DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 02 January 2026 have been entered. Claims 1-4, 9-13, 15-22, and 24-26 were previously pending in the application. Claims 1-4, 9-13, 15-22, and 24-26 are currently pending in the application. Claims 1, 9, 17, 19, 21 are independent claims.
The election of Group I, drawn to a synthetic composition, along with Examiner’s rejoinder of Group II, drawn to a construct comprising a polynucleotide encoding a Cas protein, remains in effect in the instant application. The following election of species remains in effect in the instant application:
Synthetic composition: synthetic composition of claims 1 and 9;
Amino acid sequence from claim 1 and claim 9: SEQ ID NO: 14;
Type of heterologous polynucleotide from claim 4: donor DNA molecule;
Type of eukaryotic cell from claim 13: animal cell;
Claims 19-22, and 24-26 remain withdrawn from consideration as being directed to a nonelected invention, there being no allowable generic or linking claim. Claims 15-16 remain withdrawn from consideration as being directed to a nonelected species, there being no allowable generic or linking claim.
Claims 1-4, 9-13, and 17-18 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US21/17593, filed 11 February 2021, which claims priority to 62/980,750, filed 24 February 2020 and 63/030,964, filed 28 May 2020.
Thus, the earliest possible priority for the instant application is 24 February 2020.
Information Disclosure Statement
The information disclosure statement filed 14 January 2026 has been considered by the Examiner. Examiner notes the filing of IDS Size Fee assertions for the IDS filed 14 January 2026, as required under 37 CFR 1.98, indicating that no IDS size fee is required under 37 CFR 1.17(v) at this time.
37 CFR 1.821-1.825
Applicant’s amendments to the specification inserting SEQ ID NOs into Table 1B has not brought the application into compliance with the requirements of 37 CFR 1.821 through 1.825, as discussed below.
This application still contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2), see for example Table 1B on pages 136-137 of the instant specification. However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth below and on the Notice to Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/Or Amino Acid Sequence Disclosures which is attached to the prior communication. Specifically, Table 1B on pages 136-137 of the instant specification disclose amino acid and/or nucleotide sequences but do not include sequence identifiers. Applicant amended the specification to recite SEQ ID NOs for the Cas-beta proteins referenced in columns 2-4. Column 1 is a list of amino acid sequence motifs written out as specific sequences, many of which have 4 or more specifically defined residues (i.e., any recited residue other than those represented by an “x”). Columns 2-4 provide amino acid positions within the Cas-beta sequences where each of the recited motifs begin. However, no specific SEQ ID NOs are provided for the individual motif sequences themselves. Recitation of references to starting positions within longer SEQ ID NOs is not sufficient to remedy the lack of SEQ ID NOs for the sequences recited with 4 or more specifically defined residues within Table 1. Applicant must provide individual SEQ ID NOs for each recited sequence motif which comprises at least 4 specifically defined amino acid residues.
If the unidentified sequences of Table 1B on pages 136-137 of the instant specification are included in the submitted sequence listing, Applicant must amend the specification to comply with the sequence identification requirements. Alternatively, if the unidentified sequences of Table 1B on pages 136-137 of the instant specification are not included in the presently submitted sequence listing, Applicant must submit an updated sequence listing in compliance with 37 CFR 1.821(c)-(d) and 37 CFR 1.825(b). See also the attached Notice to Comply.
APPLICANT IS GIVEN A THREE MONTH EXTENDABLE PERIOD WITHIN WHICH TO COMPLY WITH THE SEQUENCE RULES, 37 CFR 1.821-1.825. Failure to comply with these requirements will result in ABANDONMENT of this application under 37 CFR 1.821 (g). Extension of time may be obtained by filing a petition accompanied by the extension fee under the provisions of 37 CFR 1.136. In no case may an applicant extend the period for response beyond the six month statutory period. Applicant is requested to return a copy of the attached Notice to Comply with the response.
