DETAILED CORRESPONDENCE
Status of the Application
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 2, 2026 has been entered.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1, 2, 4-10, and 12 are pending in the application.
Applicant’s amendment to the claims, filed April 2, 2026, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s remarks filed April 2, 2026 in response to the final rejection mailed October 2, 2025 are acknowledged.
Restriction/Election
In response to a requirement for restriction/election mailed October 9, 2024, applicant elected without traverse species (D), Virion infectivity factor (Vif), in the reply filed March 10, 2025.
Claim 5 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected species, there being no allowable generic or linking claim.
Claims 1, 2, 4, 6-10, and 12 are being examined on the merits with claims 1 and 6 being examined only to the extent the claims read on the elected subject matter.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claim 12 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. This rejection is necessitated by applicant’s amendment to add claim 12.
Claims 1 and 6 have been amended to limit the Vif protein to Vif of HIV or SIV or fragments thereof that specifically bind to an APOBEC3 family cytidine deaminase. New claim 12, which depends from claims 1 and 6, is confusing because the recited Vif variant of claim 12 comprising “(b) a substitution of the leucine residue at position 145 of the Vif protein with another amino acid residue” is not encompassed by Vif of HIV or SIV or fragments thereof that specifically bind to an APOBEC3 family cytidine deaminase. It is suggested that applicant clarify the meaning of claim 12.
Claim 12 is indefinite in the recitation of “the Vif protein (RefSeq No. AAF20197).” It is unclear as to whether the parenthetical expression “(RefSeq No. AAF20197)” is intended to limit the sequence of the reference “Vif protein” or alternatively to recite an exemplary reference Vif protein sequence. The noted phrase is also indefinite because “AAF20197” is not a RefSeq database accession number. If the parenthetical expression “(RefSeq No. AAF20197)” is intended to recite an exemplary Vif protein, applicant is advised that description of examples is properly set forth in the specification rather than the claims (see MPEP 2173.05(d)). It is suggested that applicant clarify the meaning of the phrase “the Vif protein (RefSeq No. AAF20197).”
Claim 12 is also indefinite in the recitation of “the Vif protein” in line 4 because it is unclear as to whether the noted phrase refers to “Virion infectivity factor (Vif) of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV)” in claim 6 or “the Vif protein (RefSeq No. AAF20197)” in line 3 of claim 12.
Claim Rejections - 35 USC § 112(a)
Claims 1, 2, 4, 6-10, and 12 are newly 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. This rejection is necessitated by applicant’s amendments to claims 1 and 6 and applicant’s amendment to add claim 12.
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.
MPEP § 2163 further states that “[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.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’"
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.
Claims 1, 2, 4, and 6-10 are drawn to (in relevant part)
a nucleic acid sequence-recognizing module specifically binding to a target nucleotide sequence in a DNA, and
a DNA modifying enzyme-binding module bonded to each other,
wherein the nucleic acid sequence-recognizing module is a CRISPR-Cas system,
wherein at least one DNA cleavage ability of Cas is inactivated, and
wherein the DNA modifying enzyme-binding module is Virion infectivity factor (Vif) of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) and fragments thereof that specifically bind to an APOBEC3 family cytidine deaminase.
Given a broadest reasonable interpretation, the recitation of “that specifically bind to an APOBEC3 family cytidine deaminase” in claims 1 and 6 is interpreted as meaning binding exclusively to an APOBEC3 family cytidine deaminase and refers to both “Virion infectivity factor (Vif) of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV)” and “fragments thereof.”
New claim 12 is drawn to the complex according to claim 6, wherein the Virion infectivity factor (Vif) is a variant of the Vif protein comprising at least one of (a) a deletion of 7 to 11 amino acids at the N-terminus of the Vif protein (RefSeq No. AAF20197) and (b) a substitution of the leucine residue at position 145 of the Vif protein with another amino acid residue.
The term “comprising” is inclusive or open-ended (MPEP 2111.0.I) and given a broadest reasonable interpretation, the phrase “a variant of the Vif protein comprising at least one of…” in claim 12 is interpreted as requiring at least the modification(s) of (a) and/or (b) and any additional amino acid modifications (substitutions, insertions, deletions, and/or additions) of the Vif protein of HIV or SIV.
The specification discloses the following representative species of a Vif protein encompassed by the recited Virion infectivity factor (Vif) of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) and fragments thereof that specifically bind to an APOBEC3 family cytidine deaminase – a variant Vif, wherein the variant Vif is Vif of HIV or SIV except for a deletion of 7 to 11 amino acids at the N-terminus. Regarding claims 1, 2, 4, 6-10, and 12, the specification fails to disclose a complex comprising Vif of HIV or SIV that specifically binds to an APOBEC3 family cytidine deaminase, and regarding claim 12, other than a variant Vif, wherein the variant Vif is Vif of HIV or SIV except for a deletion of at least the 7 to 11 amino acids at the N-terminus, the specification fails to disclose any other variants of Vif that specifically binds to an APOBEC3 family cytidine deaminase.
