DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Claims 64-76 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07 October 2025.
Claim Status
Claims 1-56 were previously canceled, claim 58 was newly canceled, claims 57, 59-60, and 63 are currently amended, claims 64-76 are withdrawn, and 57 and 59-63 have been considered on their merits.
Withdrawn Objections/Rejections
The claim objection directed to the labeling of claim 69 has been withdrawn due to the amendments to the claims.
The claim rejections under 35 U.S.C. 112(b) have been withdrawn due to the amendment to the claims
The claim rejections under 35 U.S.C. 101 have been withdrawn due to the amendments to the claims. Specifically, the amendment requiring at least 90% identity to SEQ ID NO: 1, as the closest prior art points to the sequence of the natural product which is 87% identical.
The claim rejections under 35 U.S.C. 112(a) have been withdrawn due to the amendments to the claims. However, a new rejection has been set forth below.
The claim rejections under 35 U.S.C. 102 have been withdrawn due to the amendments to the claims. SEQ ID NO: 1 appears to be free of the prior art.
The claim rejections under 35 U.S.C. 103 have been withdrawn due to the amendments to the claims.
Drawings
The drawings are not of sufficient quality to permit examination. Accordingly, replacement drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to this Office action. The replacement sheet(s) should be labeled “Replacement Sheet” in the page header (as per 37 CFR 1.84(c)) so as not to obstruct any portion of the drawing figures. If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action.
Applicant is given a shortened statutory period of TWO (2) MONTHS to submit new drawings in compliance with 37 CFR 1.81. Extensions of time may be obtained under the provisions of 37 CFR 1.136(a) but in no case can any extension carry the date for reply to this letter beyond the maximum period of SIX MONTHS set by statute (35 U.S.C. 133). Failure to timely submit replacement drawing sheets will result in ABANDONMENT of the application.
The drawings are objected to under 37 CFR 1.83(a) because they fail to show details regarding the sequence information, at least Figures 4, 7, 11, 14, and 16, as described in the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112
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 57 and 59-63 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.
This is a new rejection, necessitated by applicants amendments to the claims. A response to applicant’s traversal follows the rejection below.
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.
Independent claim 57 encompasses a genus of endonuclease comprising a RuvC domain, wherein said endonuclease is derived from an uncultured microorganism, and wherein said endonuclease is a Class II, type V-K Cas effector having at least 90% sequence identity to SEQ ID NO: 1; and an engineered guide RNA, wherein said engineered guide RNA is configured to form a complex with said endonuclease and said guide RNA comprises a spacer sequence configured to hybridize to a target nucleic acid sequence, while the specification does not disclose such Class II, type V-K Cas effector having at least 90% sequence identity to SEQ ID NO: 1 that are functional. Additionally, the specification does not disclose which 10% of the amino acids of SEQ ID NO: 1 could be altered to maintain the ability to form a complex and be capable to hybridize to a target nucleic acid sequence.
Claims 59-61 encompass the guide RNA of claim 57, wherein said guide RNA comprises a sequence comprising at least 46-80 consecutive nucleotides having at least 80% or 90% identity to SEQ ID NO: 5 or wherein said guide RNA comprises a sequence having at least 80% or 90% sequence identity to SEQ ID NO: 5.
Claim 63 encompasses the PAM sequence, wherein said PAM sequence comprises 5’-nGTn-3’ or 5’-nGTt-3’.
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
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. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
Actual Reduction to Practice
Regarding claim 57, encompassing a genus of Class II, type V-K Cas effector comprising a RuvC domain and a guide RNA that is at least 90% identical to SEQ ID NO: 1 that is capable of forming a complex with said endonuclease and said guide RNA sequence configured to hybridize to a target nucleic acid sequence, while the specification discloses predicted RNA folding in Example 3, the specification does not provide sufficient written description to determine which 10% of the amino acids of SEQ ID NO: 1 could be altered to maintain the ability to form a complex and be capable to hybridize to a target nucleic acid sequence. Additionally, it appears the disclosed sequences were computationally derived, and were not tested for function.