Specification
The objection to the specification of the disclosure for the Brief Description of the Drawings not including a description of each panel in that Figure 4 does not include individual descriptions of panels A and B and Figures 25 and 26 are not individually described; and for recitation of trade names and/or marks used in commerce without the accompanying symbol and/or generic terminology, is maintained. Applicant's amendments to the specification and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended the specification to correct issues related to the Brief Description of the Drawings and to include the appropriate symbol for the recitation of “TransIT®-2020”. Applicant additionally argues that “Golden Gate” and “Gibson” are not trade names but are terms used in the art to designate methods for the assembly of multiple component vector sequences. While it is agreed that “Golden Gate” is a generic term designating a method for the assembly of multiple component vector sequences, it is not agreed that “Gibson” is not a trade name.
NEB teaches that “Gibson Assembly® is a registered trademark of Synthetic Genomics, Inc.” [NEB 2012, Gibson Assembly® Master Mix, retrieved on 19 March 2026 from: <www.neb.com/en-us/about-neb/news-and-press-releases/gibson-assembly-master-mix?srsltid=AfmBOooea6OCEvQHA-7lYpjbHq29ax8z0CT5JngQiDcLuovyV_aTvObb>, published online 07 February 2012, page 1 line 28].
Claim Rejections - 35 USC § 112(b)
The rejection of amended and previously presented claims 1-4, 9-13, and 17-18 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for multiple issues of indefiniteness is withdrawn over amended independent claim 1-4, 9-13, and 18 and maintained over amended claim 17. Applicant's amendments to the specification and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant’s amendments to claims 1, 2, 4, and 9 have adequately addressed the issues of indefiniteness for recitations specific to those claims.
However, amended claim 17 was amended to recite “wherein the Cas protein shares at least 90% sequence identity to the whole length of a sequence selected from the groups consisting of SEQIDs: 13, 14, 15, and 57” in lines 2-4. The issue of indefiniteness with the claim language, as described in the prior action, hinges on the term “shares” which implies a giving-receiving relationship or an overlapping relationship “with” something else. As such, it is unclear in what way the Cas protein is “sharing” a sequence identity “to” a sequence selected from the recited list. Therefore, the metes and bounds of the claim still cannot be determined.
*The following new rejection is necessitated by amendments to the claims.
Amended and previously presented claims 1-4, 10-13, and 18 are newly rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Dependent claims 2-4, 10-13, and 18 are included in this rejection due to their dependence on amended independent claim 1.
Applicant amended independent claim 1 to recite, “a Cas protein comprising an amino acid sequence that is at least 90% identical over the whole length of a sequence selected from the group consisting of SEQID NOs: 13, 14, 15, and 57” in lines 2-4, which is indefinite because Applicant does not indicate to what the sequence is at least 90% identical over the whole the length of the sequence selected from the group consisting of the recited sequences.
As such, the metes and bounds of the claim cannot be determined.
In the interest of compact prosecution, amended independent claim 1 has been interpreted to encompass a Cas protein comprising an amino acid sequence that is at least 90% identical to the whole length of a sequence selected from the group consisting of SEQID NOs: 13, 14, 15, and 57.
Claim Rejections - 35 USC § 112(a)- Written Description
The rejection of amended and previously presented claims 1-4, 9-13, and 18 under 35 U.S.C. 112(a) for failing to comply with the written description requirement for the issue of recitation of “a functional fragment” is withdrawn in view of Applicant’s amendments to the claims such that the phrase “or a functional fragment thereof” and “or the functional fragment thereof” have been removed. However, the rejection of amended and previously presented claims 1-4, 9-13, and 18 under 35 U.S.C. 112(a) for failing to comply with the written description requirement for the issue of recitation of “an amino acid sequence that is at least 90% identical” is maintained and newly applied to amended independent claim 17. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended independent claim 1 to recite, “an amino acid sequence that is at least 90% identical over the whole length of a sequence selected from the group consisting of SEQID Nos: 13, 14, 15, and 57” in lines 2-4”. Similarly, independent claim 9 was amended to recite, “an amino acid sequence that is at least 90% identical to the whole length of a sequence selected from the group consisting of SEQID Nos: 13, 14, 15, and 57” in lines 2-4, and independent claim 17 was amended to recite, “wherein the Cas protein shares at least 90% sequence identity to the whole length of a sequence selected from the groups consisting of SEQID NOs: 13, 14, 15, and 57” in liens 2-4.
