DETAILED CORRESPONDENCE
Application Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s amendment to the claims filed on 07/07/2026 in response to the Non-Final Rejection mailed on 04/07/2026 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
3. Claim 2 is cancelled.
4. New claims 28-30 are added.
5. Claims 1 and 3-30 are pending.
6. Claims 15-19 and 26-27 stand withdrawn pursuant to 37 CFR 1.142(b).
7. Applicant’s remarks filed on 07/07/2026 in response to the Non-Final Rejection mailed on 04/07/2026 have been fully considered and are deemed persuasive to overcome at least one of the rejections and/or objections as previously applied.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in the prior Office Action.
Information Disclosure Statement
8. The IDSs filed on 07/07/2026 and 07/28/2026 have been considered by the examiner and copies of the Form PTO/SB/08 are attached to the office action.
Claim Rejections - 35 USC § 112(b)
9. The rejection of claim 2 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of applicants’ amendment to the claims to cancel claim 2.
10. The rejections of claims 1, 3-14 and 20-25 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is maintained for the reasons of record and the reasons set forth below. The rejection has been modified in order to address applicants’ amendment to the claims and to incorporate new claims 28-30.
Claims 1, 3-14, 20-25 and 28-30 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1, 3-14, 20-25 and 28-30, the recitation of “wherein the first polypeptide is 700 to 850 amino acid residues….the second polypeptide is 150-350 amino acid residues…wherein the Type V CRISPR-Cas effector protein is a Cas12i protein” is indefinite because without a sequence or structure of a Cas12i protein to compare it is unclear what the metes and bounds of the structure is intended to encompass by the claim.
Further regarding claims 6 and 20, the recitation of “two consecutive amino acid residues selected from amino acid residues 790 to 800 of the Type V CRISPR-Cas effector protein” is indefinite because without a structure or sequence to compare it is unclear what residues 790 to 800 of the Type V CRISPR-Cas effector is referring to. The metes and bounds upon which patent protection is sought cannot be ascertained from the claims.
Further regarding claim 29, the term "optimally" is a relative term which renders the claim indefinite. The term "optimially" is a term of degree and the examiner has reviewed the specification and can find no examples or teachings that can be used for ascertaining the variance intended by the recited term of degree. Moreover, there is nothing in the specification or prior art of record to indicate that one of ordinary skill in the art could have ascertain the scope of the recited degree. It is suggested that applicant clarify the meaning of the claims. See Supplementary Examination Guidelines for Determining Compliance with 35 U.S.C. §112 and for Treatment of Related Issues in Patent Applications, 76 FR 7162 (Feb. 9, 2011), page 7165.
RESPONSE TO REMARKS: Beginning on p. 8 of applicants’ remarks, applicants contend that as amended, claim 1 recites a range for the length of the first polypeptide and second polypeptide of a Cas12i protein, and that one of ordinary skill in the art would recognize what is meant by the term Cas12i proteins given that they are known in the art.
This argument is found to be not persuasive in view of the modified rejection set forth above.
Claim Rejections - 35 USC § 112(a)
11. The written description rejection of claim 2 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of applicants’ amendment to the claims to cancel claim 2.
12. The scope of enablement rejection of claim 2 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of applicants’ amendment to the claims to cancel claim 2.
13. The written description rejection of claims 1, 3-14 and 20-25 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is maintained for the reasons of record and the reasons set forth below. The rejection has been modified in order to address applicants’ amendments to the claims and to incorporate new claims 28-30.
Claims 1, 3-14, 20-25 and 28-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.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.
As amended, claims 1, 3-14, and 28-30 are drawn to an engineered protein, complexes, and compositions comprising, from the N- to C-terminus of the engineered protein, a first polypeptide of a Type V CRISPR-Cas effector protein, an HNH domain, and a second polypeptide of the Type V CRISPR-Cas effector protein, wherein the first polypeptide is 700 to 850 amino acid residues of the Type V CRISPR-Cas effector protein and the second polypeptide is 150 to 350 amino acid residues of the Type V CRISPR-Cas effector protein, wherein the type V CRISPR-Cas effector protein is a Cas12i protein, and wherein the engineered protein is a nuclease. The structure of the engineered protein is unlimited.
