DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on 04/09/2026 has been entered.
The numbering of claims is not accordance with 37 CFR 1.126, which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
As there are two claims 78 and two claims 79,
the misnumbered claim 78 has been renumbered as claim 80,
the misnumbered claim 79 has been renumbered as claim 81,
the misnumbered claim 80 has been renumbered as claim 82,
the misnumbered canceled claim 81 has been renumbered as claim 83,
the misnumbered claim 82 has been renumbered as claim 84,
the misnumbered claim 83 has been renumbered as claim 85,
the misnumbered claim 84 has been renumbered as claim 86,
the misnumbered claim 85 has been renumbered as claim 87,
the misnumbered claim 86 has been renumbered as claim 88, and
the misnumbered claim 87 has been renumbered as claim 89.
Reference to the claims here and on the Form PTO-326 will be made to the claims as they have been renumbered.
Claims 1-19, 62-69, 71, 74-82 and 84-89 are pending in this application.
Applicant’s amendment to the claims filed 04/09/2026 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s amendment to the drawings filed 04/09/2026 is acknowledged.
Applicant’s remarks filed on 04/09/2026 in response to the final rejection mailed on 01/12/2026 are acknowledged and have been fully considered.
The rejections of claim 83 previously set forth are withdrawn in view of the cancelation of claim 83.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election
The elected subject matter is
Group I, corresponding to claims 1-11, 71, 78-82 and 84-89, drawn to a system comprising the combination of a Class 2 CRISPR-Cas endonuclease and a gRNA, a composition comprising the system, a kit comprising the system, a composition comprising the endonuclease, a polynucleotide encoding the endonuclease, a vector comprising the polynucleotide and a host cell comprising the vector, and
the species of SEQ ID NO: 1,
elected without traverse in the reply filed 10/21/2024, and
the species of SEQ ID NOs: 116, 62 and 94 from Tables 7, 1, and 4, respectively
elected without traverse in the reply filed 09/05/2025.
The species of SEQ ID NO: 62 from Table 1 is considered to correspond to the previously elected species of SEQ ID NO: 1, as both species correspond to a Class 2 Type V Cas endonuclease.
Claims 12-19, 62-69 and 74-77 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/21/2024.
The requirement for election of a single species among the species recited in part (a)(i) of claim 1, the requirement for election of a single species among the species recited in part (a)(ii) of claim 1, and the requirement for election of a single species among the species recited in part (a)(iii) of claim 1 are withdrawn in view of the amendment to claim 1 to require the Cas endonuclease comprises at least three sequences from part (a)(i), at least three sequences from part (a)(ii), or at least two sequences from part (a)(iii), respectively.
The requirement for election of species among the species of SEQ ID NOs: 1-7 and 20 corresponding to the Class 2 Type V CRISPR-Cas endonuclease is withdrawn in view of the species of SEQ ID NOs: 1-7 and 20 being free of the prior art of record.
As the originally elected species SEQ ID NOs: 1 and 62 read on the system comprising a Type V CRISPR-Cas endonuclease, the elected species are considered to correspond to a Type V CRISPR-Cas endonuclease, and as such claims 2-3, 5, 7-9, and 11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species. Election was made without traverse in the reply filed on 10/21/2024.
Claims 1, 4, 6, 10, 71, 78-82 and 84-89 are being examined on the merits only to the extent they read on the elected subject matter.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 04/09/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
Objection to Drawings
The objection to the drawings is withdrawn in view of the amendments to Figures 8, 16, 18, 51 to no longer include sequences that are duplicated from the Sequence Listing XML.
Claim Objections
The objections to claims 84 and 86-89 are withdrawn in view of the amendment to claims 84 to recite “wherein the Class 2 CRISPR-Cas endonuclease comprises … a sequence comprising 90% identity thereto”.
Applicant is advised that should claims 78-79 be found allowable, claims 80-81 will be objected to under 37 CFR 1.75 as being substantial duplicates of claims 78-79. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Improper Markush Grouping
Claim 1 is rejected on the basis that it contains improper Markush groupings of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex part Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP 2117.
The Markush groupings of claim 1 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The claim is drawn to an engineered system comprising (a) a Class 2 CRISPR-Cas endonuclease or a nucleic acid encoding the endonuclease, and (b) a gRNA or nucleic acid encoding the gRNA that is capable of forming a complex with the Class 2 CRISPR-Cas endonuclease, wherein the endonuclease of (a) is:
a Class 2 Type II CRISPR-Cas endonuclease comprising at least three of the RuvC or HNH sequences of SEQ ID NOs: 116-118, 121-123, 126-128, 131-133, or 139-141;
a Class 2 Type V CRISPR-Cas endonuclease comprising at least three of the RuvC sequences of SEQ ID NOs: 62-64, 67-69, 71-73, 75-77, 80-82, 85-87, 89-81, or 135-137; or
a Class 2 Type VI CRISPR-Cas endonuclease comprising at least two of the HEPN sequences of SEQ ID NOs: 94-95, 97, 99-100, 102, 104-105, 107-108, 110-111 or 113, wherein the HEPN sequences are not both selected from SEQ ID NOs: 94-95 and 111.
