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 .
Application Status
This action is written in response to applicant’s correspondence received on 3/30/2026. Claims 1-5, 7-17, 20-21, and 33 are pending. Claims 1 and 20-21 have been amended. Claims 6, 18-19, 22-32, and 34-37 have been previously cancelled. Claims 2, 4-5, 7-12, and 16 are withdrawn from consideration. Claims 1, 3, 13-15, 17, 20-21, and 33 are currently under examination.
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. This Office Action is Final.
Claim Rejections - 35 USC § 112 – Maintained/Updated in Response to Amendments
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, 13-15, 17, 20, 21, and 33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(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 Regents of the University of California v. Eli Lilly & Co, 119 F.3d at 1568, 43 USPQ2d at 1406.
Regarding independent claim 1, this claim recites a ribozyme comprising: a) one or two catalytic domains capable of switching between an active state and an inactive state; b) a releasable RNA segments, wherein each of said releasable RNA segment is flanked by two ribozyme cleavage sites, wherein each cleavage site is cleaved by at least one of the one or two catalytic domains in an active state; c) one or two target-binding domains, each of which is for the binding of a target RNA molecule; wherein each catalytic domain is linked to one of the one or two target-binding domains; wherein the catalytic domain is in an inactive state when the target-binding domain linked to said catalytic domain is not bound by the target RNA molecule, and wherein the catalytic domain is in an active state when the target-binding domain linked to said catalytic domain is bound by the target RNA molecule; and wherein when both cleavage sites flanking a releasable RNA segment are cleaved by the one or two catalytic domains, the releasable RNA segment is released from the ribozyme. Thus, the claims are broadly drawn to a genus of “ribozyme” with the above recited functional and structural domains. However, the Applicant has not shown species of ribozymes commensurate with the scope of the recited ribozymes to show possession of such a broad genus of ribozymes. For instance, the ribozymes are recited to “comprise” these elements, which indicates that the ribozymes can further comprise other unidentified structural domains, where it is unknown how such additional domains may affect the functionality of the ribozyme. Further, the Applicant has not identified a core structural-functional relationship to show possession of such a broad genus of domains (e.g., catalytic domain that switches between active and inactive states), where the recited ribozyme is not limited in size, structure, sequence, or content, and is only recited to comprise any number of the above functional domains. Such a broad genus of RNA molecule was not shown to be in possession by the Applicant, as it is known in the art that structure-function relationships between RNA molecule sequences and their structure are difficult to predict (see below).
With regards to guidance provided in the specification, as an initial matter, the Applicant addresses the limitations associated with the term “comprising” in paragraph 133 of the specification, stating that:
“[t]he invention illustratively described herein may suitably be practiced in the
absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "comprising", "including", "containing", etc. shall be read expansively and without limitation,” (paragraph 133).
Thus, by reciting that the ribozyme “comprises” the limitations of claim 1, and comprises “one or two of” each of the functional domains, the Applicant is indeed claiming an expansive genus of ribozyme, where the ribozyme molecule can comprise any additional features “without limitation.” The Applicant has not characterized additional RNA structures and domains in combination with the ribozymes and was therefore not in possession of the genus recited.
With regards to experimental reduction to practice, the Applicant offers Example 1, where they recite their methods of ribozyme generation and cleavage assays (pages 34-37). Example 2 offers examples of sequences used in the design of the ribozymes (pages 37-50). Results of ribozyme testing for various targets is shown in the Results Example (pages 50), where results are shown for ribozymes targeting miRNA dme-bantam-5p (Figures 4-5) and human miRNA has-let-7f (Figure 6). The Applicant shows that one ribozyme can detect RNA from a complex mixture (Figure 7), as well as detect variable lengths of target from coronavirus (Figure 8). The Applicant shows that a cleavage product can produce a fluorescent signal (Figure 9) as well as single catalytic ribozyme testing for the release of a product (Figure 10). The Applicant thus appears to have tested a few ribozymes and demonstrated functionality using a few ribozyme designs as shown in the figures, where furthermore it does not appear that the Applicant tested higher-order ribozymes comprising multiple catalytic domains, releasable RNA segments, catalytic cleavage sites, and target-binding domains, where the claims reasonably encompass embodiments with highly complex ribozymes (e.g., 8 cleavage sites for 4 RNA segments, 12 separate target-binding domains, 5 catalytic domains, etc., as the ribozyme is recited to “comprise” the recited domains).
