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 .
Claim/Application Status Summary
Claims 1, 7, 23- 28, 31- 33, 35- 38, 44, 45, 48- 50 are pending.
Claims 1, 7, 23- 28, 31- 33, 35- 38, 44, 45, 48, and 49 are examined on the merit.
Claim 50 is withdrawn.
Claims 1, 7, 23- 28, 31- 33, 35- 38, 44, 45, 48, and 49are rejected.
No Claims allowed.
Election/Restrictions
Claim 50 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 2026 June 8.
Applicant’s election without traverse of Invention Group I, species Group A, miR-155, species group B, combination miR-143, and species Group C, Caspase 9 in the reply filed on 2026 June 8 is acknowledged.
This examiner will proceed with prosecution according to the elections as noted above.
Claim Rejections - 35 USC § 112
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 1, 7, 23- 28, 31- 33, 35- 38, 44, 45, 48, and 49 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.
Those claims included in the statement of rejection but not otherwise discussed (claims 7, 23- 28, 31- 33, 35- 38, 44, 45, 48, and 49) are rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim 1 recites the limitation "the translation suppressor" in line 7 and 10 (twice). There is insufficient antecedent basis for this limitation in the claim because the claim does not previously recite any translation suppressor. It is unclear what structural element is meant by “the translation suppressor.”
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 7, 23, 25, 25, is/are rejected under 35 U.S.C. 103 as being unpatentable over Weiss (Weiss US 20180296702 A1).
Claim interpretation
Regarding claim 1, as noted above, "the translation suppressor" appears in line 7 and 10 (twice) whereas there is no proper antecedent basis for this term. However, based on the prosecution history, the original claim (filed 2023 July 10) contained proper antecedent basis for this term. However, in the amended claim (filed 2023 December 4) the term has been replaced with “Cas6” except where noted in line 7 and 10. In order to advance prosecution, where the instant claim recites the term "the translation suppressor," this examiner will instead interpret the term to read “Cas6.”
Weiss teaches “Engineered synthetic RNA-based genetic circuits are provided that are regulated exclusively at the post-transcriptional level.” [Abstract]; and shows the first and second recombinant RNA molecules of the expression regulatory system indicated by the Fig. 7A shown below.
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Weiss further teaches “a first RNA molecule comprising at least one sequence recognized by at least one first microRNA that is/are specifically expressed in a first cell type, and a sequence encoding a protein that specifically binds to a RNA motif and inhibits protein production” [0008]. Weiss’s Figure 7A teaches a miR binding to a miR recognition element in the 3’UTR. Weiss further teaches their embodiment “In some embodiments, the synthetic RNA circuit further includes a sequence encoding Csy4 protein (Cas6) and a Csy4 recognition site” [0019]; and Weiss provides an image of a Csy4 (Cas6) embodiment in Fig. 64 (shown below).
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Here, Weiss teaches the limitation “a recombinant first RNA molecule, comprising (i) a coding sequence for a Cas6 and (ii) a first microRNA (miR) recognition element in its 3′ UTR, wherein the first miR recognition element recognizes one or more first miR expressed in the target cell.” Furthermore, Weiss’s envisioned embodiments provide for the Csy4 (Cas6) substitution for L7Ae in the image above. Regarding the clause “binding of one or more of the one or more first miR to the first miR recognition element reduces translation of the [Cas6],” binding of miR-21 (as indicated by the Fig. 7A shown above) will reduce translation of the [Cas6].
Weiss continues to teach “a second RNA molecule comprising at least one sequence recognized by at least one second microRNA that is/are not expressed in the first cell type or is expressed at a low level relative to a second cell type” [0008]. Weiss’s Figure 7A teaches a miR binding to a miR recognition element in the 3’UTR. Weiss further teaches “at least one RNA motif and a sequence encoding an output molecule [coding sequence for gene of interest; EGFP in the image above]” [0008]. Regarding the clause “wherein binding of the [Cas6] to the recognition sequence for [Cas6] reduces translation of the gene of interest,” binding of Cas6 to the mRNA as indicated by the Fig. 7A (shown above), where Csy4 (Cas6) is substituted for L7Ae protein as noted in [0019] will necessarily reduce translation of the gene of interest. Regarding the clause “binding of one or more of the one or more second miR to the second miR recognition element reduces translation of the gene of interest,” binding of miR146a (as indicated by the Fig. 7A shown above) will reduce translation of the gene of interest.