As amended, claims 20-25 drawn to an engineered protein and compositions comprising an HNH domain; and a Type V CRISPR-Cas effector protein, wherein the Type V CRISPR-Cas effector protein is a Cas12i protein, wherein the HNH domain is between two amino acid residues of the Type V CRISPR-Cas effector protein, wherein the two amino acid residues are different and are each selected from amino acid residues 790 to 800 of the Type V CRISPR-Cas effector protein, wherein the HNH domain is in a region of the Type V CRISPR-Cas effector protein that is exposed to the target strand of a target nucleic acid, and the region is a loop that comprises the two amino acid residues of the Type V CRISPR-Cas effector protein, and wherein the engineered protein is a nuclease. The structure of the engineered protein is unlimited.
In this case, the specification discloses an actual reduction to practice of the following representative species of the genus of “engineered proteins” as encompassed by the claims (i.e. first portion comprising the amino acid sequence of SEQ ID NO: 236-240, HNH domain comprising the amino acid sequence of 190, 192, 196, 199, 208-235 and 291-293, and second portion comprising the amino acid sequence of SEQ ID NO: 176-207 having target strand nickase activity). Other than the above disclosed species there is no other drawings or structural formulas disclosed of the infinite number of engineered proteins comprising a first portion of a Type V CRISPR-Cas effector protein, an HNH domain, and a second portion of a Type V CRISPR-Cas effector protein as encompassed by the claims.
The reference of Singh et al. (Current Protein and Peptide Science, 2017; cited on PTO-892 mailed on 04/07/2026) 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].
The reference of Zhang et al. (Structure, 2018; cited on PTO-892 mailed on 04/07/2026) discloses that a mutation of a residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide [p. 1475, column 1].
There is no prior-art or disclosed teaching regarding the structure of the infinite structure of the portion of a Type V CRISPR-Cas effector, and there is no disclosed or art recognized correlation between any structure other than a first portion comprising the amino acid sequence of SEQ ID NO: 236-240, HNH domain comprising the amino acid sequence of 190, 192, 196, 199, 208-235 and 291-293, and second portion comprising the amino acid sequence of SEQ ID NO: 176-207 having target strand nickase activity. Given what is known in the art about the likely outcome of substitutions on structure, conservation of structure is not necessarily a surrogate for conservation of function. In this case, there is no disclosed correlation between structure and function. Accordingly, one of skill in the art would not accept the disclosure of a first portion comprising the amino acid sequence of SEQ ID NO: 236-240, HNH domain comprising the amino acid sequence of 190, 192, 196, 199, 208-235 and 291-293, and second portion comprising the amino acid sequence of SEQ ID NO: 176-207 having target strand nickase activity as being representative of all engineered proteins comprising a first portion of Type V CRISPR-Cas effector protein, an HNH domain, and a second portion of the Type V CRISP-Cas effector protein of any activity as encompassed by the claims. As such, the specification, taken with the pre-existing knowledge in the art of amino acid substitution, fails to satisfy the written description requirement of 35 U.S.C. 112(a).
RESPONSE TO REMARKS: Beginning on p. 8 of applicants’ remarks, applicants in summary contend that Cas12i protein along with their structural and functional features are well known in the art and the application as filed reasonably conveys to one of ordinary skill in the art that the inventors had possession of the claimed invention at the time of filing the application.
