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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 August 18, 2026 has been entered.
Application Status
Applicant’s remarks and amendments to the claims filed August 18, 2026 are acknowledged. Claims 92 and 101 were amended. Claims 1-3, 5, 7, 11, 13, 15-18, 20, 25, 27-29, 33, 38, 43-44, 48-50, 55, 62-63, 85-103 are pending.
Restriction/Election
The election of species requirement set forth in the Office action mailed July 11, 2024, has been reconsidered in view of the updated search which uncovered art relevant to additional species. Specifically, the election of species requirements for a single nucleotide deaminase protein or catalytic domain thereof, and a single delivery means, are withdrawn.
In view of the above noted withdrawal of the election of species requirement, Applicant is advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 28, 49-50, 95-99, and 102 directed to additional species of nucleotide deaminase protein or catalytic domain thereof, and additional species of delivery means, are no longer withdrawn from consideration. Claims 55, 62-63, and 103 remain withdrawn from consideration, there being no allowable or generic linking claim. Claims 1-3, 5, 7, 11, 13, 15-18, 20, 25, 27-29, 33, 38, 43-44, 48-50, and 85-102 are under examination below.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/610,041 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically, Application No. 62/610,041 does not disclose an adenosine deaminase or catalytic domain thereof with an “S370” mutation relative to hADAR2. The first disclosure of an “S370” mutation is in PCT/US2018/067207 ([0351]). Accordingly, all claims under examination have an effective filing date of December 21, 2018.
Withdrawn Rejections
Applicant’s amendments to the claims resolve the § 112(b) rejections raised in the prior action. These rejections are withdrawn, accordingly.
Applicant’s remarks refer to a “statement… signed under 37 C.F.R. § 1.33(b)… submitted on a separate sheet concurrently with this response,” which Applicant states establishes that the subject matter of Jones is excepted from prior art under the provisions of 35 U.S.C. § 102(b)(2)(C). The papers submitted August 18, 2026 were thoroughly reviewed, but no such signed statement on a separate sheet was found.
MPEP 2154.02(c) states that “A clear and conspicuous statement by the applicant (or the applicant's representative) that the claimed invention of the application under examination and the subject matter disclosed in the U.S. patent document applied as prior art were owned by the same person or subject to an obligation of assignment to the same person not later than the effective filing date of the claimed invention will be sufficient to establish that the AIA 35 U.S.C. 102(b)(2)(C) exception applies.” Applicant has provided such a clear and conspicuous statement on pg. 11 of the remarks. Jones (Jones et al., US 2021/0163944 A1, effectively filed 26 October 2018), therefore, is not available as prior art. The rejections made over Zhang in view of Jones are withdrawn, accordingly.
Regarding the non-statutory double patenting rejections raised over co-pending 17/265,910 and 16/773,000, Applicant’s remarks regarding the non-obviousness of the instant claims over the co-pending claims is found persuasive. With respect to co-pending 17/265,910, the co-pending claims do not recite a method requiring a catalytically inactive (dead) C2c1 or C2c1 nickase protein linked to an adenosine deaminase protein or catalytic domain thereof, wherein the adenosine deaminase protein or catalytic domain thereof comprises at least a mutation at each of the recited positions. The claims of co-pending 16/773,000 also fail in this regard. None of the prior art reviewed during examination teaches or suggests the missing elements of the instantly claimed method so as to remedy the deficiencies of the co-pending claims.