Weiss further teaches their embodiment “all cytosine and uridine residues are replaced with 5-methylcytosine and pseudouridine” and “modRNAs used in this study contain antireverse cap analog” [0263].
It would have been obvious for a person having ordinary skill in the art (PHOSITA) at the time of filing to have substituted Weiss’s L7Ae for the Csy4 (Cas6) they described in their embodiment because it is simply combining prior art elements according to known methods to yield predictable results. Weiss taught all of the elements of the instant claim and further envisioned the embodiment of a first RNA coding a Cas6 and microRNA recognition element in the 3’ UTR as claimed. A PHOSITA would recognize that both L7Ae and Cas6 may regulate RNA expression according their individual specificities. A PHOSITA would further recognize the Cas9 of Weiss would function in Weiss’s system (recognize RNA sequences and cleave nucleic acids) in the same manner it would function outside of the system. Therefore, a PHOSITA would have predicted the combination of Weiss’s Cas6 embodiment within the same cited system would successfully regulate expression of a gene of interest.
Regarding claim 7, Weiss teaches their RNA regulatory circuit system targets tumor cells by differentiating tumor cells from non-tumor cells, “RNA-only multi-input microRNA classifier circuit differentiates between HeLa [tumor cells], HEK 293 and MCF7 cells” [0110].
Regarding claims 23 and 24, Weiss further teaches “I.m. [intramuscular] delivery of RNA [circuit] is accomplished by packaging the RNAs into LNPs [lipid nanoparticle]” [0488] in their “Example 6 Self-Replicating RNA Prime/Boost Circuit Vaccine for Respiratory Syncytial Virus (RSV).”
Regarding claim 25, a nanoparticle will have any one of “a positive charge, a negative charge, or a neutral charge” and no other charge. Weiss’s nanoparticle has at least one of these charges and therefore anticipates claim 25.
Claim(s) 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weiss (Weiss US 20180296702 A1) as applied to claim 1 above, and further in view of Kent (Kent et al. Nucleic Acids Res. 2014 Jul;42(12):7528-38.).
The applicant is reminded the election of species group B, mir-143 reads on the instant claim 26.
Weiss teaches all of the elements of claim 1.
Weiss does not teach the limitation “wherein the second miR recognition element includes a miR-143 recognition element.”
Kent teaches the differential cellular expression patterns of miR-143 “Importantly, a recent discovery demonstrates that miR-143 and miR-145 are not expressed in colonic epithelial cells; rather, these two miRNAs are highly expressed in mesenchymal cells such as fibroblasts and smooth muscle cells” and further states miR-143 has a “cell type-restricted expression pattern.” (Abstract).
It would have been obvious for a person having ordinary skill in the art (PHOSITA) at the time of filing to have taken Weiss’s expression regulatory system and substituted any/all of the second miR recognition element for a miR-143 recognition element as taught by Kent because it is a simple substitution of one known element for another to obtain predictable results. As noted above, Weiss’s system successfully utilizes differential cellular miR expression as a core regulatory element in their invention. Additionally, Kent showed miR-143 has similar differential cellular expression. A PHOSITA would recognize miR recognition elements function in a similar manner (induce mRNA degradation), and are therefore interchangeable based the individual needs (cellular expression level of a particular miR) of the inventor. Therefore, a PHOSITA would have predicted the combination of Weiss system with Kent’s miR-143.
Claim(s) 27, 37, 44, and 45, is/are rejected under 35 U.S.C. 103 as being unpatentable over Weiss (Weiss US 20180296702 A1) as applied to claim 1 above, and further in view Mahesh (Mahesh et al. J Interferon Cytokine Res. 2019 Jun;39(6):321-330.).