Regarding claims 59-62, encompassing the sequence of the guide RNA, SEQ ID NO: 5 with limitations directed to the sequence having an 80 or 90% identity to said sequence and/or having 46-80 consecutive nucleotides in common. The specification does not provide sufficient written description to determine the critical sequential nucleotides nor which portion of the sequence could be modified and still maintain the ability to form a complex with the Type V-K Cas effector.
Regarding claim 63, encompassing the sequence for the PAM sequence, wherein said PAM sequence comprises 5’-nGTn-3’ or 5’-nGTt-3’, wherein the PAM sequences are for specific Cas effectors.
Accordingly, Applicant did not demonstrate the full a genus of endonuclease comprising a RuvC domain, wherein said endonuclease is derived from an uncultured microorganism, and wherein said endonuclease is a Class II, type V-K Cas effector having at least 90% sequence identity to SEQ ID NO: 1; and a guide RNA, wherein said engineered guide RNA is configured to form a complex with said endonuclease and said guide RNA comprises a spacer sequence configured to hybridize to a target nucleic acid sequence, nor did Applicant adequately set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention (e.g., rational approach to making such substitutions in amino acid sequence of Cas effector protein and corresponding RNA guides yet retain targeting function) that are sufficiently detailed to show that Applicant was in possession of the claimed genus of compositions.
Disclosure of Structure
The Applicant has provided a limited genus of compositions comprising Class II, type V-K Cas effector protein sequences in general, with just SEQ ID NO:1. Certainly, with the help of computer and recombinant expression system, a skilled artisan could make genus of compositions comprising an engineered polypeptide that is at least 90% identical to SEQ ID NO:1 and a genus of RNA guides. However, the prior art is silent with respect to an engineered polypeptide that is 90% identical to SEQ ID NO:1. Furthermore, neither the specification nor the art indicate a relationship between the structure of the claimed genus of compositions comprising an engineered polypeptide that is as low as 90% identical to SEQ ID NO:1 and the ability to make and use a functional engineered protein.
The prior art, Shmakov et al., (WO 2018/035250, of record), disclose a sequence for type V-U5 CRISPR effector protein which is 87.6% identical to instant SEQ ID NO: 1, see sequence results file us-18-188-231-1.rag, result 12. Type V-U5 Cas effector was later categorized as type V-K Cas effector protein. However, the art is silent to modifications that can be made in type V-K Cas effector proteins and guide RNAs that result in a functional ribonucleoprotein complex for targeting a target nucleic acid.
The breadth of the claims encompass a genus of compositions comprising a genus of Type V-K Cas effector proteins that is at least 90% identical to SEQ ID NO:1 and their corresponding RNA guides such that they are capable of targeting a target nucleic acid, yet the present specification provides no guidance nor description which modifications would result in a functional engineered Cas/RNA ribonucleoproteins, therefore the skilled artisan would not know what rational approach to take to make the genus of engineered proteins with any predictable outcome on function. Therefore, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of the claimed genus of engineered Type V-K Cas systems.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
State of the Art and Quantity of Experimentation
The method of making the claimed invention is not well established. Although the sequence data for certain bacteria that express Type V-K Cas systems was known in the state of the art, one of skill in the art would neither expect nor predict an appropriate function of the modified Type V-K Cas systems according to the claimed genus of compositions.
Specifically, there is no prior art for how to modify Type V-K Cas proteins or their corresponding RNA guides so as to maintain their function.