Specifically, the search uncovered prior art which teaches some elements of the instant claims. For example, Zhang (US 2021/0009972 A1, effectively filed 4 October 2018; of record) teaches a similar method utilizing a different Cas protein (i.e., Cas13), linked to an adenosine deaminase protein or catalytic domain thereof ([0034]; [0145]). The use of C2c1 proteins linked to an adenosine deaminase protein was suggested by at least Zhang ([0337]; [0393]) and Liu (Liu and Gaudelli, US 2018/0073012 A1, effectively filed 3 August 2017; of record) ([00308]). Zhang generically teaches the instantly recited mutations ([0040]; [0171]-[0248]), but does not appear to teach or suggest the specific combination of mutations required of the instant claims; for example, S495 is disclosed amongst 16 other positions, wherein the other positions do not even include each of the instantly recited positions ([0192]). Zhang and the remaining available prior art reviewed during the search recite many possible mutations relative to hADAR2, and/or various specific, sub-combinations of the recited mutations (see, for example, Zhang, US 2021/0130800 A1, effectively filed 23 October 2018, Example 5, [1184]-[1186]; and Zhang, US 2020/0332272 A1, effectively filed 23 October 2018, Example 6, [1379]-[1381]), but make no apparent suggestion of the specific combination of mutations recited in the instant claims. Prior art related to hADAR2 mutations was also reviewed (e.g., Kuttan, of record), but the specific combination does not appear to be taught or suggested. The non-statutory double patenting rejections raised in the prior action are withdrawn, accordingly.
Applicant’s remarks and amendments to the claims have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow. Any rejection or objection not reiterated herein has been overcome by amendment.
Claim Objections
Claims 7, 11, 50, and 101 are objected to because of the following informalities:
Claim 7 recites “wherein the mutation corresponds to position D570A, E848A, or D977A in AacC2c1.” It is clear that D570A, E848A, or D977A are the mutations required of the RuvC domain. It would be preferable to amend the claim to recite “wherein the mutation corresponds to
Claim 11 recites “said target sequence.” It would be preferable to use the same terminology throughout the claims. Claim 11 should be amended to recite “said target locus
Claim 50 recites “a target sequence comprising said Cytosine.” It is clear that this phrase is intended to refer to the previously recited target locus. It would be preferable to use the same terminology throughout the claims. Claim 50 should be amended to recite “said[[a]] target locus
Claim 50 also recites “a heteroduplex.” It is clear that this term intends to refer to the previously recited heteroduplex. It would be preferable to amend claim 50 to recite “the[[a]] heteroduplex.”
Claim 101 recites “comprising the mutation T375G/S, N473D, or both.” It is reasonably clear that the claim requires one of T375G, T375S, N473D, or one of the recited T375 mutations in combination with N473D. It would be preferable to amend the claim to recite “comprising the mutation T375G, T375S, or N473D, the mutations T375G and N473D, or the mutations T375S and N473D.
Appropriate correction is required.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 13, 16, and 50 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. The rejections that follow are new.
Claim 13 recites that “said adenosine deaminase protein or catalytic domain thereof has been modified to increase activity against a DNA-RNA heteroduplex relative to a wild-type nucleotide deaminase.” Claim 1 recites that the adenosine deaminase protein or catalytic domain comprises a “modification to reduce off-target effects relative to a wild-type adenosine deaminase, wherein the modification comprises mutations at positions V351….” Neither the claim nor specification clearly set forth the modifications which would result in such increased activity, or establish what encompasses “increased activity.” The skilled artisan could reasonably interpret reduced off-target activity as increased activity for a target site. It is not clear, therefore, whether the adenosine deaminase protein or catalytic domain of claim 1 “has been modified” so as to meet the limitations of claim 13, such that claim 13 does not further limit the claim, and merely recites a function of the modified adenosine deaminase of claim 1, or whether claim 13 intends to require some unrecited, additional modification to the adenosine deaminase of claim 1.
Claim 16 recites that “said adenosine deaminase protein or catalytic domain thereof more efficiently deaminates said nucleotide present in said target locus relative to a wild-type nucleotide deaminase.” Claim 1 recites that the adenosine deaminase protein or catalytic domain comprises a “modification to reduce off-target effects relative to a wild-type adenosine deaminase, wherein the modification comprises mutations at positions V351….” Neither the claim nor specification clearly set forth the modifications which would result in more efficient deamination, or establish what encompasses “more efficient” deamination. The skilled artisan could reasonably interpret reduced off-target activity as more efficient deamination at a target site. It is not clear, therefore, whether the adenosine deaminase protein or catalytic domain of claim 1 already meets the limitations of claim 16, such that claim 16 does not further limit the claim, and merely recites a function of the modified adenosine deaminase of claim 1, or whether claim 16 intends to require some unrecited, additional modification to the adenosine deaminase of claim 1.