The phrases corresponding to a “Class 2 Type II”, “Class 2 Type V”, and “Class 2 Type VI” CRISPR-Cas endonuclease recited in parts (i)-(iii), respectively, are not structurally limiting. While the specification gives examples of Class 2 Type II, Class 2 Type V, and Class 2 Type VI CRISPR-Cas endonucleases as SEQ ID NOs: 16, 1 and 8, respectively, these sequences share less than 21% identity with each other [see Appendices A, B and C] indicating these different endonuclease Types do not share a single structural similarity and a common use. As the structure of the claimed endonuclease is not defined by a sequence identifier (i.e., SEQ ID NO) in the claims, the only required structural elements are the motifs listed in parts (i)-(iii) which comprise as few as 12 amino acids, and each of the respective groups in parts (i)-(iii) do not share a single structural similarity and common use with each other, as RuvC, HNH and HEPN domains are known in the art as structurally distinct motifs defined from structurally distinct enzyme families such as RuvC, HNH, and HEPN nuclease families as evidenced by Schmakov et al. (Mol Cell, 2015, 60:385; cited on the Form PTO-892 mailed 02/24/2025) on [p 385, col 1, final paragraph; Figure 2; and p 393, col 1, middle paragraph]. Therefore the species as recited in claim 1 corresponding to an endonuclease that is either a Class 2 Type II, Class 2 Type V, or Class 2 Type VI CRISPR-Cas endonuclease, wherein each choice is further defined by a selection from a group of enumerated sequence motifs, is considered an improper Markush grouping as the members of the grouping do not share both a single structural similarity and a common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(a)
Claim interpretation: The claims are drawn (in relevant part) to an engineered system comprising a Class 2 CRISPR-Cas endonuclease or nucleic acid encoding the endonuclease and a gRNA or nucleic acid encoding the gRNA, wherein the gRNA and endonuclease do not naturally occur together, wherein the gRNA is capable of hybridizing to a target sequence in a DNA or RNA sequence, and the gRNA is capable of forming a complex with the endonuclease. The endonuclease is further limited to containing at least three RuvC sequences of the sequences disclosed in the claim. As the Class 2 CRISPR-Cas endonuclease is structurally defined by having at least three of the recited sequences corresponding to domains as small as 12 amino acids, and is without structural limitation to the full length polypeptide, the remaining amino acid sequence of the Class 2 CRISPR-Cas endonuclease is considered unlimited. As such, the genus of recited Class 2 CRISPR-Cas endonucleases encompasses species that are considered to be widely variant with respect to sequence.
Claims 1, 4, 6, 71 and 78-82 are rejected under 35 U.S.C. 112(a) 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 at the time the application was filed, had possession of the claimed invention.
The instant rejection is maintained from the previous office action, and has been modified to address any amendments to the claims.
MPEP 2163.II.A.2.(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 Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
According to MPEP 2163.II.A.3.(a).ii), [s]atisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
The factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP § 2163.
The claims recite (in relevant part) a genus of Class 2 CRISPR-Cas endonucleases or nucleic acid encoding the endonucleases comprising at least three RuvC domains of the sequences disclosed in claim 1. As stated above, with the exception of the recited domain sequences in the claims, the remaining amino acid sequences of the genus of Class 2 CRISPR-Cas endonucleases are unlimited. In this case, the genus of recited Class 2 CRISPR-Cas endonucleases encompass species that are considered to be widely variant with respect to sequence.
The specification discloses the following representative species of the genus of Class 2 CRISPR-Cas endonucleases:
the Class 2 CRISPR-Cas endonucleases of SEQ ID NOs: 1-20.
Regarding the level of skill and knowledge in the art of amino acid modification, the reference of Singh et al. (Curr. Protein Pept. Sci. 18:1-11, 2017; cited on the Form PTO-892 mailed 02/24/2025) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see p. 7, column 1, top). Also, the unpredictability associated with residue substitution is exemplified by the reference of Zhang et al. (Structure 26:1474-1485, 2018; cited on the Form PTO-892 mailed 02/24/2025), which discloses that even a substitution of a surface residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1).