The specification teaches that the amino acid sequence of elected SEQ ID NO: 14 is an amino acid sequence of a Cas beta2 protein from Armatimonadetes bacterium [Table 1A]. The specification also teaches that the nucleic acid sequence of SEQ ID NO: 11 is a polynucleotide sequence encoding Cas beta2 [Table 1A]. The specification additionally teaches generally, as claimed, that the amino acid sequence of the Cas protein has at least 90% identity with at least 825 contiguous amino acids of SEQ ID NO: 14 [0039, 0044, 0074, 0336]. The specification further teaches that “a Cas-beta endonuclease is further defined as an RNA-guided double-strand DNA cleavage protein that shares… at least 90%... sequence identity with… at least 500 contiguous amino acids of any of SEQ ID Nos: 13, 14, 15, or 57, or a functional fragment thereof, or functional variant thereof that retains at least partial activity” [0413]. The specification teaches that SEQ ID NOs: 13, 15, and 57 encode alternative Cas beta proteins (beta1, beta3, and beta4, respectively), which have 59.3%, 39.8%, and 84.7% sequence identity with the amino acid sequence of Cas beta2 according the SEQ ID NO: 14.
The specification does not teach any specific sequence variants of the Cas beta2 amino acid sequence, and no sequence other than SEQ ID NO: 14 itself which has at least 90% sequence identity with Cas beta2. The examples disclose two alternative polynucleotide sequences encoding each of the Cas beta genes, including one that was codon optimized for E. coli expression and one that was codon optimized for Zea mays expression [0683, 0705]. The specification does not teach that such codon optimization resulted in any alteration of the amino acid sequence produced therefrom.
The specification teaches a table of amino acid motifs which are conserved among the 4 Cas beta proteins [Table 1B]; however, the specification does not teach whether or not these conserved domains are required to maintain Cas beta identity and/or functionality nor to what extent they could be mutated while still preserving Cas beta identity and/or functionality. The specification further teaches that the Cas beta proteins comprise two bridge-helix-like domains, a helix-turn-helix motif, and a split RuvC domain comprised of a RuvC-l domain, a RuvC-II domain, and a RuvC-III domain [0009, 0107, Figure 2, 7]. The specification teaches that the presence of the two bridge-helix-like motifs, the tri-split RuvC domain, and a helix-turn-helix motif supports the classification of the proteins as distinct type V nucleases [0675]; however, the specification does not teach what extent these domains could be mutated while still preserving Cas beta identity and/or functionality.
The specification does not disclose which variants of the sequence of SEQ ID NO: 14 would encode an amino acid sequence which would retain the essential functional properties of the Cas beta2 protein nor which variants would disrupt such functions. The specification additionally does not disclose any % identity which would retain the necessary identity and functionality in the Cas beta2 protein. As such, the specification fails to provide any specific guidance as to which up to 10% of the sequence of SEQ ID NO: 14 could be changed to allow for a functional Cas beta2 polypeptide of the instant invention. Therefore, the description is not sufficient to adequately describe and demonstrate possession of any variants of SEQ ID NO: 14, and particularly variants of SEQ ID NO: 14 which comprise up to 10% sequence differences.
The following guidance provided in MPEP 2163 is informative. 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. 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 (see i)(A) above), reduction to drawings (see i)(B) above), 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 i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. In other words, describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See for example Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product; however, the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described."). Furthermore, written description issues may also arise if the knowledge and level of skill in the art would not have permitted the ordinary artisan to immediately envisage the claimed product arising from the disclosed process. See, e.g., Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996). While it has been held that what is conventional or well known to one of ordinary skill in the art need not be disclosed in detail, for inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession.