However, independent claim 1 recites ribozymes with structural-functional relationships (i.e., a catalytic domain capable of switching between active and inactive states recited is inherently associated with a structure or sequence). The Applicant is not claiming and has not defined or identified a core structural element which defines the recited functional limitations of the claims, and the ribozymes reduced to practice are not representative of the unpredictable genus of ribozyme domains recited. The recited genus of ribozymes comprise multi-functional domains, which act in a coordinated multi-level fashion, and the Applicant has not recited and defined specifically what core sequences of ribozyme is required to meet such functional expectations for a given ribozyme sequence.
Regarding the current state-of-the-art, it is known that ribozyme sequence influences secondary structure, and furthermore that such predictions concerning sequence and structure with respect to RNA molecules and ribozymes is unpredictable. For instance, Roberts (Roberts JM et al. Elife. 2023 Jan 19;12:e80360) is a research article that focuses on associating RNA sequence with structure and function of ribozymes (Title, Abstract, and throughout). Roberts teaches that high-throughput sequencing experimentation using mutational analysis is required in order to identify functional consequences of mutations in ribozymes (Abstract). Roberts teaches that it is known that challenges exist when attempting to design RNA molecules, as variations in RNA sequences are known to have unknown functional effects (Introduction, first sentence). Roberts teaches that predicting functionality of RNA molecules from sequence is challenging and unpredictable owing to a sparsity information of RNA structures (Introduction, first paragraph). Roberts further teaches that RNA molecules with an ensemble of structures and functions (such as those presently recited) present particular challenges when trying to characterize RNA functionality by prediction (Introduction, first paragraph). For instance, the recited ribozymes comprise multiple structural/functional domains which are coordinated and interact with one another; Roberts teaches that, with regard to such structures:
“[i]t is unclear that predictions based on individual structures alone will be able to predict the functional effects of mutations with the precision needed for many biotechnical and synthetic biology applications,” (Introduction, first paragraph).
Roberts further teaches that in-depth sequencing and mutational analysis is required to characterize functional aspects of ribozymes, as ribozymes comprise complex folding and three dimensional structures (page , second paragraph).
To further corroborate the fact that RNA structure and function must be empirically demonstrated and confirmed because RNA structures are complex and unpredictable, Beck (Beck JD et al. Front Mol Biosci. 2022 Aug 15;9:893864) is a research article that focuses on predicting sequence effects on higher order RNA structure and function (Title, Abstract, throughout). Beck teaches that:
“the rational design of ribozyme activity remains challenging, and many ribozyme-based systems are engineered or improved by random mutagenesis and selection (in vitro evolution). Improving a ribozyme-based system often requires several mutations to achieve the desired function, but extensive pairwise and higher-order epistasis prevent a simple prediction of the effect of multiple mutations that is needed for rational design,” (Abstract).
and;
“ribozymes often need optimization for sequence dependent and cell specific effects. This can be achieved by modifying the sequence of the ribozymes, but this often requires multiple mutational changes and the vast sequence space requires extensive trial and error. Given this large sequence space, even the most high-throughput approaches can only find the optimal solutions present in the sequences that can be explored experimentally, which is a fraction of the total possible sequences,” (Introduction, first paragraph)
Thus, Beck teaches that predicting ribozyme function from sequence alone is complex and unpredictable and requires extensive empirical testing and design.