In view of the high level of unpredictability in the art of amino acid modification, because the genus of Class 2 CRISPR-Cas endonucleases is widely variant with respect to structure, and the specification discloses the actual reduction to practice of only 20 representative species among a widely variant genus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that the applicant was not in possession of the recited genus of Class 2 CRISPR-Cas endonucleases. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
Response to Remarks: beginning on page 15 of Applicant’s response to the rejection under 35 USC 112(a); Applicant in summary contends the amendments to require 100% sequence identity to the sequences of the recited sub-domains in the claim would be recognized by one of skill in the art as the Applicant being in possession of the claimed invention in view of the Sequences disclosed in Tables 1, 4 and 7 of the specification.
Applicant’s remarks are considered and found not convincing. While the limitation of sub-domains to exact sequences as recited in the claims limits the scope to better define all active sub-motifs as stated by Applicant, the only defined structural features of the claimed endonucleases are these sub-domains, and not any full-length polypeptide. As such, beyond the occurrence of the recited sub-domains, some of which as small as 12 amino acids in length, the rest of the amino acid sequence of the claimed genus of endonucleases is unlimited, and is represents a genus that is widely variant with respect to structure. Tables 1, 4 and 7 of the specification merely recite the sequences of the sub-domains recited in the claims, and as such do not serve as representative examples of structurally defined endonucleases. For these reasons in addition to those stated in the rejection above, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus.
Claim Rejections - 35 USC § 101
Claims 1, 4, 6, 71 and 78-81 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Applicant’s attention is directed to the "Guidance for Determining Subject Matter Eligibility Of Claims Reciting Or Involving Laws of Nature, Natural Phenomena, & Natural Products”, released on December 16, 2014.
The instant rejection is maintained from the previous office action, any newly recited portions are necessitated by claim amendment.
Claim Interpretation: The claims are drawn to an engineered system comprising a Class 2 CRISPR-Cas endonuclease or nucleic acid encoding the endonuclease, and a gRNA or nucleic acid encoding the gRNA, wherein the gRNA and endonuclease do not naturally occur together, wherein the gRNA is capable of hybridizing to a target sequence in a DNA or RNA sequence, and the gRNA is capable of forming a complex with the endonuclease. The endonuclease is further limited to containing at least three RuvC sequences from those enumerated in part (ii) of claim 1.
As NCBI Accession No. NCU42495.1 (30 January 2020, 2 pages; cited on the \ Form PTO-892 mailed 01/12/2026; herein NCBI2) discloses a type V Cas protein Cpf1 from the bacterium Candidatus Moraniibacteriota that has a sequence sharing 100% identity with SEQ ID NOs: 75-77 [see Appendices D, E and F], the claims encompass the naturally occurring Cas protein of NCBI2.
The claims additionally recite “the gRNA and the Class 2 CRISPR-Cas endonuclease do not naturally occur together” and given a broadest reasonable interpretation, the claims encompass a combination of a recombinantly produced Class 2 CRISPR-Cas endonuclease and a naturally occurring gRNA, a combination of a naturally-occurring Class 2 CRISPR-Cas endonuclease and a recombinantly produced gRNA, and a combination of a recombinantly produced Class 2 CRISPR-Cas endonuclease and a recombinantly produced gRNA, wherein the recombinantly produced Class 2 CRISPR-Cas endonuclease and the recombinantly produced gRNA are structurally and functionally indistinguishable from the corresponding naturally occurring Class 2 CRISPR-Cas endonuclease and gRNA.
Patent Eligibility Analysis Step 1: The claims are drawn to a composition of matter, which is one of the statutory categories of invention.
Patent Eligibility Analysis Step 2A Prong 1: The claims recite an engineered system comprising a CRISPR-Cas endonuclease and/or a gRNA that is structurally and functionally indistinguishable and not markedly different from the corresponding naturally occurring Class 2 CRISPR-Cas endonuclease and gRNA and thus the claimed system is considered to be a law of nature or natural phenomena (a natural product). Accordingly, claims 1, 4, 6, 71 and 78-81 are directed to a judicial exception.
Patent Eligibility Analysis Step 2A Prong 2: As noted above, claim 1 recites the limitation “the gRNA and the Class 2 CRISPR-Cas endonuclease do not naturally occur together.” This limitation, however, does not structurally and/or functionally distinguish the Class 2 CRISPR-Cas endonuclease and gRNA from than their naturally-occurring counterparts.
Claims 79 and 81 recite the additional element that one of the components of the system are lyophilized. As lyophilization is understood in the art to encompass a substance with substantial amounts of water removed and thereby does not change the structure of the substance, the characteristic of being lyophilized does not distinguish any of the components as markedly different than their naturally occurring counterparts.
There are no other additional elements recited in the claims beyond the judicial exception.
Patent Eligibility Analysis Step 2B: The claims only recite the judicial exception, without more and do not include any additional elements that could add significantly more to the judicial exception.
As such, the claims do not qualify as eligible subject matter. For these reasons the claim is rejected under section 101 as being directed to non-statutory subject matter.
