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 .
The Response of 26 Nov. 2026 has been entered.
Claims 1-22 are currently pending.
Election/Restrictions
Applicant’s election of the invention of Group I, claims 1-14, and the species of: SEQ ID 13 as the ribozyme, modifications to stem I/loop I as the additional modification, EPO as the target gene, and cancer as the disease, in the reply filed on 26 Nov. 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 15-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 26 Nov. 2026.
The elected hammerhead ribozyme variant of SEQ ID 13 as well as those of SEQ IDs 8-12 and 14-22 are free of the prior art. The examination has thus been extended to additional species of variants (see 103 rejection, below).
Claims 1-14 are considered here.
Claim Objections
Claims 1-22 are objected to as being subject to an improper claim amendment in the Preliminary Amendment of 14 April 2022. Any amendments to the claims must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application (see 37 CFR 1.121(c)).
Allowable Subject Matter
Claims 3, 7, 12 and 14, drawn to hammerhead ribozyme variants of SEQ IDs 8-22, are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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, 2, 4-6, 8-11 and 13 are 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, 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.
The instant claims are directed to a "type III variant of a type I cis-acting hammerhead ribozyme". The specification describes basic structural elements of the claimed ribozymes, including "a conserved core, three stems that extend from the core, referred to herein as stem I, stem II, and stem III, and at least one loop" (Published Spec. US20230265422, [0037]) wherein the conserved core is "approximately 13 conserved or invariant “core” nucleotides … flanked by stems I, II and III" ([0054]). While the claims recite a variant of a type I cis-acting hammerhead ribozyme, the type I HHR from which the claimed HHR is derived can be any known natural or unnatural HHR and can further comprise additional modifications (see 112(b) rejection, below). As such, the claims encompass essentially any type III HHR. de la Peña et al., Rna 16.10 (2010): 1943-1950, evidences that HHRs having a range of structures occur ubiquitously throughout the phylogenetic spectrum, including in bacteria, plants, animals, insects, etc. (under Results). Thus, the instant claims encompass a huge genus of potential HHRs.
To show possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus, which in the case of a chemical invention such as a polypeptide requires a precise definition, such as by structure, formula, chemical name, or physical properties (MPEP 2163). The requirement may be satisfied through sufficient description of a representative number of species sufficient to show the applicant was in possession of the claimed genus; A "representative number of species" means that the species which are adequately described are representative of the entire genus (MPEP 2163).
The instant specification discloses a number of type III variant HHRs falling within the scope of the claims, including SEQ IDs 8-22 recited in claims 3, 7, 12 and 14. However, each of the disclosed species are variants of a specific type I HHR, S. mansoni HHR N107, which has been modified to convert to a type III HHR and has structural modifications to stem III to adjust annealing energy (by adjusting stem lengths or base-stackings) and/or modifications to stem I/loop II to enhance interactions between them (Spec., Example 1). Thus, the disclosed species are not representative of the claimed genus of essentially any type of type III cis-acting HHR. While claims 4, 11 and 13 recite specific structural modifications, it is unclear based on the specification how one could incorporate and evaluate such modifications outside of the particular N107-based subgenus described in the specification (e.g., it is unclear what base structure such modifications would be made relative to; see 112(b) rejection, below). Claims 5, 6 and 8-10 recite short structural or functional elements (defining several nucleotides or defining a physical property of stem III) that also do not limit the claimed genus commensurate in scope with the disclosure. Thus, the instant specification does not evidence possession of the full scope of the claimed invention at the time of filing.
Claim Rejections - 35 USC § 112(b) (indefiniteness)
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.
Claims 1, 2, 4-6, 8-11 and 13 are 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 (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites a "type III variant of a type I cis-acting hammerhead ribozyme". The specification discloses that the claimed variants can be made by converting a known type I HHR to a type III HHR, and that "[c]onversion of a type I HH ribozyme into a type III variant can be readily accomplished as described herein or via standard techniques of molecule biology" (Published Spec. US20230265422, [0056]). The specification does not describe the conversion procedure in detail (e.g., Example 1 states only that known S. mansoni HHR N107 was converted to a type III HHR), but a comparison of the N107 structure with the converted structures (e.g., N107 in Fig. 5a vs. elected species SEQ ID 13 (T3H38) in Fig. 1c) indicates that the stem I structure of N107 was shortened with an added loop at the end, and that loop III of N107 was removed to yield free 5' and 3' ends. However, there is nothing in the specification that limits the conversion to such modifications, making it unclear what structural features define a "type III variant of a type I cis-acting hammerhead ribozyme" from other type III HHRs. Moreover, the specification states that the known type I HHR can be any naturally occurring or modified/variant HHR ([0055]), making it unclear what type I structural elements must be present to fall within the scope of the claimed HHR variants. The metes and bounds of the claims are thus unclear. For purposes of applying prior art below, a "type III variant of a type I cis-acting hammerhead ribozyme" is construed herein as including any type III HHR comprising a structural element of a type I HHR.
Claim 4 recites that the HHR can include an additional modification comprising "optimization of stem III". The term “optimization” is a relative term which renders the claim indefinite. The specification states that "Optimization of stem III sequence is intended to balance cleavage and disassembly rates. A more stable stem III facilitates cleavage but slows disassembly, whereas a less stable stem III works in the opposite direction. Thus, an optimal stem III sequence that balances these processes affords the maximum inhibition of gene expression. As exemplified herein, the optimization involves designing stem III of varying lengths and/or with varied base locations." ([0057]). Despite the above disclosure, the specification does not indicate how one would ascertain whether a particular stem III sequence was "optimized". For example, neither the specification nor the claims indicates what the stem III sequence is being optimized in relation to. Moreover, the cleavage and disassembly processes noted in the above-cited portion of the specification would be expected to vary based on a range of variable and undefined factors, such as the identity of the target sequence and the conditions under which the cleavage and disassembly took place (see MPEP 2173.05(b)). As such, the metes and bounds of the "optimization" in claim 4 are unclear.
Claim 4 further recites additional modifications comprising "modifications of stem I and loop I to facilitate formation of the "UAC" bulge at stem I and stabilize the tertiary interactions between the "UAC" bulge and loop II". The scope of such modifications are similarly unclear since neither the specification nor the claims indicate what the stem I/loop I sequences are being optimized in relation to, making it unclear how one could ascertain whether a particular stem I/loop I sequence falls within the scope of the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1 and 2 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of US20060121466 to Khvorova et al.
Claim 1 is directed to a "type III variant of a type I cis-acting hammerhead ribozyme", which is construed herein as including any type III HHR comprising a structural element of a type I HHR (see 112(b) rejection, above). Khvorova teaches variant cis-acting HHRs wherein the variant is modified to comprise structural elements (a loop 2 region and a bulge structure from stem I) from a type I S. mansoni HHR ([0006]; [0016]; [0091]; Example 5; Figs. 17A and B; claims 2, 5, 6). The variant HHR can be a type III HHR ([0091]; Figs. 17A and B; claims 5, 6).
Regarding claim 2, Khvorova teaches that the donor S. mansoni HHR (referred to as Schistozyme) is a naturally occurring type I HHR ([0183]).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT J YAMASAKI whose telephone number is (571)270-5467. The examiner can normally be reached M-F 930-6 PST.
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/ROBERT J YAMASAKI/Primary Examiner, Art Unit 1657