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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 29 August 2025 has been entered.
Application Status
This action is written in response to applicant’s correspondence received 29 August 2025. Claims 4, 23, 25-28, 33, 36-37, 39-40, 65-67, 70-72, and 74-76 are currently pending. Claims 25-28, 33, 36-37, and 39-40 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 4, 23, 65-67, 70-72, and 74-76 are examined herein. The restriction requirement mailed 8 March 2021 is still deemed proper. Applicant's elected Group I without traverse in the reply filed 10 May 2021.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Drawings
The drawings are objected to because of the following informalities:
The drawings were received on 6 December 2021. These drawings are unacceptable because they contain new matter in light of the instant specification.
Regarding FIG. 12, it is noted that the figure filed 6 December 2021, reproduced below, comprises a typo in light of the figure description in paragraph [0142] in the instant specification.
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FIG. 12 depicts a constitutively active cgRNA that, following the addition of an input target X, is “conditionally activated by the input target X.” However, paragraph [0142] in the instant specification describes the conditional inactivation of the cgRNA following the addition of an input target X, as depicted in FIG. 12 (Instant specification; [0142]). Therefore, examiner suggests amending FIG. 12 to recite “cgRNA conditionally inactivated by input target X.”
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The amendment filed 6 December 2021 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows: FIG. 12 depicts a constitutively active cgRNA that, following the addition of an input target X, is “conditionally activated by the input target X.” However, paragraph [0142] in the instant specification describes the conditional inactivation of the cgRNA following the addition of an input target X, as depicted in FIG. 12 (Instant specification; [0142]). Therefore, the new matter present in FIG. 12 where the active cgRNA is conditionally activated by the input target X is new matter that is not supported by the original disclosure.
Applicant is required to cancel the new matter in the reply to this Office Action.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 4, 23, 65-67, and 70-72, and 74-76 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.
Regarding claim 4, the claims broadly claim a conditional guide (cgRNA) comprising, 5’ to 3’, a target binding region that is not sequestered and configured to bind to a target nucleic acid sequence; an effector handle region; a terminator insert region comprising input target binding sequence with complementarity to an input target; and a terminator region wherein the target nucleotide sequence is independent of the input target sequence. The claim further recites functional limitations of the cgRNA, including the inactivation of the cgRNA if the input target sequence binds to the input target binding sequence and the activation of the cgRNA if the input target sequence does not bind to the input target binding sequence.
Accordingly, the claims are interpreted as claiming a large genus of cgRNA structures that comprise a target binding region, an effector handle region, a terminator insert region, and a terminator region that can perform the claimed function.
The MPEP lists factors that can be used to determine if sufficient evidence of possession
has been furnished in the disclosure of the application. These include "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. Disclosure of any combination of
such identifying characteristics that distinguish the claimed invention from other materials and
would leave one of skill in the art to the conclusion that the applicant was in possession of the
claimed species is sufficient." MPEP 2163. A claimed genus may be satisfied through sufficient
descriptions of a representative number of species or disclosure of relevant, identifying
characteristics such as functional characteristics coupled with known or disclosed correlation
between function and structure. MPEP 2163(3)a(II). The number of species that describe the
genus must be adequate to describe the entire genus; if there is substantial variability, a large
number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice,
(b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying
characteristics in the way of complete/partial structure or physical and/or chemical properties or
functional characteristics when coupled with known or disclosed correlation with structure, and
(d) representative number of samples.
As the claims currently recite, as described above, the claim is directed towards a genus
of cgRNA structures that comprise a target binding region, an effector handle region, a terminator insert region, and a terminator region that can perform the claimed function. While claiming a structure by a function is not prohibited, there must be sufficient structure-function relationship described in the specification such that the claimed genus was represented by a representative number of species or the teachings of the specification, or, the prior art can be used support a well-known structure-function relationship.