Response to Remarks: beginning on page 16 of Applicant’s response to the rejection under 35 USC 101; Applicant in summary contends the amendment to claim 1 to require at least three RuvC sequences establish the claimed endonuclease as markedly different from its naturally occurring counterpart.
Applicant’s remarks are considered and found not convincing.
As stated in the rejection above, the type V Cas protein Cpf1 from the bacterium Candidatus Moraniibacteriota has a sequence sharing 100% identity with each of SEQ ID NOs: 75-77 [see Appendices D, E and F], and therefore the claims are considered to encompass the naturally occurring Cas protein of NCBI2. As such, the amendments to claim 1 do not distinguish the system as markedly different from the naturally occurring counterpart system.
Claim Rejections - 35 USC § 103
Claims 1, 4, 6, 71, 78 and 80 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng et al. (US 2019/0002889; cited on the Form PTO-892 mailed 02/24/2025; herein Cheng) in view NCBI Accession No. NCU42495.1 (30 January 2020, 2 pages; cited on the Form PTO-892 mailed 01/12/2026; herein NCBI2).
The instant rejection is maintained from a previous office action, and any newly recited portions are necessitated by claim amendment.
Claim 1 is drawn to an engineered system comprising
(a) a Class 2 CRISPR-Cas endonuclease or a nucleic acid encoding the endonuclease, wherein the Class 2 CRISPR-Cas endonuclease is
(i) a Class 2 Type II CRISPR-Cas endonuclease comprising at least three of the RuvC or HNH sequences SEQ ID NOs: 116-118, 121-123, 126-128, 131-133, or 138-141;
(ii) a Class 2 Type V CRISPR-Cas endonuclease comprising at least three of the RuvC sequences of SEQ ID NOs: 62-64, 67-69, 71-73, 75-77, 80-82, 85-87, 89-91, or 135-137; or
(iii) a Class 2 Type VI CRISPR-Cas endonuclease comprising at least two of the HEPN sequences of SEQ ID NOs: 94-95, 97, 99-100, 102, 104-105, 107-108, 110-111 or 113, and
(b) a gRNA or a nucleic acid encoding the gRNA, wherein the gRNA and the Class 2 CRISPR-Cas endonuclease do not naturally occur together, wherein the gRNA is capable of hybridizing to a target sequence in a target DNA or RNA, and the gRNA is capable of forming a complex with the Class 2 CRISPR-Cas endonuclease.
Cheng discusses novel CRISPR RNA targeting systems [title], and describes systems for the manipulation of nucleic acids in a targeted fashion using non-naturally occurring engineered CRISPR systems and components [abstract].
Regarding claims 1 and 6 and the limitation of a Class 2 CRISPR-Cas endonuclease, Cheng discloses a system comprising an RNA guide capable of hybridizing to a target nucleic acid and a non-naturally occurring CRISPR-associated (Cas) protein capable of binding to the RNA guide [para 0010], wherein the Cas protein is a Class 2 CRISPR-Cas protein selected from the group consisting of a Type VI, Type V and Type II Cas protein [para 0017]. The gRNA recited in the claim is understood to be a guide RNA, and as the Cas protein is non-naturally occurring, it is understood that the Cas and the gRNA do not naturally occur together.
Cheng does not teach a Type V Cas protein comprising at least three of the RuvC sequences recited in part (a)(ii) of claim 1.
NCBI2 discloses a Type V Cas protein Cpf1 from the bacterium Candidatus Moraniibacteriota that has a sequence sharing 100% identity with SEQ ID NOs: 75-77 [see Appendices D, E and F].
In view of Cheng and NCBI2, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the system of Cheng by using the endonuclease of NCBI2 to arrive at the claimed invention, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the Type V Cas protein of Cheng and the endonuclease of NCBI2 are both Type V Cas proteins, and as such one would have predicted that both are capable of being incorporated into such a system as described by Cheng. Thus it would have been obvious to one of ordinary skill in the art to replace the Type V Cas protein of Cheng with the Type V Cas protein of NCBI2, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both Cheng and NCBI2 relate to Type V Cas proteins.
Regarding claim 4, Cheng discloses a vector which includes multiple nucleic acids, each encoding a component of a Cas system described herein [para 0210], wherein the gRNA is considered a component of the Cas system as described above, and the encoding of a gRNA on a single nucleic acid encompasses a single-molecule gRNA as recited in the claims.
Regarding claim 71, Cheng discloses the incubation of effectors, corresponding to the Cas protein, with pre-crRNAs, corresponding to gRNAs, for a cleavage assay in a buffer of 20 mM Tris, pH 8.0 held at 37 °C for 10 minutes [para 0365]. As the instant specification does not define a stabilizing buffer, the 20 mM Tris buffer of Cheng is considered to correspond to a stabilizing buffer, and therefore the combination of Cas, gRNA and buffer as disclosed by Cheng is considered to correspond to the composition recited in the claim.