The specification, as discussed above in detail, provides guidance only for a single amino acid sequence encoded by only 3 alternative polynucleotide sequences (e.g., the native Armatimonadetes bacterial sequence, the E. coli plant codon optimized sequence, and the Zea mays codon optimized sequence) which each appear to encode the amino acid sequence as set forth in SEQ ID NO: 14, without providing sufficient detailed descriptions of the various variants of a polypeptide with sufficient structural and functional properties of a Cas beta2 protein. As such, the specification fails to provide a description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), 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 any of the claimed genus of variants of SEQ ID NO: 14 comprising up to 10% differences in amino acid sequence or variant polynucleotides encoding a polypeptide comprising up to 10% differences in amino acid sequence compared to the sequence of SEQ ID NO: 14.
Although the specification discussed the presence of some domains and conserved motifs within the Cas beta2 protein, the extent to which theses structures are essential and/or the extent to which these structures tolerate variation has not been disclosed. There is no disclosure of what amino acids are in the active site, the binding pocket, or the hydrophobic core of the protein. There is no structure/function relationship taught for SEQ ID NO: 14 beyond the general identification of domain regions. The specification provides only a single amino acid sequence for Cas beta2. The scope of the claims as written encompass any variation in the amino acid sequence, or within the polynucleotide sequence encoding the Cas beta2 amino acid sequence, which include variations which change the amino acid sequence at any position to any other amino acid. As such, the claims as written encompass variations which may change the structure sufficiently to adversely affect the function and/or alter the function of the Cas beta2 protein.
Kleinstiver teaches that a single amino acid alteration in a Cas nuclease protein can abolish PAM-specific activity, such as the R1333Q or R1335Q mutation in a Cas9 protein which severely reduced Cas9 activity at canonical NGG PAMs without providing altered specificity for the expected NAG, NAA, and/or NGA PAMs [Kleinstiver et al. 2015, Nature, 526, 481-485, column 1 ¶ 2-column 2 ¶ 1, Figure 1a]. Kleinstiver teaches additional mutations that likewise severely reduce or abolish NGG-targeted activity without providing altered PAM specificity at the tested PAM sequences [Figure 1h]. Accordingly, given the teaching of Kleinstiver that single amino acid changes can severely reduce the on-target PAM-directed activity of a Cas nuclease protein, without providing an accompanying desirable alteration of specificity, the scope of the claims encompass variants of a Cas nuclease protein which would result in non- or dys-functional Cas nuclease proteins. As such, variations in the Cas protein sequence up to 10% non-identities relative to the sequence of SEQ ID NO: 14, such that a functional Cas protein is still encoded, were neither conventional nor predictable at the time of filing, and the knowledge and level of skill in the art at the time of filing would not have permitted the ordinary artisan to immediately envisage all the variations of the sequence of SEQ ID NO: 14, up to 10% variation, which would still produce a functional Cas beta2 protein from the generic description provided by the specification. In view of these considerations, an ordinarily skilled artisan would not have viewed the teachings of the specification as sufficient to show that the applicant was in possession of the claimed invention.
Applicant has provided no arguments beyond indicating that the claims have been amended to delete all references to “functional fragments” or “fragments” in response to the written description rejection under 35 U.S.C. 112(a) in the prior action. As indicated above, Applicant’s amendment has overcome the issue related specifically to recitation of “functional fragments” and “fragments”. However, Applicant has not addressed the issue of a lack of written description for recitation of a Cas protein “at least 90% identical” to the amino acid sequence of SEQ ID NO: 14.
Therefore, Applicant’s arguments do not overcome the written description rejection under 35 U.S.C. 112(a).