Shmakov et al., (WO 2018/035250, of record) teach some of the V-U systems might be involved in distinct regulatory roles, specifically the V-U5 variant which appears to encompass a catalytically inactive TnpB homolog, which suggests distinct functions for these putative type V loci (para. [0090]). Shmakov et al. teach although functional characterization of the Class 2 subtypes is not complete, even at this stage, remarkable functional diversity is apparent (para. [00104]). Shmakov et al. teach the V-U5 variant that encompasses an inactivated TnpB homolog is limited to Cyanobacteria, being perhaps involved in a unique regulatory pathway and the exclusion of Class 2 systems from archaea implies a major functional distinction between the two classes of CRISPR-Cas systems the nature of which remains enigmatic (para. [00108]). Shmakov et al. teach the C2c5 variant is a putative effector protein and contains replacements of the catalytic residues of the RuvC-like nuclease domain and lacks the Zn-finger, compared to the other V-U variants (para. [0017] and Fig. 3).
Applicant has claimed a genus of compositions comprising an engineered Type V-K Cas nuclease system that is at least 90% identical to SEQ ID NO:1, the specification has not set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention (e.g., structural studies through crystallography or molecular modeling) that are sufficiently detailed to show that Applicant was in possession of the claimed a genus of compositions comprising an engineered ribonucleoprotein that is functional. It is well known that there is limited protein tolerance to random amino acid changes (see Guo et al., PNAS, 2004, 101:9205, see https://www.pnas.org/doi/10.1073/pnas.0403255101), therefore the state of the art indicated that making the claimed genus of engineered Type V-K Cas systems was not well established with the claimed function for targeting a target nucleic acid, and would require undue experimentation, and one of skill in the art would neither expect nor predict a functional Type V-K Cas system according to the claimed a genus of compositions.
Conclusion
Therefore, the Examiner concludes that there is insufficient written description of the instantly claimed genus of endonuclease comprising a RuvC domain, wherein said endonuclease is derived from an uncultured microorganism, and wherein said endonuclease is a Class II, type V-K Cas effector having at least 90% sequence identity to SEQ ID NO: 1; and a guide RNA, wherein said engineered guide RNA is configured to form a complex with said endonuclease and said guide RNA comprises a spacer sequence configured to hybridize to a target nucleic acid sequence. Specifically, there is limited description of the structure-function relationship between the claimed genus of compositions, which 10% of the amino acids found in SEQ ID NO: 1 could be altered to maintain the ability to form a complex and their ability to produce a functional RNA and Cas ribonucleoprotein complex capable of targeting a nucleic acid, and the Examiner further concludes a skilled artisan would find the specification inadequately describes the claimed genus of compositions.
Response to Traversal
Applicant's arguments filed 18 February 2026 have been fully considered but they are not persuasive.
In section I of the remarks, applicant argues the specification provides clear evidence of reduction to practice of the claimed engineered nuclease system, pointing to Fig. 8, which shows a phylogenetic tree including the claimed MG64-1 sequence (SEQ ID NO: 1). This figure does not disclose any functional endonuclease sequences with less than 100% identity to SEQ ID NO: 1, nor does it point to any reduction to practice. This figure simply points out how MG64-1 is related to other Cas12k effector sequences.
Applicant continues to provide specification citations and figures which exemplify functionality of the disclosed nuclease system. However, no where in the specification discloses a functional example with a 90% identity to SEQ ID NO: 1. Therefore, the arguments are not persuasive regarding which 10% of SEQ ID NO: 1 could be altered and still maintain a functional nuclease system. These arguments do not support the claim for possession of the claimed invention.
Applicant identifies an example in Fig. 4A, however, this figure is undecipherable.
In section II of the remarks, applicant argues the specification provides a rational approach for sequence modification. Applicant states Fig. 9 provides a graphical representation of sequence conservation within the MG64 family. This does not provide a comparative roadmap for making rational substitutions because this represents a small portion of the sequence. One would need to show which 90% of the sequence would need to be conserved. Applicant also points to Fig. 1A, however, it is unclear how this figure indicates structural landmarks specific to MG64-1. It is unclear from the specification which 10% of SEQ ID NO: 1 could be altered to maintain a functional nuclease system.
Conclusion
No claims are 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 NICHOLAS A. HUMPHRIES whose telephone number is (703)756-5556. The examiner can normally be reached Monday - Friday, 7:30am - 4:30 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Schultz can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
Prosecution Insights