Regarding claims 78 and 80, in light of the combined system of Cheng and NCBI2 as described above, it would have been obvious for one of skill in the art to combine each of the components disclosed in the rejection of claim 1 into a kit for convenience.
Therefore, the invention of claims 1, 4, 6, 71, 78 and 80 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 79 and 81-82 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng and NCBI2 as applied to claims 1, 4, 6, 71, 78 and 80 above, and further in view of Broughton.
The instant rejection is maintained from a previous office action, and any newly recited portions are necessitated by claim amendment.
Claims 79 and 81 are drawn to the kit of claims 78 and 80, respectively, wherein one or more components are lyophilized.
The teachings of Cheng and NCBI2 as applied to claims 1, 4, 6, 71, 78 and 80 are described above. These references do not teach lyophilized components.
Broughton discusses CRISPR-Cas12-based detection of SARS-CoV-2 [title], and describes CRISPR-based lateral flow assays for that are rapid, accurate, and easy-to-implement for the detection of SARS-CoV-2 from respiratory swab RNA extracts [abstract].
Regarding claims 79 and 81, Broughton teaches the use of a system comprising CRISPR-Cas12, gRNA and a target RNA derived from nasopharyngeal swabs to detect the presence of SARS-CoV-2 [Figure 1d], and teaches that the lyophilization of reagents from the system could enable point-of-care testing outside of the clinical diagnostic laboratory, such as airports, local emergency departments and clinics, and other locations [p 874, col 1, final paragraph].
In view of Broughton, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined system of Cheng and NCBI2 by lyophilizing the components, as taught by Broughton, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined system of Cheng and NCBI2, because Broughton teaches that systems for rapid, accurate, and easy-to-implement detection of SARS-CoV-2 from RNA extracts could be improved and applied to point-of-care diagnostics by lyophilizing the system components. One of ordinary skill in the art would have had a reasonable expectation of success because Cheng and Broughton relate to systems comprising CRISPR-Cas proteins and gRNAs.
Regarding claim 82, Broughton teaches the system comprising CRISPR-Cas12, gRNA and a target RNA derived from nasopharyngeal swabs to detect the presence of SARS-CoV-2 in the presence of a labeled reporter [Figure 1d], wherein the gRNA is understood to be directed towards SARS-CoV-2.
Therefore, the invention of claims 79 and 81-82 would have been obvious to one of ordinary skill in the art before the effective filing date.
Response to Remarks: beginning on page 18 of Applicant’s response to rejections under 35 USC 103; Applicant in summary contends the prior art of record does not disclose the features of the amended claims, particularly that the Type V Cas endonuclease comprises at least three of the RuvC motifs recited in part (a)(ii) of claim 1.
Applicant’s remarks are considered and found not convincing in view of NCBI2, which discloses a Type V Cas protein with an amino acid sequence comprising three of the RuvC domains recited in part (a)(ii) of claim 1. For this reason as well as those stated in the rejections above, the rejections of claims 1, 4, 6, 71, 78 and 80 and claims 79 and 81-82 are maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
A. Claims 1, 4, 6, 71, 78 and 80 are newly provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20, 81 and 86 of copending Application No. 17/616121 (herein “reference application”) in view of Cheng and NCBI2.
The instant rejection is newly recited and is necessitated by claim amendment.
Regarding instant claim 1, claims 20, 81 and 86 of the reference application recite a method of modifying a target DNA or RNA comprising the use of a Class 2 Type V CRISPR-Cas endonuclease comprising at least two RuvC domains selected from a list of enumerated SEQ ID NOs, and a guide RNA (gRNA) or nucleic acid encoding the gRNA, wherein the gRNA and the endonuclease do not occur naturally together, wherein the gRNA is capable of hybridizing to a target DNA or RNA, and the gRNA is capable of forming a complex with the endonuclease.
The claims of the reference application do not recite the Class 2 Type V endonuclease comprises at least three of the RuvC domains listed in part (a)(ii) of instant claim 1.
Cheng discusses novel CRISPR RNA targeting systems [title], and describes systems for the manipulation of nucleic acids in a targeted fashion using non-naturally occurring engineered CRISPR systems and components [abstract].
Regarding instant claims 1 and 6 and the limitation of a Class 2 CRISPR-Cas endonuclease, Cheng discloses a system comprising an RNA guide capable of hybridizing to a target nucleic acid and a non-naturally occurring CRISPR-associated (Cas) protein capable of binding to the RNA guide [para 0010], wherein the Cas protein is a Class 2 CRISPR-Cas protein selected from the group consisting of a Type VI, Type V and Type II Cas protein [para 0017]. The gRNA recited in the claim is understood to be a guide RNA, and as the Cas protein is non-naturally occurring, it is understood that the Cas and the gRNA do not naturally occur together.