In the instant case, the instant specification does not support the claimed structure-function relationship that utilizing a cgRNA comprising the claimed structure would predictably result in the inactivation of the cgRNA if the input target sequence binds to the input target binding sequence and the activation of the cgRNA if the input target sequence does not bind to the input target binding sequence. Further, the prior art does not support a clear, well-defined, and predictable structure-function relationship between the claimed cgRNA structure and having the function of inactivation of the cgRNA if the input target sequence binds to the input target binding sequence and the activation of the cgRNA if the input target sequence does not bind to the input target binding sequence
Prior Art
Prior to the effective filing date of the claimed invention, the prior art does not provide evidence that guide RNAs could be conditionally inactivated through the use of a terminator insert region comprising input target binding sequence with complementarity to an input target.
Doudna (PG Pub No. US 2014/0068797 A1) is drawn towards an invention concerned with DNA-targeting RNA (Abstract). Doudna teaches the use of a guide RNA comprising a DNA-targeting segment (i.e., a target binding region), and a protein-binding segment (an effector handle region ([0410])) that is capable of binding to Cas9 (an RNA-guided effector) (Fig. 1 and [0034]). However, there is no express teaching of an "input target binding region/sequence" in Doudna.
Accordingly, the prior art does not teach or suggest that utilizing an input target binding region within a guide RNA utilized to conditionally inactivate the guide RNA, as required by the instant claims, is predictable or well-known in the art.
Working Examples
With regard to working examples, the specification provides little evidence on the possession of a sufficient number of species which are encompassed by the claimed genus of structures and possess the claimed function. Further, the instant specification teaches that structures that fall within the claimed genus of structures do not possess the claimed function and instead possess alternative functions.
It is noted that the claimed "input target sequence [that] bind[s] to the input target binding region sequence" is not limited to any particular structure and therefore broadly encompasses the genus of all possible input target sequences that could bind and control the cgRNA’s function. Accordingly, possession of the cgRNA as broadly claimed requires possession of the genus of such cgRNAs that have this claimed functional limitation.
The specification describes five different structures of cgRNAs that comprise the claimed structure and are capable of being constitutively inactivated in the presence of an input target (see Fig. 9-13). However, it is noted that the instant specification also describes cgRNAs comprising the claimed structure that are constitutively activated [emphasis added] in the presence of a target input (see Fig. 3-7). Therefore, the instant specification provides evidence that the broadly claimed cgRNA structure is capable of performing opposite functions.
Regarding the current claims that do not specify the particular structure for the "input target sequence" mainly responsible for the claimed function, the specification itself contains evidence that supports the sensitivity and unpredictability of whether any given "input target sequence" or sequence would have the same claimed function of rending the complex "conditionally perform any downstream function". For example, the specification simultaneously teaches two guide RNA structures comprising a target binding region, an effector handle region, a terminator insert region, and a terminator region (compare Fig. 3 to Fig. 9). However, despite having these similar structures, the specification characterizes one as being a cgRNA that can be "constitutively activated" (see Fig. 3) and the other as a cgRNA that can be "constitutively inactivated" (see Fig. 9), which are mutually exclusive of each other. The close similarly between these two guide RNAs’ structures despite the mutually exclusive functions is evidence of the sensitivity and criticality of the input target binding region structure, which is not recited in the current claims. The difference between these two designs appears to reside in the length of regions 302 (comprising domain d) or 902 (comprising domains b* and d), which are immediately 5' to hairpins 303 or 903. The specification does provide a description of mechanism 1 as depicted in Fig. 3 and states that domain d, has a length of 0 or 1-8 nucleotide in length, but also that "In some embodiments ... domain d may be any lengths" ([0106]).
The specification similarly provides a description of mechanism 7 as depicted in Fig. 9 and states that domain b* can be length 4-200 nucleotides in length, domain d can be 0-20 nucleotides in length, and further that domain b* and domain d "may be any lengths" ([0116]). The overlap in these descriptions of the relevant lengths of the relevant domains despite the opposite function is evidenced by the insufficiency of the respective descriptions (sequences). In addition, the teachings that such domains "may be any lengths" for each of these embodiments having mutually exclusive functions is further evidence of the insufficiency of these descriptions in view of the mutually exclusive functions as identified above.