Claim 50 recites “wherein said guide sequence comprises a non-pairing Cytosine at a position corresponding to an Adenine resulting in an C-A or C-U mismatch in the heteroduplex formed.” It is not clear how a guide sequence comprising a non-pairing Cytosine, when corresponding to an Adenine in the target locus, which is DNA based on claim 1 (“a first DNA strand at said target locus… in a heteroduplex formed by the guide sequence and the target locus”), would result in a “C-U mismatch” in the heteroduplex.
Claim Rejections - 35 USC § 112(a) – Written Description
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 1-3, 5, 7, 11, 13, 15-18, 20, 25, 27-29, 33, 38, 43-44, 48-50, and 85-102 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. This is a new matter rejection.
MPEP 2163.03(I) provides that “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).”
Claim 1 was amended in the claims filed February 18, 2026 to recite “wherein the modification comprises mutations at positions V351, S486, T375, S370, P462, N597, and S495 relative to human adenosine deaminase that act on RNA 2 (hADAR2).” As stated in the previous action (paragraph 3), this limitation is interpreted as requiring an adenosine deaminase protein or catalytic domain thereof comprising, at least, mutations at each of the recited positions relative to hADAR2.
Applicant’s remarks filed February 18, 2026 do not indicate where support for the amendment can be found in the disclosure. A thorough review of the disclosure as filed failed to uncover any literal description of the aforementioned limitation in claim 1. The specification sets forth various positions relative to hADAR2, in which the adenosine deaminase or catalytic domain thereof may comprise a mutation ([0310]-[0390]). Even where the specification recites series of positions, the series are prefaced by the phrase “comprises one or more of mutations…” or the like ([0320]-[0323]; [0354]-[0360]; [0362]-[0363]; [0371]-[0373]; [0383]), such that, in many instances the series encompass a large genus of positions at which the adenosine deaminase or catalytic domains thereof may be mutated. Notably, none of the series recite each of the instantly recited positions in combination. Indeed, the only apparent instances in the disclosure in which mutations at each position in a series are required, are the series set forth in [0361]; however, these series, at most, provide support for only three specific mutations in combination, not the seven mutations instantly recited. The disclosure also does not appear to provide any description which would equivalently describe the aforementioned limitation, e.g., a direction to select specific mutations from series of positions across different embodiments (e.g., across embodiments [0322] and [0356]).
Based on a thorough review of the disclosure as filed, there is neither a literal description or equivalent description of an adenosine deaminase or catalytic domain thereof comprising, at least, a mutation at each of the recited positions relative to hADAR2. Accordingly, claim 1 is rejected for failing to comply with the written description requirement.
Claims 2-3, 5, 7, 11, 13, 15-18, 20, 25, 27-29, 33, 38, 43-44, 48-50, and 85-102 are rejected for depending from claim 1 and failing to remedy the written description issues therein described above.
Claims 1-3, 5, 7, 11, 13, 15-18, 20, 25, 27-29, 33, 38, 43-44, 48-50, and 85-102 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. This is a new rejection.
MPEP 2163.II.A3.(a).(i) states the following:
“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 inventor was in possession of the claimed genus.”
“Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor 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. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. 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.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).”
Species Encompassed
Claim 1 recites an “adenosine deaminase protein or catalytic domain thereof [which] comprises a modification to reduce off-target effects relative to a wild-type adenosine deaminase, wherein the modification comprises mutations at positions V351, S486, T375, S370, P462, N597, and S495 relative to human adenosine deaminase that act on RNA 2 (hADAR2).” As stated in previous action (paragraph 3), this limitation is interpreted as requiring an adenosine deaminase protein or catalytic domain thereof comprising, at least, mutations at each of the recited positions relative to hADAR2. The term “adenosine deaminase” is interpreted as any adenosine deaminase or variant thereof, derived from any species, which is capable of deaminating a nucleotide, e.g., adenine to hypoxanthine, or cytidine to uracil ([0382]). For example, the claims encompass “hADAR1d” (claim 100), or any “human, squid, or Drosophila” adenosine deaminase protein or catalytic domain thereof (claim 48). The term “mutation” is not explicitly defined in the context of an adenosine deaminase or catalytic domain thereof ([0309]). Based on its usage in the specification in general, however, the term “mutation” is interpreted as encompassing point mutations, insertions, deletions, etc., with any known natural or non-natural amino acid(s)([0154]-[0155]).