The applicant is reminded the election of species group A, mir-155 reads on the instant claims 27 and 37.
Weiss teaches all of the elements of claim 1.
Weiss does not teach the limitation “wherein the first miR recognition element comprises a miR-155 recognition element.”
Mahesh teaches the differential cellular expression patterns of mir-155 “MiR-155 expression varies in different cell types and tissue environment” (page 497). In this scenario, miR-155 is the “one or more first miR expressed in a target cell” that “the first miR recognition element recognizes.”
It would have been obvious for a person having ordinary skill in the art (PHOSITA) at the time of filing to have taken Weiss’s expression regulatory system and substituted any/all of the first miR recognition element for a miR-155 recognition element as taught by Mahesh because it is a simple substitution of one known element for another to obtain predictable results. As noted above, Weiss’s system successfully utilizes differential cellular miR expression as a core regulatory element in their invention. Additionally, Mahesh showed miR-155 has similar differential cellular expression. A PHOSITA would recognize miR recognition elements function in a similar manner (induce mRNA degradation), and are therefore interchangeable based the individual needs (cellular expression level of a particular miR) of the inventor. Therefore, a PHOSITA would have predicted the combination of Weiss system with Mahesh’s miR-155.
Regarding claim 44, Weiss teaches the limitation “wherein the target cell comprises a tumor cell” as described above.
Regarding claim 45, Mahesh teaches “The lncRNA MIAT (myocardial infarction associated transcript) acts as a ceRNA to regulate DUSP7 mRNA by sponging miR-155 in breast cancer cells.” Here Mahesh teaches miR-155 (the targeting microRNA) is expressed in breast cancer cells and therefore teaches the limitation “wherein the tumor cell comprises a breast tumor cell.”
Claim(s) 28 and 38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weiss (Weiss US 20180296702 A1) as applied to claim 1 above, and further in view of Kent (Kent et al. Nucleic Acids Res. 2014 Jul;42(12):7528-38.) as applied to claim 26 above, and Mahesh (Mahesh et al. J Interferon Cytokine Res. 2019 Jun;39(6):321-330.) as applied to claim 27 above.
The applicant is reminded the election of species group A, mir-155 and species group B, mir-143 read on the instant claims 28 and 38.
Weiss-Mahesh teaches all of the elements of claim 1 and claim 27.
Weiss-Kent teach all of the elements of claim 26.
Therefore for all of the reasons stated above, the instant claim limitation “wherein the second miR recognition element comprises a miR-143 recognition element” is obvious.
Claim(s) 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weiss (Weiss US 20180296702 A1) as applied to claim 1 above, and further in view of Malizia (Malizia et al. Wiley Interdiscip Rev Syst Biol Med. 2011 Mar-Apr;3(2):183-90.).
Weiss teaches all of the elements of claim 1.
Weiss does not teach the limitation “wherein the target cell is a heart tissue cell.”
However Weiss teaches a “first microRNA that is/are specifically expressed in a first cell type” and a “second microRNA that is/are not expressed in the first cell type.”
Malizia teaches differential cellular expression patterns of microRNAs, “Many miRNAs are expressed in a tissue/organ-specific manner” (Abstract) and specifically highlights heart tissue “A subset of miRNAs are either specifically or highly expressed in cardiac muscle” (Abstract). Malizia finishes this statement with motivation to exploit the heart tissue’s differential microRNA expression, “providing an opportunity to understand how gene expression is controlled by miRNAs at the post-transcriptional level in this muscle type.”
It would have been obvious for a PHOSITA at the time of filing to use Weiss’s system target heart tissue as taught by Malizia because there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention (“TSM”). Weiss’s successful system is designed to exploit differential miR expression in tissues. Malizia gave a motivation to exploit these miR expression differences in heart tissues. Therefore, a PHOSITA would have had a reasonable expectation of success targeting Weiss’s system in Malizia’s heart tissue cells.