Claim Rejections - 35 USC § 103
The rejection of amended and previously presented claims 1-4, 9-13, and 17-18 under 35 U.S.C. 103 as being unpatentable over NCBI [2018, MAG: Armatimonadota bacterium isolate ATM2 J3_scaffold_278, whole genome shotgun sequence, retrieved on 27 August 2025 from the Internet: <https://www.ncbi.nlm.nih.gov/nuccore/QEUN01000014 >, latest sequence update on 19 September 2018]; in view of Koonin & Makarova [2019, Philosophical Transactions of the Royal Society B, 374, 20180087, 1-16]; Shmakov et al. [2017, Nature Reviews Microbiology, 15(3), 169-182]; UniProt [2018, A0A399X2Y8, retrieved on 25 August 2025 from the Internet:<https://www.uniprot.org/uniprotkb/A0A399X2Y8/entry>, last sequence update 05 December 2018]; Burstein et al. [2017, Nature Letter, 542, 237-241]; Foss et al. [2019, Transfusion, 59, 1389-1399]; Moon et al. [2019, Experimental & Molecular Medicine, 51(130), 1-11]; Gupta & Musunuru [2014, Journal of Clinical Investigation, 124(10), 4154-4161]; Jung et al. [2017, Cell, 170, 35-47]; and Maggio et al. [2014, Scientific Reports, 4, 5105, 1-11], is withdrawn over amended and previously presented claims 1-4, 9-13, and 18 and maintained over amended independent claim 17 in view of Applicant’s claims which now recite “a target double-stranded DNA polynucleotide that comprises a PAM sequence CCY” in lines 6-7 and “wherein the Cas protein recognizes the PAM sequence on the target double-stranded DNA polynucleotide” in lines 10-11. Note that although PAM recognition is an inherent property for a Cas protein having the polypeptide sequence according to SEQ ID NO: 14, recitation of the specific PAM consensus sequence for targeting limits the structure of both the target double-stranded DNA polynucleotide and the structure of the guide polynucleotide in that the guide polynucleotide must target sequences within the target polynucleotide adjacent to the recited PAM sequence. Regarding amended claim 17, Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended independent claim 17 to recite “wherein the Cas protein shares at least 90% sequence identity to the whole length of a sequence selected from the group consisting of SEQID Nos: 13, 14, 15, and 57” in lines 2-4. However, the rejection of record addressed this new limitation in that NCBI was cited for teaching a polypeptide sequence (locus DCC46_10025, protein ID RIJ98969.1) from an Armatimonadota bacterium which is 857 amino acids and is 98.9% identical to the sequence of SEQ ID NO: 14 of the instant application [see prior office action page 13 for a sequence alignment] [page 11 line 83- page 12 line 20].
Therefore, the new limitation that the at least 90% identity be over the whole length of the sequence according to one of the recited SEQ ID Nos does not overcome a finding of obviousness over NCBI, Koonin, Shmakov, UniProt, Burstein, Foss, Moon, Gupta, Jung, and Maggio under 35 USC 103.
Applicant argues that:
none of NCBI, Koonin, nor any of the other cited references teach or suggest the CCY PAM recognition and binding recited in the pending claims;
Shmakov supports the non-obviousness of the presently claimed Cas proteins by teaching that additional variants that remain to be found will be either extremely rare or confined to bacterial phyla that are currently unknown or poorly sampled;
the teaching of UniProt that the protein A0A399X2Y8 is a transposase is not prior art; and
an obvious to try rejection inappropriately fails to articulate a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem and a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
However, this is not agreed.
In response to Applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). One cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Specifically, regarding Applicant’s argument 1), amended independent claim 17 has not been amended to recite the CCY PAM recognition, or any other PAM recognition, and so this argument is moot with respect to amended independent claim 17.