Regarding the level of skill and knowledge in the art of Vif of HIV or SIV binding to an APOBEC3 family cytidine deaminase, the specification discloses that Vif is known to bind to an E3 ubiquitin ligase complex and promote proteolysis of APOBEC3 (specification at paragraph [0032]). Given that the recited Vif of HIV or SIV does not specifically bind to an APOBEC3 family cytidine deaminase, one of skill in the art would recognize that it is highly unlikely that using Vif of HIV or SIV in the claimed complex would result in specific binding of Vif of HIV or SIV to an APOBEC3 family cytidine deaminase. Rather, one of skill in the art would have instead expected that using Vif of HIV or SIV in the claimed complex would result in binding to an E3 ubiquitin ligase complex and promoting proteolysis of APOBEC3.
Given that claims 1, 2, 4, and 6-10 recite Vif of HIV or SIV and require specific binding to an APOBEC3 family cytidine deaminse while it was known that Vif of HIV or SIV does not specifically bind to an APOBEC3 family cytidine deaminse and it is highly unlikely that using Vif of HIV or SIV in the claimed complex would result in binding of the DNA modifying enzyme APOBEC3 without also binding to an E3 ubiquitin ligase complex and promoting proteolysis of APOBEC3, one of skill would reasonably conclude that the applicant was not in possession of the claimed invention.
Regarding a variant Vif recited in claim 12, before the effective filing date of the claimed invention, the state of there was a high level of unpredictability in the art of amino acid modification. For example, the reference of Singh et al. (Curr. Protein Pept. Sci. 18:1-11, 2017; cited on the attached Form PTO-892) 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 unpredictability associated with amino acid modification is exemplified by the reference of Zhang et al. (Structure 26:1474-1485, 2018; cited on the attached Form PTO-892), which discloses that even a mutation that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1). As such, one of skill in the art would recognized a high level of unpredictability that a variant Vif as encompassed by claim 12 would exhibit specific binding to an APOBEC3 family cytidine deaminase.
Given that claim 12 recites a genus of Vif variants having widely variant structures and requires specific binding to an APOBEC3 family cytidine deaminse while there was a high level of unpredictability in the art of amino acid modification and the specification discloses only a single representative species among a widely variant genus, one of skill would reasonably conclude that the applicant was not in possession of the claimed invention.
Claims 1, 2, 4, 6-10, and 12 are newly rejected under 35 U.S.C. 112(a) because the specification, while being enabling for a complex comprising
a nucleic acid sequence-recognizing module specifically binding to a target nucleotide sequence in a DNA, and
a DNA modifying enzyme-binding module bonded to each other,
wherein the nucleic acid sequence-recognizing module is a CRISPR-Cas system,
wherein at least one DNA cleavage ability of Cas is inactivated, and
wherein the DNA modifying enzyme-binding module is a variant Virion infectivity factor (Vif) that specifically binds to an APOBEC3 family cytidine deaminase, wherein the variant Vif is Vif of HIV or SIV except for a deletion of 7 to 11 amino acids at the N-terminus,
does not reasonably provide enablement for all complexes as encompassed by the claims, particularly with regard to the recited Vif protein. 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.
This rejection is necessitated by applicant’s amendments to claims 1 and 6 and applicant’s amendment to add claim 12.
“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.
The nature of the invention: The claimed invention encompasses a complex of a fusion of a catalytically impaired Cas (corresponding to “a nucleic acid sequence-recognizing module specifically binding to a target nucleotide sequence in a DNA in claim 1) and Virion infectivity factor (Vif) of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) (corresponding to “a DNA modifying enzyme- binding module” in claim 1) and a guide RNA (corresponding to a component of the “CRISPR-Cas system” in claim 1). The specification discloses Vif binds to APOBEC, particularly APOBEC3 as the DNA modifying enzyme (specification at paragraph [0032]).
The breadth of the claims: As amended, claims 1, 2, 4, and 6-10 are drawn to (in relevant part)
a nucleic acid sequence-recognizing module specifically binding to a target nucleotide sequence in a DNA, and
a DNA modifying enzyme-binding module bonded to each other,
wherein the nucleic acid sequence-recognizing module is a CRISPR-Cas system,
wherein at least one DNA cleavage ability of Cas is inactivated, and
wherein the DNA modifying enzyme-binding module is Virion infectivity factor (Vif) of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) and fragments thereof that specifically bind to an APOBEC3 family cytidine deaminase.
Given a broadest reasonable interpretation, the recitation of “that specifically bind to an APOBEC3 family cytidine deaminase” in claims 1 and 6 is interpreted as meaning binding exclusively to an APOBEC3 family cytidine deaminase and refers to both “Virion infectivity factor (Vif) of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV)” and “fragments thereof.”
New claim 12 is drawn to is drawn to the complex according to claim 6, wherein the Virion infectivity factor (Vif) is a variant of the Vif protein comprising at least one of (a) a deletion of 7 to 11 amino acids at the N-terminus of the Vif protein (RefSeq No. AAF20197) and (b) a substitution of the leucine residue at position 145 of the Vif protein with another amino acid residue.