The same reasoning can be applied to the additional embodiments described by the
specification. Each of the embodiments described by FIGs. 3-7 contain some variation of the claimed structure but are considered cgRNAs that can be constitutively activated (see FIG. 3-7). However, the embodiments described by FIGs. 8 and 10-13 also have variations of the claimed structure but are considered cgRNAs that can be constitutively inactivated (see FIG. 8 and 10-13). The specification does not describe a common characteristic in terms of the structure sequence of the input target binding region that is responsible for rendering the cgRNA inactivated if the input target sequence binds to the input target binding region of the cgRNA (see Claim 4) sufficient to show possession of the broad genus of all possible such input target binding regions that can perform the claimed function.
Conclusion
The specification does not identify a structure-function relationship between the broadly claimed cgRNA structure and the function of being conditionally inactivated when bound to an input target. Further, the closest prior art shows that it was not predictable that utilizing an input target binding region within a guide RNA utilized to conditionally inactivate the guide RNA, as required by the instant claims, is predictable or well-known.
Based on the limited amount of guidance provided by the specification in terms of specific structures for the cgRNA that satisfy the claimed function, the lack of teaching regarding the common structural characteristics of the input target binding regions capable of achieving the claimed function, the unpredictability in the art, and lack of specific teachings regarding input target binding regions, one of ordinary skill in the art would conclude that Applicant was not in possession of the genus of all possible cgRNA structures that can perform the claimed function as recited by the claims. Further, the unpredictability and extreme sensitivity of the technology is evidenced by the examples in the instant specification in which very similar cgRNA structures resulted in very different conditional outcomes when bound to an input X. Taken together, the skilled artisan would not have reasonably concluded at the time of the invention that applicant was in possession of the invention as claimed. Thus, claim 4 is rejected under 35 U.S.C. 112(a).
Regarding claims 23, 65-67, 70-72, and 74-76, as the claims are ultimately dependent on claim 4 and do not rectify the written description rejection descried above, the claims are also rejected under USC 112(a).
Response to Arguments
Applicant’s arguments, filed 29 August 2025, have been fully considered but are not deemed persuasive for the reasons that follow.
Applicant alleges that the claimed cgRNA has a specific structure as disclosed in the instant specification and as depicted in FIG. 12.
This argument is not found persuasive because the claimed cgRNA is not limited by any particular structure as depicted in FIG. 12. Further, MPEP 2111.01(II) teaches that it is improper to import claim limitations from the specification. Accordingly, arguments pertaining to how the claimed cgRNA comprises a specific structure as depicted in FIG. 12 are not found persuasive as the claim is drawn to a cgRNA that has a very broadly claimed structure.
Applicant alleges that the claimed cgRNA is different from other cgRNAs that operate via different mechanisms because the claimed cgRNA’s target binding region is not sequestered while the target binding region in FIGs. 3-6 are sequestered in the absence of an input target.
This argument is not found persuasive because the claim does not claim the inclusion or the exclusion of the target input sequence. Further, as described above in the 112(a) rejection of record, there is not any specific sequence requirements for the terminator insert region other than complementarity to a sequence of an undefined input target sequence. Thus, the broadest reasonable interpretation of the structure of the terminator insert region is any sequence of nucleotides since the input target sequence is also not defined by any specific structure. As depicted the right side of FIG. 3, the broadly claimed target binding region, effector handle region, terminator insert region, and terminator region maps to a cgRNA that is conditionally activated by an input target X. The cgRNA of the right side of FIG. 3 comprises, 5’ to 3’, a “previously sequestered b* domain of the target binding region” (i.e., a non-sequestered target binding region), an effector handle, a nucleotide sequence that bridges the handle and a terminator region, and a terminator region (see FIG. 3). Because the claimed terminator insert region does not comprise any specific structural limitations other than complementarity to a sequence of an input target, the structure of the claimed terminator insert region is not patentably distinct from the nucleotide sequence that bridges the handle and a terminator region present in FIG. 3.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636