Claim(s) 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weiss (Weiss US 20180296702 A1) as applied to claim 1 above, and Mahesh (Mahesh et al. J Interferon Cytokine Res. 2019 Jun;39(6):321-330.) as applied to claim 27 above, and further in view of Zhang (Zhang et al. FEBS Lett. 2013 Nov 15;587(22):3661-7.).
Weiss and Mahesh teach all of the elements of claims 1, 27, and 37.
Weiss and Mahesh do not teach the limitation “wherein the one or more off-target cell is selected from one or more of a non-cardiomyocyte heart tissue cell, a lung tissue cell, a liver tissue cell, and a spleen tissue cell.”
Mahesh further teaches miR-155 is expressed in several types of tissues “The expression of miR-155 was first reported in human spleen and thymus, liver, lung, and kidney” (page 324). In this scenario, miR-155 is the “one or more first miR expressed in a target cell” that “the first miR recognition element recognizes.”
Zhang teaches the off-target cell is lung tissue by teaching miR-143 is expressed in lung tissue “we demonstrate that miR-143 is aberrantly downregulated in NSCLC [Non-small cell lung cancer] tissue and negatively correlates with expression of PKCε.” (Abstract). In this scenario, miR-143 is the “one or more second miR expressed in an off-target cell” that “the second miR recognition element recognizes.”
It would be obvious to a PHOSITA to have combined the system of Weiss-Mahesh in a scenario that targets either a spleen, thymus, liver or kidney tissue and further included Zhang’s miR-143 that is expressed in the off-target lung tissue cell and arrive at the instant claimed invention because it is simply combining prior art elements according to known methods to yield predictable results. As shown by Zhang, a PHOSITA would have known miR-143 is expressed in lung tissue. Furthermore, a PHOSITA would have known of Weiss’s system designed to exploit differences in cellular expression of microRNAs. Therefore, a PHOSITA would have predicted the Weiss-Mahesh’s system would work successfully where the off-target cell is lung tissue as taught by Zhang.
Claim(s) 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weiss (Weiss US 20180296702 A1) as applied to claim 1 above, and Mahesh (Mahesh et al. J Interferon Cytokine Res. 2019 Jun;39(6):321-330.) as applied to claim 27 above, and further in view of Seok (Seok et al. Circ Res. 2014 May 9;114(10):1585-95.).
Weiss and Mahesh teach all of the elements of claims 1 and 27.
Weiss and Mahesh do not teach the limitation “wherein the target cell is a cardiomyocyte.”
However, Mahesh further teaches “Misregulation of specific miRNAs leads to various human diseases, including … cardiovascular diseases” (page 321, 2nd column). Here, Mahesh teaches a motivation to look toward targeting heart related tissue, for example cardiomyocytes.
Seok teaches the target cell is a cardiomyocyte by teaching miR-155 is expressed in cardiomyocytes “we found that miR-155 is expressed in cardiomyocytes” (Abstract). Here, miR-155 is the “one or more first miR expressed in a target cell” that “the first miR recognition element recognizes.”
It would be obvious to a PHOSITA to have combined the system of Weiss-Mahesh in a scenario that targets cardiomyocytes as taught by Seok because there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention (“TSM”). As noted above, Weiss-Mahesh’s system is designed to exploit differential cellular expression of microRNAs. Mahesh went further to provide motivation to use the system in cardiomyocytes as taught by Seok as stated above. Therefore, a PHOSITA would have had a reasonable expectation of success targeting Weiss-Mahesh’s system in Seok’s cardiomyocytes cells.
Claim(s) 35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weiss (Weiss US 20180296702 A1) as applied to claim 1, 23, and 25 above, and Mahesh (Mahesh et al. J Interferon Cytokine Res. 2019 Jun;39(6):321-330.) as applied to claim 27 above, and further in view of Mazed (Mazed US 20220003676 A1).
Weiss and Mahesh teach all of the elements of claims 1, 23, 25 and 27.
Weiss and Mahesh further teach all of the elements of the instant claim except the limitation “wherein the nanoparticle comprises … a positive charge.”