The specification has not sufficiently described the genus of adenosine deaminase or catalytic domain thereof which exhibit deaminase activity and has reduced off-target effects relative to wild-type adenosine deaminase, and comprises a mutation (i.e., point mutation, insertion, deletion, with any known natural or non-natural amino acid(s)) at least at each of the recited positions relative to hADAR2.
Species Disclosed in the Specification
The specification does not actually describe any adenosine deaminase or catalytic domain thereof comprising mutations at each of the recited positions. The specification does not actually disclose any specific mutations at position S370; the specification only once discloses the position ([0356]). The specification generally discloses various positions relative to hADAR2, in which the adenosine deaminase or catalytic domain thereof may comprise a mutation ([0310]-[0390]). The specification lists specific mutations which “improve editing efficiency” ([0320]), and “reduce editing efficiency” ([0321]). The specification states that “it can be of interest to use an adenosine deaminase enzyme with reduced efficacy to reduce off-target effects” ([0321]). The specification also lists specific mutations which “reduce off-target effects” ([0323]). The specification also generally discloses mutations which an adenosine deaminase having C-to-U deamination activity may comprise ([0383]). The specification references the crystal structure of human ADAR2, and discloses that at least one region which contributes to substrate specificity is known ([0324]). The specification also recites series of positions prefaced by the phrase “comprises one or more of mutations…” or the like ([0320]-[0323]; [0354]-[0360]; [0362]-[0363]; [0371]-[0373]; [0383]). None of the series recite the instantly claimed positions.
The specification does not provide any guidance (working examples or otherwise) to determine which mutations at the recited positions will reduce off-target effects relative to a wild-type adenosine deaminase and preserve deaminase activity, let alone in combination with other mutations encompassed by the claims. For example, the specification discloses several mutations which “reduce editing efficiency,” including N597F ([0321]). Beyond the assertion that such mutations “can be of interest… to reduce off-target effects,” there is no guidance to determine how mutation N597F, which allegedly reduces editing efficiency, when combined with mutations at each of the other recited positions, will affect deaminase activity or off-target effects. As another example, the specification recites series of positions, and in some instances, specific mutations at those positions ([0322]-[0323]). Beyond asserting that the mutations “reduce off-target effects,” there is no guidance to determine which mutations at one or more of the 17 possible positions, or which one or more of the 18 mutations, will affect deaminase activity or off-target effects, let alone with other distinct positions or mutations recited in different embodiments, or other mutations encompassed by the claims. As yet another example, there is no guidance to determine the function of non-hADAR2 adenosine deaminases or catalytic domains thereof (e.g., hADAR1, or squid or Drosophila adenosine deaminase), when comprising mutations at each of the recited positions. Taken together, the specification has not sufficiently described any species of the instantly claimed adenosine deaminase protein or catalytic domain thereof.
Guidance in the Prior Art
Zhang (of record), Zhang II (Zhang, US 2021/0130800 A1, effectively filed 23 October 2018) and Zhang III (Zhang, US 2020/0332272 A1, effectively filed 23 October 2018) are the closest prior art documents to the claimed invention. The Zhang references each recite adenosine deaminase or catalytic domains thereof comprising many possible mutations relative to wild-type adenosine deaminase (see, for example, Zhang, [0040]; [0171]-[0248]). The Zhang references also disclose adenosine deaminases comprising specific sub-combinations of mutations at the recited positions (see, Zhang I, Example 4, [1098]-[1103]; Zhang II, Example 5, [1184]-[1186]; and Zhang III, Example 6, [1379]-[1381]). For example, “RESCUEv6” of Zhang III, wherein the modification consists of E488Q, V351G, S486A, T375S, S370C, P462A, N597I which “convert adenosine deaminase activity to cytidine deaminase activity” ([1379]). It is evident that RESCUEv6 has deaminase activity (Fig. 75), but it is not evident based on the disclosure of Zhang III that RESCUEv6 has “reduced off-target effects” compared to a wild-type adenosine deaminase.