This argument is found to be not persuasive in view of the modified rejection set forth above. Furthermore, MPEP 2163.II.A.3.(a).ii states "when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the genfus]." See Enzo Biochem, S2S F.Sd at 966, 63 USPQ2d at 1615; Noelle v. Ledermon, 355 F.3d 1343,1350, 69 USPQ2d 1508,1514 (Fed. Cir. 2004) (Fed. Cir. 2004)". In the instant case, the genus of proteins is highly variant and not limited to those polypeptides disclosed in the specification. In the Federal Circuit decision, Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337 (Fed. Cir. 2021), the courts found that for broad claims to a nucleic acid encoding a chimeric T cell receptor with a functional requirement to bind a target, “the written description must demonstrate that the applicant made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus”. In the instant case, the claims are drawn to an engineered protein have a first polypeptide of residues 700-850 of any Cas12i protein and a second polypeptide of residues 150-350 amino acid residues of any Cas12i of any sequence and structure, and the specification does not disclose sufficient structural features of the claimed engineered protein that can result in an active nuclease. While a person skilled in the art might be able to embark on their own research program to find suitable fragments of Cas12i proteins to piece together into an engineered protein having nuclease activity, the four corners of the written description do not demonstrate possession of such. This analysis is consistent with AbbVie Deutschland GmbH v. Janssen Biotech, Inc., 759 F.3d 1285, 1300 (Fed. Cir. 2014) which required an inventor to show “that one has truly invented the genus, i.e. that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus”.
As such, the specification fails to disclose an adequate number of species of the infinite possibilities of machines that are encompassed by the claims.
14. The scope of enablement rejection of claims 1, 3-14 and 20-25 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is maintained for the reasons of record and the reasons set forth below. The rejection has been modified in order to address applicants’ amendments to the claims and to incorporate new claims 28-30.
Claims 1, 3-14, 20-25 and 28-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while enabling for an engineered protein comprising a first portion comprising the amino acid sequence of SEQ ID NO: 236-240, HNH domain comprising the amino acid sequence of 190, 192, 196, 199, 208-235 and 291-293, and second portion comprising the amino acid sequence of SEQ ID NO: 176-207 having target strand nickase activity does not reasonably provide enablement for all engineered proteins as encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
“The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
(A) The breadth of the claims: As amended, claims 1, 3-14, and 28-30 are drawn to an engineered protein, complexes, and compositions comprising, from the N- to C-terminus of the engineered protein, a first polypeptide of a Type V CRISPR-Cas effector protein, an HNH domain, and a second polypeptide of the Type V CRISPR-Cas effector protein, wherein the first polypeptide is 700 to 850 amino acid residues of the Type V CRISPR-Cas effector protein and the second polypeptide is 150 to 350 amino acid residues of the Type V CRISPR-Cas effector protein, wherein the type V CRISPR-Cas effector protein is a Cas12i protein, and wherein the engineered protein is a nuclease. The structure of the engineered protein is unlimited.
As amended, claims 20-25 drawn to an engineered protein and compositions comprising an HNH domain; and a Type V CRISPR-Cas effector protein, wherein the Type V CRISPR-Cas effector protein is a Cas12i protein, wherein the HNH domain is between two amino acid residues of the Type V CRISPR-Cas effector protein, wherein the two amino acid residues are different and are each selected from amino acid residues 790 to 800 of the Type V CRISPR-Cas effector protein, wherein the HNH domain is in a region of the Type V CRISPR-Cas effector protein that is exposed to the target strand of a target nucleic acid, and the region is a loop that comprises the two amino acid residues of the Type V CRISPR-Cas effector protein, and wherein the engineered protein is a nuclease. The structure of the engineered protein is unlimited.
C) The state of the prior art; (D) The level of one of ordinary skill; and (E) The level of predictability in the art: As noted above, the structure of the claimed engineered protein comprising a first polypeptide of a Type V CRISPR-Cas effector protein, an HNH domain, and second polypeptide of the Type V CRISPR-Cas effector protein is unlimited.
It is well-known in the prior art that the amino acid sequence of a polypeptide determines the polypeptide’s functional properties. The positions within a protein's sequence where modifications can be made with a reasonable expectation of success in obtaining a polypeptide having the desired activity/utility are limited in any protein and the result of such modifications is highly unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g., multiple substitutions.
