via a nickase activities) downstream (distal) of its target sequence as explained in a previous section due to the presence of instant SEQ ID NO: 4. This is a provisional nonstatutory double patenting rejection because the reference application claims have not in fact been patented. As 17/772,960 is currently abandoned, this rejection will be withdrawn once abandonment is irrevocable.
Conclusion
No claim is allowed.
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 ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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