None of the Zhang references teach or suggest the specific combination of mutations recited in the instant claims. For example, the Zhang references merely disclose position S495 amongst 16 other positions to “reduce off-target effects,” wherein the other options do not include each of the instantly recited positions (see at least, Zhang, [0192]). The Zhang references also provide no guidance to determine which of the many possible positions should be mutated, or which mutations at the possible positions should be chosen, to prepare an adenosine deaminase or catalytic domain thereof with reduced off-target effects which preserves deaminase activity. Similarly to the specification, the Zhang references also fail to provide guidance as to determine the function of non-hADAR2 adenosine deaminases or catalytic domains thereof, when comprising mutations at each of the recited positions.
The prior art was also searched for guidance regarding mutations at the instantly claimed positions. Kuttan (of record), suggests that a specific mutation at N597 in hADAR2 may result in higher binding affinity (E3301; right col; Fig. 5C). No guidance was uncovered regarding position S370, and only generic guidance (e.g., their relative position within the ADAR2 structure, or level of conservation) was found regarding positions V351, S486, T375, P462, and S495. See, for example, Matthews (Matthews et al., 11 April 2016, Nature Structural & Molecular Biology, 23, 426-433) and Wang (Wang and Beal, 2016, Nucleic Acids Research, Vol. 44, No. 20, 9872-9880). Taken together, the skilled artisan would not be able to reasonably predict the deaminase activity or off-target effects of adenosine deaminase or catalytic domains thereof encompassed by the claims, based on the limited, specific examples of the Zhang references, the generic disclosure of hundreds of possible positions/mutations relative to hADAR2 in the Zhang references, accompanied by limited guidance regarding the functional roles of the recited positions, or mutations thereto.
Considering the large variation in the genus, the small percentage of species described in the specification, and the lack of predictability provided by the art for the full scope of the claimed genus, it is reasonable to conclude that Applicant did not possess the invention as claimed at the time of filing.
Claims 2-3, 5, 7, 11, 13, 15-18, 20, 25, 27-29, 33, 38, 43-44, 48-50, 85-102 are rejected for depending from claim 1 and failing to remedy the written description issues therein described above.
Claim Rejections - 35 USC § 112(a) – Enablement
Claims 1-3, 5, 7, 11, 13, 15-18, 20, 25, 27-29, 33, 38, 43-44, 48-50, 85-102 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is a new rejection.
The test of enablement is whether one skilled in the art could make or use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics Inc., 857 F.2d 778, 785, 8 USPQ2d 1217, 1223 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor, but rather is a conclusion reached by weighing many factors. These factors were outlined in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention and Breadth of the Claims
Claim 1 is drawn to a method of modifying a nucleotide (e.g., an adenine or cytosine, see claims 43 and 49) in a target locus, by delivering (a) a catalytically inactive (dead) C2c1 or C2c1 nickase protein, (b) a guide molecule comprising a guide sequence linked to a direct repeat, and (c) an adenosine deaminase or catalytic domain thereof as interpreted in paragraph 20 above linked or adapted to link to (a) or (b). Element (b) must form a complex with (a), and bind a first DNA strand at the target locus to form a heteroduplex, wherein based on the functional limitation “resulting in a mismatch,” the guide molecule comprises a mismatch relative to the target locus.
Accordingly, enablement of the claims requires that one of ordinary skill in the art be able to deliver any catalytically inactive (dead) C2c1 or C2c1 nickase protein, an adenosine deaminase or catalytic domain thereof as interpreted in paragraph 20 above, and guide molecule to a target locus, e.g., in a cell, animal, plant, or in vitro (see claims 20, 25 and 27), and modify a nucleotide at the target locus, without undue experimentation.