Mazed teaches the instant claimed limitation “nanoparticles of iron oxide can be synthesized with a positive electrical charge” [1448]. ]. Mazed teaches a nanoshell and nanoparticle are interchangeable “a nanoshell …can be any one of the following: ... an iron nanoparticle, a lipidoid, a liposome… a ribonucleic acid (RNA) origami based nanostructure… a solid-lipid nanoparticle.” [0224]. Mazed further shows their embodiment is in the same field of endeavor (RNA circuits/regulatory systems) as Weiss-Mahesh and therefore compatible by teaching “The nanoshell can also include RNAi based logic circuit.” [0226]; and “synthetically designed biological logic circuits (e.g., RNA based logic gates) can enable a programmable neural network based intelligent system, which can produce a biological output, based on thresholds of many biological inputs [miR expression]” [0287].
It would be obvious to a PHOSITA using the system of Weiss-Mahesh to also use an embodiment of positively charged nanoparticles as taught by Mazed because it is simply combining prior art elements according to known methods to yield predictable results. As noted above, Weiss-Mahesh envisioned nanoparticles for RNA regulatory systems/circuits of no particular charge, but capable of any charge. Mazed similarly envisioned nanoparticles for RNA regulatory systems/circuits where the nanoparticles were positively charged. Therefore a PHOSITA would have predicted Mazed’s positively charged particle would work successfully in Weiss-Mahesh’s RNA regulatory systems/circuits.
Claim(s) 36, 48, and 49 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weiss (Weiss US 20180296702 A1) as applied to claim 1 above, and Mahesh (Mahesh et al. J Interferon Cytokine Res. 2019 Jun;39(6):321-330.) as applied to claim 27 above, and further in view of Flynn (Flynn US 20210171582 A1). Claim 49 is further evidenced by Soengas (Soengas et al. Science. 1999 Apr 2;284(5411):156-9.)
The applicant is reminded the election of species group C, caspase 9 protein reads on the instant claim 36.
Weiss and Mahesh teach all of the elements of claims 1 and 27.
Weiss and Mahesh do not teach the limitation “wherein the gene of interest encode a caspase 9 protein.”
Weiss further teaches they envisioned embodiments comprising proteases (repression enhancers, RE and/or general transcriptional enhancers, GTE) as disclosed in Table RE [page 66] and Table GTE [page 71] respectively; and they further show an embodiment in Fig. 77 (shown below) and Fig 68 (shown below Fig. 77).
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Flynn teaches the same field of endeavor (RNA circuit/regulatory systems) “Disclosed herein include methods, compositions, and kits suitable for robust and tunable control of payload [gene of interest, GOI] gene expression. Some embodiments provide rationally designed circuits, including miRNA-level and/or protein-level incoherent feed-forward loop circuits” [Abstract]; and “rationally designed circuits that control the expression of its payload, including miRNA-level and protein-level incoherent feed-forward loop circuits.” [0085].
Flynn further teaches the instant limitation “in some embodiments, the payload gene encodes a … Caspase-9” [0149].
It would be obvious to a PHOSITA using the system of Weiss-Mahesh to use the caspase 9 gene of interest (payload) as taught by Flynn because it is simply combining prior art elements according to known methods to yield predictable results. As noted above, Weiss-Mahesh envisioned proteases within their RNA regulatory systems/circuits. Flynn similarly envisioned proteases, specifically caspase 9 within their RNA regulatory systems/circuits. Therefore a PHOSITA would have predicted Flynn’s caspase 9 protease would work successfully as envisioned by Weiss-Mahesh’s RNA regulatory systems/circuits.
Furthermore, regarding claim 49, caspase-9 is a tumor suppressor as evidenced by Soengas. Soengas teaches “Apaf-1 and Casp9 had a profound effect on suppressing the tumorigenicity of Myc-Ras MEFs” (page 157, 3rd column).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AARON DUREL WARD whose telephone number is (571)272-8495. The examiner can normally be reached Monday to Thursday 8:00AM 6:00PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 15712705919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AARON DUREL WARD/ Examiner, Art Unit 1636
/NEIL P HAMMELL/ Supervisory Patent Examiner, Art Unit 1636
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