It is well-known in the art that even a single amino acid alteration can alter the folding of a polypeptide. See, e.g., MPEP 2144.08.II.A.4.(c), which states, “[i]n the area of biotechnology, an exemplified species may differ from a claimed species by a conservative substitution (“the replacement in a protein of one amino acid by another, chemically similar, amino acid... [which] is generally expected to lead to either no change or only a small change in the properties of the protein.” Dictionary of Biochemistry and Molecular Biology 97 (John Wiley & Sons, 2d ed. 1989)). The effect of a conservative substitution on protein function depends on the nature of the substitution and its location in the chain. Although at some locations a conservative substitution may be benign, in some proteins only one amino acid is allowed at a given position. For example, the gain or loss of even one methyl group can destabilize the structure if close packing is required in the interior of domains. James Darnell et al., Molecular Cell Biology 51 (2d ed. 1990).”
The reference of Singh et al. (Current Protein and Peptide Science, 2017; cited on PTO-892 mailed on 04/07/2026) 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].
The reference of Zhang et al. (Structure, 2018; cited on PTO-892 mailed on 04/07/2026) discloses that a mutation of a residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide [p. 1475, column 1].
(F) The amount of direction provided by the inventor and (G) The existence of working examples: The specification discloses the following working examples of engineered protein comprising a first portion of a Type V CRISPR-Cas effector protein, an HNH domain, and second portion of the Type V CRISPR-Cas effector protein, i.e. an engineered protein comprising a first portion comprising the amino acid sequence of SEQ ID NO: 236-240, HNH domain comprising the amino acid sequence of 190, 192, 196, 199, 208-235 and 291-293, and second portion comprising the amino acid sequence of SEQ ID NO: 176-207 having target strand nickase activity. Other than these working examples, the specification fails to disclose any other working examples of engineered proteins of any function. Moreover, the specification fails to provide guidance regarding what additional modifications to said engineered protein that result in any activity.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability, and the state of the prior art, undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
RESPONSE TO REMARKS: Beginning on p. 9 of applicants’ remarks, applicants in summary contend that the claims as presented further define the structure and function of the claimed engineered protein by reciting that the protein is a Cas12i protein and define the positioning of the an HNH domain in regard to the Cas12i protein.
This argument is found to be not persuasive in view of the modified rejection set forth above. The genus of engineered Cas12i proteins as encompassed by the claims is not limited to those disclosed in the specification and the prior art. In the Federal Circuit decision of Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 1156 (Fed. Cir. 2019), the court stated that “the key enablement question is whether a person of ordinary skill in the art would know, without undue experimentation, which [species] would be effective….because of the many thousands of [species] which need to be screened for…efficacy, the quantity of experimentation needed is large and weighs in favor of non-enablement.” In the instant case, the number is not thousands but an infinite number of Cas12i variants only defined by fragments of a Cas12i of unknown amino acid sequence, and as such, the quantity of experimentation would be many orders of magnitude more than that in Idenix. While methods for modifying the amino acid sequence of a polypeptide were known before the effective filing date of the claimed invention, it would not routine in the art to screen by a trial an error process of all variants as broadly encompassed by the claims. Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Double Patenting
15. The provisional nonstatutory double patenting rejection of claims 1-14 and 20-25 over claims 1, 4-5, 7, 11-14, 16-17, 22-23, 47-53, and 75-79 of copending Application No. 17/459166 is withdrawn in view of applicants’ amendment to the claims to cancel claim 2 and amendment to the claims in the ‘166 application to recite a Cas12a protein.
Conclusion
16. Status of the claims:
Claims 1 and 3-30 are pending.
Claims 15-19 and 26-27 stand withdrawn pursuant to 37 CFR 1.142(b).
Claims 1, 3-14, 20-25 and 28-30 are rejected.
No claims are in condition for an allowance.
THIS ACTION IS MADE FINAL. 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 PAUL J HOLLAND whose telephone number is (571)270-3537. The examiner can normally be reached Monday to Friday from 8AM to 5PM.
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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656
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