Regarding Applicant’s argument 2), Schmakov was cited for teaching the motivation for discovering novel class 2 effector molecules as alternative tools for CRISPR-mediated editing to enhance and expand the capabilities of the genome editing toolbox for research, biotechnology, and medicine [page 11 ¶ 3-4]. Shmakov was also cited for teaching a computational pipeline to systematically identify novel class 2 CRISPR-cas loci in genomic an metagenomic sequences, such that by using Cas1, which is the most highly conserved Cas protein, as a seed, they identified previously unknown class 2 subtypes [page 2 ¶ 2, BOX 1]. Additionally, to identify Cas effector proteins which may rely on Cas1 protein expressed from a distinct locus, they alternatively used the CRISPR array itself as a seed to identify more novel class 2 subtypes [page 2 ¶ 3- page 3 ¶ 1]. Shmakov further teaches that after the cas1 genes or CRISPR array were detected, their respective ‘neighborhoods’ were examined for the presence of other cas genes by searching within ~400 previously developed profiles for Cas proteins ad applying the criteria for the classification of the CRISPR-cas loci [Box 1]. Shmakov also teaches that putative Cas effector proteins were screened for known protein domains using sensitive profile-based methods, such as HHpred, to identify proteins comprising nuclease domains to identify novel Cas effector proteins [Box 1]. Therefore, Shmakov teaches motivations for identifying Cas effector proteins from among known sequences and additionally provides teachings for how to carry out the methods to identify them.
Any teaching of Shmakov that additional variants that remain to be found will be either extremely rare or confined to bacterial phyla that are currently unknown or poorly sampled is not a teaching of non-obviousness for applying their teachings to the discovery of additional Cas effector proteins, but merely an indication that they could have missed some Cas effector proteins based on poor representation within the database which they used. As such, Shmakov recognizes that additional Cas effector proteins may still remain unidentified, particularly in bacterial species which had been poorly sample and/or characterized when they did their analysis. Therefore, Shmakov does not teach the non-obviousness of identifying a previously known sequences as a Cas effector protein.
Regarding Applicant’s argument 3), the function of a protein is inherent to the amino acid sequence of the protein. Although the specific teaching of the classification of UniProt A0A399X2Y8 as a transposase was not made prior to the effective filing date of the instant application, such teaching is specifically addressing an inherent feature of a protein having the sequence according to SEQ ID NO: 14. Reliance upon inherency is not improper even though rejection is based on Section 103 instead of Section 102. In re Skoner, et al. 186 USPQ 80 (CCPA). As stated in MPEP 2112, The express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 or 103. "The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness." In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995). See also In re Grasselli, 713 F.2d 731,739, 218 USPQ 769, 775 (Fed. Cir. 1983). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003). Therefore, the post-filing disclosure of UniProt designating the previously known (prior to filing) protein sequence as a transposase is a teaching of an inherent property of the protein sequence, and as such is an acceptable citation for supporting a finding of obviousness under 35 USC 103.
Regarding Applicant’s argument 4), note that the rationale presented in the prior action was not an “obvious to try” rationale. As such, “obvious to try” basis is not needed. The rationale presented in the prior action was based on teachings, suggestions, and motivations in the prior art that would have led one of ordinary skill to modify the prior art reference and/or to combine prior art reference teachings to arrive at the claimed invention. The teachings of NCBI, Shmakov, UniProt, and Koonin were relied upon to teach the motivation for testing the sequence of NCBI protein ID RIJ98969.1 for Cas endonuclease activity in an attempt to identify and characterize novel class 2 Cas effector molecules to enhance the application of CRISPR systems to genome engineering to provide additional tools for research biotechnology, and/or medicine. Such a test itself would require the combination of elements recited in independent claim 17, including expressing the polynucleotide sequence encoding NCBI protein ID RIJ98969.1 by operably linking it with a heterologous expression element in a construct. Given the strong motivation taught by the prior art, including the intense interest in identifying additional Cas effector proteins from less-characterized microbial sources, it would have been obvious to an ordinarily skilled artisan to build a polynucleotide construct comprising a polynucleotide encoding a putative Cas protein, and to link it with a heterologous expression element, to thereby assess the functionality of the protein with a reasonable expectation of success.
Therefore, Applicant’s arguments do not overcome a finding of obviousness over NCBI, Koonin, Shmakov, UniProt, Burstein, Foss, Moon, Gupta, Jung, and Maggio under 35 USC 103, and the rejection of amended independent claim 17 is maintained.
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 Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634