The term “comprising” is inclusive or open-ended (MPEP 2111.0.I) and given a broadest reasonable interpretation, the phrase “a variant of the Vif protein comprising at least one of…” in claim 12 is interpreted as requiring at least the modification(s) of (a) and/or (b) and any additional amino acid modifications (substitutions, insertions, deletions, and/or additions) of the Vif protein of HIV or SIV.
The amount of direction provided by the inventor and The existence of working examples: The specification discloses that while Vif binds to APOBEC3, Vif also binds to an E3 ubiquitin ligase complex and promotes proteolysis of APOBEC3 and that it is preferable to alter the Vif so that it binds only to APOBEC3 (specification at paragraph [0032]). The specification discloses the following working examples of a Vif protein that binds to APOBEC3 without also binding to an E3 ubiquitin ligase complex and promoting proteolysis of APOBEC3 – a variant Vif, wherein the variant Vif is Vif of HIV or SIV except for a deletion of 7 to 11 amino acids at the N-terminus. Regarding claims 1, 2, 4, 6-10, and 12, the specification fails to disclose a complex comprising Vif of HIV or SIV that specifically binds to an APOBEC3 family cytidine deaminase, and regarding claim 12, other than a variant Vif, wherein the variant Vif is Vif of HIV or SIV except for a deletion of at least the 7 to 11 amino acids at the N-terminus, the specification fails to disclose any other variants of Vif that specifically binds to an APOBEC3 family cytidine deaminase.
The state of the prior art; The level of one of ordinary skill; and The level of predictability in the art: According to MPEP 2164.03, “…what is known in the art provides evidence as to the question of predictability” and “[I]f one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art.”
Regarding Vif of HIV or SIV as recited in claims 1 and 6, before the effective filing date of the claimed invention, the prior art disclosed that Vif is known to bind to an E3 ubiquitin ligase complex and promote proteolysis of APOBEC3 (specification at paragraph [0032]). As such, it is highly unpredictable that using Vif of HIV or SIV in the claimed complex would result in binding of the DNA modifying enzyme APOBEC3 without also binding to an E3 ubiquitin ligase complex and promoting proteolysis of APOBEC3. Rather, one of skill in the art would have instead expected that using Vif of HIV or SIV in the claimed complex would result in binding of the Vif of HIV or SIV to an E3 ubiquitin ligase complex and promote proteolysis of APOBEC3.
Regarding a variant Vif recited in claim 12, before the effective filing date of the claimed invention, the state of there was a high level of unpredictability in the art of amino acid modification. For example, the reference of Singh et al. (Curr. Protein Pept. Sci. 18:1-11, 2017; cited on the attached Form PTO-892) 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 unpredictability associated with amino acid modification is exemplified by the reference of Zhang et al. (Structure 26:1474-1485, 2018; cited on the attached Form PTO-892), which discloses that even a mutation that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1). As such, one of skill in the art would recognized a high level of unpredictability that a variant Vif as encompassed by claim 12 would exhibit specific binding to an APOBEC3 family cytidine deaminase.
In view of the breadth of the claims, the lack of guidance and working examples provided in the specification, and the high degree of unpredictability in the relevant 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).
Claim Rejections - 35 USC § 102
The rejection of claims 1, 2, 4, 6-8, and 10 under 35 U.S.C. 102(a)(1) as being anticipated by Nishida et al. (WO 2015/13554 A1; cited on the IDS filed on December 14, 2023; hereafter “Nishida”) as evidenced by Salter et al. (Trends Biochem. Sci. 41:578-594, 2016; cited on Form PTO-892 filed October 2, 2025; hereafter “Salter”) is withdrawn in view of applicant’s amendments to claims 1 and 6 to limit the Vif protein to Vif of HIV or SIV. One of ordinary skill in the art would not reasonably interpret “Virion infectivity factor (Vif) of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV)” to encompass the protein binding domain of Nishida (see paragraph [0046] of US 2017/0073670 A1) as being encompassed by “Virion infectivity factor (Vif) of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV)” in claims 1 and 6.
Claim Rejections - 35 USC § 103
The rejection of claim 9 under 35 U.S.C. 103 as being unpatentable over Nishida in view of Komor et al. (Nature 533:420-424, 2016; cited on the IDS filed on December 14, 2023; hereafter “Komor”) is withdrawn in view of applicant’s amendments to claims 1 and 6 to limit the Vif protein to Vif of HIV or SIV. One of ordinary skill in the art would not reasonably interpret “Virion infectivity factor (Vif) of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV)” to encompass the protein binding domain of Nishida (see paragraph [0046] of US 2017/0073670 A1) as being encompassed by “Virion infectivity factor (Vif) of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV)” in claims 1 and 6.
Conclusion
Status of the claims:
Claims 1, 2, 4-10, and 12 are pending.
Claim 5 is withdrawn from consideration.
Claims 1, 2, 4, 6-10, and 12 are rejected.
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID J STEADMAN whose telephone number is (571)272-0942. The examiner can normally be reached Monday to Friday, 7:30 AM to 4:00 PM.
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/David Steadman/Primary Examiner, Art Unit 1656
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