Aside from the fact that the recited genus of “ribozyme,” recited with specific functional and structural domains, remains uncharacterized and highly unpredictable based on sequence variations and complex three-dimensional structures which such RNA molecules could adopt, the genus of “ribozyme” is itself uncharacterized within the art. For example, Zhou (Yaoqi Zhou et al., 2023 eLife) teaches that:
“self-cleaving ribozymes in human genome are few and poorly studied. Here, we performed deep mutational scanning and covariance analysis of two previously proposed self-cleaving ribozymes (LINE-1 andOR4K15 ribozymes). We found that the functional regions for both ribozymes are made of two short segments, connected by a non-functional loop with a total of 46 and 47 contiguous nucleotides only. The discovery makes them the shortest known self-cleaving ribozymes. Moreover, the above functional regions of LINE-1 and OR4K15 ribozymes are circular permutated with two nearly identical catalytic internal loops, supported by two stems of different lengths. This new self-cleaving ribozyme family, named as lantern ribozyme for their shape, is similar to the catalytic core region of the twister sister ribozymes in term of sequence and secondary structure. However, the nucleotides at the cleavage sites have shown that mutational effects on lantern ribozymes are different from twister sister ribozymes. Lacking a stem loop for stabilizing the core active region and two mismatches in the internal loops may force lantern ribozymes to adopt a tertiary structure (and functional mechanisms) different from twister sister, requiring further studies. Nevertheless, the discovery of the lantern ribozymes reveals a new ribozyme family with the simplest and, perhaps, the most primitive structure needed for self-cleavage,” (Abstract).
Zhou is a post-filing publication, which means that after the application was filed, novel ribozymes were still being discovered (Abstract). Thus, the Applicant could not be in possession of the genus of “ribozyme” presently recited, as the genus itself is not fully characterized as evidenced by the fact that Zhou has discovered a new ribozyme with alternative structures which need further studies in order to be fully understood. For instance it is unclear whether or not the catalytic domain of the “lantern family” of ribozyme, identified by Zhou, would function with the recited ribozyme structure because this novel family or ribozyme is not fully characterized and adapts a unique structure/mechanism (above). Thus, the recited ribozymes and their functional domains such as the “catalytic” domain are not fully characterized within the art and were not shown to be in possession by the Applicant, as such ribozyme domains as the catalytic domain are still being discovered.
Claims 3, 13-15, 17, 20, 21, and 33 depend from claim 1 and do not resolve this 112(a) issue and are therefore also rejected.
The Applicant appears to be in possession of the specific sequences tested; however, specific sequences are not recited within the claims which are instead drawn to a broad genus of structurally undefined RNA structures/ribozymes.
Response to Arguments
The Applicant’s arguments filed 3/30/2026 have been considered but are not persuasive. The Applicant argues that the amendments of the original claim, from “one or more” to “one or two” addresses the previous 112(a) rejection directed to a ribozyme “without limitation” of sequence and structure. This argument is not found to be persuasive, because the ribozymes are still recited to “comprise” the recited elements, and are therefore recited without limitation of sequence and structures, per the specification (paragraph 133, see 112(a) argument, above). The Applicant argues that they have reduced to practice exemplary embodiments of the recited structures. This argument is not persuasive because the claims are presently drawn to broad, unpredictable categories of functional domains (e.g., catalytic domains which switch between active and inactive states based on target binding). However, the art teaches with regards to the broad category of ribozymes and RNA structures, that high-throughput sequencing experimentation using mutational analysis is required in order to identify functional consequences of mutations in ribozymes (e.g., Roberts, Abstract). Roberts teaches that predicting functionality of RNA molecules from sequence is challenging and unpredictable owing to a sparsity information of RNA structures (Introduction, first paragraph). Furthermore, the art teaches post-filing novel ribozyme sequences and structures which rely on different structural and sequence motifs in order to function as catalytic domains (“lantern ribozymes” as taught by Zhou, see 112(a) rejection, above). The fact that novel ribozyme catalytic domains with previously unidentified structures and sequences and novel mechanisms of action are still being discovered is strong evidence of the unpredictability of the recited genus of ribozyme/structural domains. When this fact is coupled with the teachings of Beck, that “the rational design of ribozyme activity remains challenging, and many ribozyme-based systems are engineered or improved by random mutagenesis and selection (in vitro evolution). Improving a ribozyme-based system often requires several mutations to achieve the desired function, but extensive pairwise and higher-order epistasis prevent a simple prediction of the effect of multiple mutations that is needed for rational design,” (Abstract), it is clear that the recited genus of ribozymes with structural motifs is unpredictable, as Beck teaches that designing and engineering such ribozymes is unpredictable and requires empirical reduction to practice. For instance, it is unclear if the novel ‘lantern ribozyme” could function as a switchable on/off catalytic domain, as it is a novel sequence and structure, where the art teaches difficulty and unpredictability when trying to engineer ribozymes with desired functions (Beck, above, Zhou, Abstract). Thus, the Applicant’s reduction to practice of specific ribozymes are not representative species of the claimed genus of ribozyme owing to unpredictable structural/sequence relationships of ribozymes (Zhou) and difficulty of engineering high-order, complex ribozymes as taught by Beck.