NCBI2 discloses a Type V Cas protein Cpf1 from the bacterium Candidatus Moraniibacteriota that has a sequence sharing 100% identity with SEQ ID NOs: 75-77 [see Appendices D, E and F].
In view of Cheng and NCBI2, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the reference application by using the system of Cheng and the endonuclease of NCBI2 to arrive at the claimed invention, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the system of Cheng and the endonuclease and gRNA of the reference application are both systems comprising a Cas endonuclease and a gRNA, and as such both are capable of being incorporated in the method as disclosed by the reference application. Thus it would have been obvious to one of ordinary skill in the art to replace the system of the reference application with the system of Cheng, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both the reference application and Cheng describe systems comprising a Cas endonuclease and gRNA.
One of ordinary skill in the art would have recognized that the Type V Cas protein of Cheng and the endonuclease of NCBI2 are both Type V Cas proteins, and as such one would have predicted that both are capable of being incorporated into such a system as described by Cheng and the reference application. Thus it would have been obvious to one of ordinary skill in the art to replace the Type V Cas protein of Cheng with the Type V Cas protein of NCBI2, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both Cheng and NCBI2 relate to Type V Cas proteins.
Regarding instant claim 4, Cheng discloses a vector which includes multiple nucleic acids, each encoding a component of a Cas system described herein [para 0210], wherein the gRNA is considered a component of the Cas system as described above, and the encoding of a gRNA on a single nucleic acid encompasses a single-molecule gRNA as recited in the claims.
Regarding instant claim 71, Cheng discloses the incubation of effectors, corresponding to the Cas protein, with pre-crRNAs, corresponding to gRNAs, for a cleavage assay in a buffer of 20 mM Tris, pH 8.0 held at 37 °C for 10 minutes [para 0365]. As the instant specification does not define a stabilizing buffer, the 20 mM Tris buffer of Cheng is considered to correspond to a stabilizing buffer, and therefore the combination of Cas, gRNA and buffer as disclosed by Cheng is considered to correspond to the composition recited in the claim.
Regarding instant claims 78 and 80, in light of the combined system of Cheng and NCBI2 as described above, it would have been obvious for one of skill in the art to combine each of the components disclosed in the rejection of claim 1 into a kit for convenience.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 79 and 81-82 are newly provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20, 81 and 86 of copending Application No. 17/616121 in view of Cheng and NCBI2 as applied to claims 1, 4, 6, 71, 78 and 80 above, and further in view of Broughton.
The instant rejection is newly recited and is necessitated by claim amendment.
The claims of the reference application and the disclosures of Cheng and NCBI2 as applied to claims 1, 4, 6, 71, 78 and 80 are described above. The claims of the reference application do not recite lyophilized components.
Broughton discusses CRISPR-Cas12-based detection of SARS-CoV-2 [title], and describes CRISPR-based lateral flow assays for that are rapid, accurate, and easy-to-implement for the detection of SARS-CoV-2 from respiratory swab RNA extracts [abstract].
Regarding instant claims 79 and 81, Broughton discloses the use of a system comprising CRISPR-Cas12, gRNA and a target RNA derived from nasopharyngeal swabs to detect the presence of SARS-CoV-2 [Figure 1d], and discloses that the lyophilization of reagents from the system could enable point-of-care testing outside of the clinical diagnostic laboratory, such as airports, local emergency departments and clinics, and other locations [p 874, col 1, final paragraph].
In view of Broughton, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined system of the reference application, Cheng and NCBI2 by lyophilizing the components, as disclosed by Broughton, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined system of the reference application, Cheng and NCBI2, because Broughton discloses that systems for rapid, accurate, and easy-to-implement detection of SARS-CoV-2 from RNA extracts could be improved and applied to point-of-care diagnostics by lyophilizing the system components. One of ordinary skill in the art would have had a reasonable expectation of success because Cheng and Broughton relate to systems comprising CRISPR-Cas proteins and gRNAs.
Regarding instant claim 82, Broughton discloses the system comprising CRISPR-Cas12, gRNA and a target RNA derived from nasopharyngeal swabs to detect the presence of SARS-CoV-2 in the presence of a labeled reporter [Figure 1d], wherein the gRNA is understood to be directed towards SARS-CoV-2.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
B. Claims 1, 4, 6, 71, 78 and 80 are newly provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 36 of copending Application No. 17/541398 (herein “reference application”) in view of Cheng and NCBI2.
The instant rejection is newly recited and is necessitated by claim amendment.
Regarding instant claim 1, claim 36 of the reference application recites a method of detecting target nucleic acid in sample comprising contacting the sample with a Class 2 Type V CRISPR-Cas endonuclease comprising at least two RuvC motifs selected from a list of enumerated SEQ ID NOs, and a gRNA capable of hybridizing with a target sequence in the target nucleic acid.