Guidance in the Specification
The specification does not appear to provide any working examples of the claimed method. The specification generally describes the elements to be delivered. As further described in the preceding paragraphs, the specification does not sufficiently describe the genus of adenosine deaminase or catalytic domain thereof encompassed by the claims. The specification does not provide any guidance to predict which adenosine deaminase or catalytic domain thereof, comprising any of the many possible mutations at each of the recited positions relative to hADAR2, when delivered with elements (a) and (b), would be capable of achieving the method’s outcome, i.e., modifying a nucleotide in a target locus, e.g., in a cell, animal, plant, or in vivo.
State of the Prior Art
The Zhang references are the closest prior art to the claimed invention. However, as described above, none of the Zhang references describe an adenosine deaminase or catalytic domain thereof encompassed by the claims. Neither the Zhang references nor the remaining prior art reviewed during the search provide sufficient guidance to predict the deaminase activity or off-target effects of adenosine deaminase or catalytic domain thereof encompassed by the claims, based on the limited, specific examples of the Zhang references, the generic disclosure of hundreds of possible positions/mutations relative to hADAR2 in the Zhang references, accompanied by limited guidance regarding the functional roles of the recited positions, or mutations thereto.
The Zhang references do disclose adenosine deaminases comprising specific sub-combinations of mutations at the recited positions (see, Zhang I, Example 4, [1098]-[1103]; Zhang II, Example 5, [1184]-[1186]; and Zhang III, Example 6, [1379]-[1381]). For example, “RESCUEv6” of Zhang III, wherein the modification consists of E488Q, V351G, S486A, T375S, S370C, P462A, N597I which “convert adenosine deaminase activity to cytidine deaminase activity” ([1379]). It is not evident based on the Zhang references, nor the remaining prior art reviewed during the search, which mutations at each of the recited positions will confer adenine deaminase or cytidine deaminase activity, because of the lack of working examples which meet the scope of the instant claims, and the lack of guidance in the prior art regarding the function of each of the recited positions.
Taken together, the prior art does not provide sufficient guidance to predict which adenosine deaminase or catalytic domain thereof, comprising any of the many possible mutations at each of the recited positions relative to hADAR2, when delivered with elements (a) and (b), would be capable of achieving the method’s outcome, i.e., modifying a nucleotide in a target locus, e.g., in a cell, animal, plant, or in vivo.
Experimentation Required and Level of Skill in the Art
In order to practice the methods, a large amount of highly unpredictable experimentation would be required. The skilled artisan would essentially need to produce representatives of the large genus of adenosine deaminase protein or catalytic domain thereof, for which the specification and prior art provide no working examples and limited guidance, design guide molecules to target the virtually unlimited genus of nucleotides in a target locus encompassed by the claims, and deliver these elements together with any dead C2c1 or C2c1 nickase protein. Given that there is insufficient guidance to determine which of the large genus of adenosine deaminase protein or catalytic domain thereof encompassed by the claims are adenine or cytidine deaminases, the skilled artisan would essentially need to deliver each representative to a variety of target loci, and determine whether the nucleotide in the target locus was modified.
The level of skill in the art is high, and the aforementioned experimentation is within the technical abilities of the skilled artisan. However, the level of experimentation required to practice the claims is undue. Practicing the claimed method would essentially amount to a massive screening effort at least because the genus of adenosine deaminase protein or catalytic domain thereof is insufficiently described for the reasons described above, neither the specification nor prior art teach a working example of the claimed method, and neither the specification nor prior art provide sufficient guidance to determine which target loci are even amenable to the methods, because, as evidenced by Zhang, specific mutations at several of the recited positions appear to change activity from an adenosine deaminase to a cytidine deaminase.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the lack of guidance provided in the specification and prior art, and the lack of working examples to meet the scope of the claims, it is the conclusion that undue experimentation would be required to make and use the invention as claimed.
Claims 2-3, 5, 7, 11, 13, 15-18, 20, 25, 27-29, 33, 38, 43-44, 48-50, 85-102 are rejected for depending from claim 1 and failing to remedy the written description issues therein described above.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNA L PERSONS whose telephone number is (703)756-1334. The examiner can normally be reached M-F: 9-5pm.
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, JENNIFER A DUNSTON can be reached at (571) 272-2916. 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.
/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
Prosecution Insights