The Applicant argues that the arrangement and organization of the different functional domains in relation to each other are based on known structural domains of self-cleaving ribozymes, and that the sequences are therefore known in the art. This argument is not persuasive because it does not address the merits of the rejection, where Zhou teaches novel functional domains which were not known in the art, where furthermore engineering such novel sequences into complex functional ribozymes is unpredictable, per Beck. Furthermore, the Applicant is not claiming specific, known sequences of functional domains, but rather broad categories such as “ribozyme” and “catalytic domain” without specifically recited sequences and structures. The Applicant’s disclosure does not appear to be commensurate in scope with what is claimed because of the unpredictability and novel catalytic structures/motifs/sequences that are still being discovered in the art. The Applicant’s reduction to practice of known, predictable structures is therefore not representative of the genus of molecules presently claimed.
Furthermore, the Applicant has previously stated in the prosecution history that:
“[a]pplicant further submits that it is not reasonable to conclude that a person skilled in the art would be able to make a trigger-activated self-cleaving ribozyme by combining trigger-binding (as allegedly taught by Nilsen-Hamilton) with ribozyme enzymatic cleavage (Soukup). This is because enzymatic properties for ribozymes are not additive, like Lego blocks. Thus, such a conclusion is a severe underestimation of the foreseeable experimental burden and inventive skill required to modify a ribozyme's functional property (e.g., enzymatic cleavage capability) to switch-based or molecular signal-dependent,” (Remarks filed 8/18/2025, page 19).
Thus, the Applicant has acknowledged in the prosecution record that modifying catalytic/enzymatic cleavage capability of ribozymes to generate switch-based ribozymes requires a high degree of experimental burden and inventive skill, as enzymatic properties of higher or ribozymes are not additive, where ribozyme functional properties would need to be determined experimentally in the context of the presently recited structures (Remarks filed 8/18/2025, page 19). Such analysis applies to ribozymes of novel structural and sequence motifs such as “lantern ribozymes” as taught by Zhou.
The Applicant argues that Weinberg (Exhibit A) teaches that there are known ribozymes with defined structures and sequence motifs, where mutations in conserved catalytic cleavage sites reduce ribozyme activity where mutations in other sites do not have noticeable effect (Figure 1 of Weinberg, Exhibit A). This argument is not persuasive because the teachings of Weinberg demonstrate that mutations in ribozymes can reduce their catalytic activity, where such mutations must be empirically validated. Furthermore, the fact that there are known ribozymes with known structures and sequences such as the twister and hammerhead ribozymes does not address the unpredictability of novel, previously undefined ribozyme catalytic structures such as those taught by Zhou. This argument is therefore not persuasive.
The Applicant is in possession of the specific sequences tested; however, specific sequences are not recited within the claims which are instead drawn to a broad genus of ribozyme molecules, where core structure-function relationships are known to be unpredictable in the art as taught by Zhou. Furthermore, the Applicant’s arguments do not fully address the merits of the 112(a) rejection, which is based in part on the fact that novel structures/motifs/sequences unknown at the time of filing (the lantern catalytic ribozyme) were discovered after the application was filed, where such catalytic domains were not characterized and are inherently unpredictable with regards to their integration into the present ribozyme as it is taught in the art that it is difficult and unpredictable to engineer ribozyme designs (see 112(a) rejection, above).
The Applicant has shown possession of specific sequences of known domains and ribozymes, but such individual domains are not sufficient to show possession of the broader genus claimed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 DOUGLAS CHARLES RYAN whose telephone number is (571)272-8406. The examiner can normally be reached M-F 8AM - 5PM.
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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