The claims of the reference application do not recite the Class 2 Type V endonuclease comprises at least three of the RuvC domains listed in part (a)(ii) of instant claim 1.
Cheng discusses novel CRISPR RNA targeting systems [title], and describes systems for the manipulation of nucleic acids in a targeted fashion using non-naturally occurring engineered CRISPR systems and components [abstract].
Regarding instant claims 1 and 6 and the limitation of a Class 2 CRISPR-Cas endonuclease, Cheng discloses a system comprising an RNA guide capable of hybridizing to a target nucleic acid and a non-naturally occurring CRISPR-associated (Cas) protein capable of binding to the RNA guide [para 0010], wherein the Cas protein is a Class 2 CRISPR-Cas protein selected from the group consisting of a Type VI, Type V and Type II Cas protein [para 0017]. The gRNA recited in the claim is understood to be a guide RNA, and as the Cas protein is non-naturally occurring, it is understood that the Cas and the gRNA do not naturally occur together.
NCBI2 discloses a Type V Cas protein Cpf1 from the bacterium Candidatus Moraniibacteriota that has a sequence sharing 100% identity with SEQ ID NOs: 75-77 [see Appendices D, E and F].
In view of Cheng and NCBI2, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the reference application by using the system of Cheng and the endonuclease of NCBI2 to arrive at the claimed invention, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the system of Cheng and the endonuclease and gRNA of the reference application are both systems comprising a Cas endonuclease and a gRNA, and as such both are capable of being incorporated in the method as disclosed by the reference application. Thus it would have been obvious to one of ordinary skill in the art to replace the system of the reference application with the system of Cheng, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both the reference application and Cheng describe systems comprising a Cas endonuclease and gRNA.
One of ordinary skill in the art would have recognized that the Type V Cas protein of Cheng and the endonuclease of NCBI2 are both Type V Cas proteins, and as such one would have predicted that both are capable of being incorporated into such a system as described by Cheng and the reference application. Thus it would have been obvious to one of ordinary skill in the art to replace the Type V Cas protein of Cheng with the Type V Cas protein of NCBI2, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both Cheng and NCBI2 relate to Type V Cas proteins.
Regarding instant claim 4, Cheng discloses a vector which includes multiple nucleic acids, each encoding a component of a Cas system described herein [para 0210], wherein the gRNA is considered a component of the Cas system as described above, and the encoding of a gRNA on a single nucleic acid encompasses a single-molecule gRNA as recited in the claims.
Regarding instant claim 71, Cheng discloses the incubation of effectors, corresponding to the Cas protein, with pre-crRNAs, corresponding to gRNAs, for a cleavage assay in a buffer of 20 mM Tris, pH 8.0 held at 37 °C for 10 minutes [para 0365]. As the instant specification does not define a stabilizing buffer, the 20 mM Tris buffer of Cheng is considered to correspond to a stabilizing buffer, and therefore the combination of Cas, gRNA and buffer as disclosed by Cheng is considered to correspond to the composition recited in the claim.
Regarding instant claims 78 and 80, in light of the combined system of Cheng and NCBI2 as described above, it would have been obvious for one of skill in the art to combine each of the components disclosed in the rejection of claim 1 into a kit for convenience.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 79 and 81-82 are newly provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 36 of copending Application No. 17/541398 in view of Cheng and NCBI2 as applied to claims 1, 4, 6, 71, 78 and 80 above, and further in view of Broughton.
The instant rejection is newly recited and is necessitated by claim amendment.
The claims of the reference application and the disclosures of Cheng and NCBI2 as applied to claims 1, 4, 6, 71, 78 and 80 are described above. The claims of the reference application do not recite lyophilized components.
Broughton discusses CRISPR-Cas12-based detection of SARS-CoV-2 [title], and describes CRISPR-based lateral flow assays for that are rapid, accurate, and easy-to-implement for the detection of SARS-CoV-2 from respiratory swab RNA extracts [abstract].
Regarding instant claims 79 and 81, Broughton discloses the use of a system comprising CRISPR-Cas12, gRNA and a target RNA derived from nasopharyngeal swabs to detect the presence of SARS-CoV-2 [Figure 1d], and discloses that the lyophilization of reagents from the system could enable point-of-care testing outside of the clinical diagnostic laboratory, such as airports, local emergency departments and clinics, and other locations [p 874, col 1, final paragraph].
In view of Broughton, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined system of the reference application, Cheng and NCBI2 by lyophilizing the components, as disclosed by Broughton, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined system of the reference application, Cheng and NCBI2, because Broughton discloses that systems for rapid, accurate, and easy-to-implement detection of SARS-CoV-2 from RNA extracts could be improved and applied to point-of-care diagnostics by lyophilizing the system components. One of ordinary skill in the art would have had a reasonable expectation of success because Cheng and Broughton relate to systems comprising CRISPR-Cas proteins and gRNAs.
Regarding instant claim 82, Broughton discloses the system comprising CRISPR-Cas12, gRNA and a target RNA derived from nasopharyngeal swabs to detect the presence of SARS-CoV-2 in the presence of a labeled reporter [Figure 1d], wherein the gRNA is understood to be directed towards SARS-CoV-2.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Allowable Subject Matter
The closest prior art of record to claims 84-89 is considered to be NCBI Accession No. WP_003034647.1 (2 pages, 2019; cited on the Form PTO-892 mailed 02/24/2025, herein NCBI1), which discloses a Type V CRISPR-associated protein Cas12a/Cpf1 from Francisella tularensis [title] that shares 46.1% sequence identity with SEQ ID NO: 1 [see Appendix G].
The teachings of NCBI1 alone or in combination with the other prior art of record do not teach or suggest:
an engineered system comprising (a) a Class 2 CRISPR-Cas endonuclease or a nucleic acid encoding the endonuclease; and (b) a gRNA or a nucleic acid encoding the gRNA, wherein the gRNA and the Class 2 CRISPR-Cas endonuclease do not naturally occur together, wherein the gRNA is capable of hybridizing to a target sequence in a target DNA or RNA, and the gRNA is capable of forming a complex with the Class 2 CRISPR-Cas endonuclease, and wherein the Class 2 CRISPR-Cas endonuclease comprises SEQ ID NOs: 1-7 or 20, or 90% sequence identity thereto as recited in claim 84, or
an engineered system comprising (a) a Class 2 CRISPR-Cas endonuclease or a nucleic acid encoding the endonuclease; and (b) a gRNA or a nucleic acid encoding the gRNA, wherein the gRNA and the Class 2 CRISPR-Cas endonuclease do not naturally occur together, wherein the gRNA is capable of hybridizing to a target sequence in a target DNA or RNA, and the gRNA is capable of forming a complex with the Class 2 CRISPR-Cas endonuclease, and wherein the Class 2 CRISPR-Cas endonuclease comprises SEQ ID NOs: 1-7 or 20 as recited in claim 85.
Therefore claims 84-89 are allowable over the prior art of record.
Examiner Comment
The closest prior art of record to the limitation of “the Class 2 Type V CRISPR-Cas endonuclease comprises any one of SEQ ID NOs: 1-7 or 20, or a sequence comprising at least 90% sequence identity thereto” in claim 10 is considered to be NCBI Accession No. WP_003034647.1 (2 pages, 2019; cited on the Form PTO-892 mailed 02/24/2025, herein NCBI1), which discloses a Type V CRISPR-associated protein Cas12a/Cpf1 from Francisella tularensis [title] that shares 46.1% sequence identity with SEQ ID NO: 1 [see Appendix G].
The teachings of NCBI1 alone or in combination with the other prior art of record do not teach or suggest the limitation of “the Class 2 Type V CRISPR-Cas endonuclease comprises any one of SEQ ID NOs: 1-7 or 20, or a sequence comprising at least 90% sequence identity thereto” as recited in claim 10. Therefore this limitation in claim 10 is considered to be free of the prior art of record.
Conclusion
Status of the Application:
Claims 1-19, 62-69, 71, 74-82 and 84-89 are pending.
Claims 2-3, 5, 7-9, 11-19, 62-69 and 74-77 are withdrawn.
Claims 1, 4, 6, 71 and 78-82 are rejected.
Claim 10 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 84-89 are in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH SPANGLER whose telephone number is (571)270-0314. The examiner can normally be reached M-F 7:30 am - 4:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached at (571) 272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656
APPENDIX A
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231
626
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Greyscale
Sequence alignment of SEQ ID NO: 1 with SEQ ID NO: 8.
APPENDIX B
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238
640
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Greyscale
Sequence alignment of SEQ ID NO: 1 with SEQ ID NO: 16.
APPENDIX C
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235
637
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Greyscale
Sequence alignment of SEQ ID NO: 8 with SEQ ID NO: 16.
APPENDIX D
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142
675
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Greyscale
Sequence alignment of SEQ ID NO: 75 with NCBI Accession No. NCU42495.1 (reference NCBI2).
APPENDIX E
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164
642
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Sequence alignment of SEQ ID NO: 76 with NCBI Accession No. NCU42495.1 (reference NCBI2).
APPENDIX F
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154
648
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Sequence alignment of SEQ ID NO: 77 with NCBI Accession No. NCU42495.1 (reference NCBI2).
APPENDIX G
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399
645
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Greyscale
Sequence alignment of SEQ ID NO: 1 with NCBI Accession No. WP_00303467.1 (reference NCBI1).
Prosecution Insights