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 .
Status of the Claims
This action is in response to papers filed 28 Dec 2025 in which claims 1, 6-7, 9-10, 13-14, 18 and 23 were amended, claims 8 and 15-16 were canceled, and no new claims were added. All of the amendments have been thoroughly reviewed and entered.
Any rejection or objection not reiterated herein has been overcome by amendment.
Claims 1, 6-7, 9-14, 18 and 23-24 are under consideration.
Amendments & Response to Arguments
Applicant has amended:
Claims 1 and 7 to overcome the 112b and 112a rejections; the previous 112b and 112a rejections have been withdrawn.
Applicants argue:
The 103 rejections constitute hindsight reasoning. Applicants arguments are not persuasive; the previous 103 rejection has been maintained.
Arguments are further addressed at the end of this Office Action.
Rejections not reiterated here are withdrawn.
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, 6-7, 9-14, and 18 remain rejected under 35 U.S.C. 103 as being unpatentable over Weiss (WO 2019027414) wherein claim 18 is evidenced by Ebert (Ebert MS, Sharp PA. RNA. 2010 Nov;16(11):2043-50. doi: 10.1261/rna.2414110. Epub 2010 Sep 20. ).
Regarding gene expression modulation as recited in the preamble, this amendment is being interpreted as intended use, which does not carry patentable weight, absent evidence showing that the composition rendered obvious in the rejection having all structural limitations cannot perform the intended use.
Weiss teaches genetic circuits wherein the different components of the circuit modulate and control each other’s expression; i.e., feed-forward and feedback motifs are integrated into the circuits (Fig. 1).
Regarding claims 1 and 7, Weiss teaches cell state classifiers comprising genetic circuits which are contained in vectors (The different genetic circuits of the cell state classifier may be included in one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) nucleic acid molecules (e.g., vectors) and introduced into a cell, pg. 48, lines 10-14). The cell state classifiers contain: a signal circuit containing a first activatable/repressible promoter ( reads on 1st expression vector comprising inducible promoter) that is activated by the activator of a first sensor circuit and an external inducer ( reads on inducer) and is repressed by a repressor encoded on a second sensor circuit ( reads on 2nd expressor vector encoding a regulatory RNA polynucleotide). Inducible promoters include any inducible promoter (pg. 33, lines 25 -26). Weiss teaches that the promoter of the signal circuit is operably linked to a nucleotide sequence encoding an output molecule ( reads on a first nucleic acid sequence comprising a coding sequence of said gene of interest ) and one or more target sites for a first set of microRNAs, (reads on a second nucleic acid sequence encoding a polynucleotide). Weiss teaches that a plurality of sensor and signal circuits may exist. The signal circuit comprises an inducible promoter that is operably linked to the output molecule. See recitation from pg. 4:
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Weiss teaches an example of a regulatory RNA polynucleotide is miR-FF3 (last paragraph on pg. 3, claim 35). miR-FF3 represses output (miR-FF3 repressing Output-2, pg. 10, line 25; One or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) target sites of the second regulatory microRNA may be placed in the second signal circuit, pg. 55, 2nd paragraph). MiR-FF3 is operably linked to a constitutive promoter (operably linked to the promoter of the second sensor circuit, pg. 55, line 9, Fig. 4). Weiss further teach, "microRNA target site" is a nucleotide sequence that is complementary to the nucleotide sequence of the microRNA (pg. 18, lines 13 - 14).
Weiss teaches that various modifications of the genetic circuits are possible (Using the rules described herein, one can design and test cell state classifiers and circuits having the same function but having increased performance, pg. 7, lines 4 – 5) and provide the method steps to follow in constructing a circuit from the various parts (Parts construction, pgs. 61 - 64). The teachings of Weiss describe a circuit of gene modulation which is activated by addition of an agent and provide a list of various such agents (inducible promoters may be induced by; Inducible promoters include any inducible promoter, last 2 paras on pg. 33).
Regarding claim 6, the circuit of Weiss is described above. Weiss teaches an in vitro cell comprising the genetic circuit (e.g., 4T1 breast cancer cells, last para of pg. 60).
Regarding claims 9 and 11, the circuit of Weiss is described above. Weiss further teach wherein the coding sequence encodes a therapeutic protein (pg. 49, line 22).
Regarding claims 10 and 12, the circuit of Weiss is described above. Weiss further teach wherein the coding sequence encodes interferon (IFN-gamma, IFN-alpha, pg. 29, line 23).
Regarding claims 13 and 14, Weiss teaches wherein the regulatory polynucleotide of claim 1 is a miRNA (e.g., miR-FFE-3, as discussed for claim 1 and 7).
Regarding claim 18, Weiss teaches wherein in the genetic circuit, the miRNA target sites (interpreted as second nucleic acid sequence) are binding-site sponge (BSS). This is evidenced by Ebert that define one or more target sites for a set of microRNAs are sponges (Ebert, 2nd para, 2nd sentence).
Weiss does not teach the second nucleic acid sequence must encode a polynucleotide that inhibits or reduces activity of a regulatory polynucleotide rather teaches that the second regulatory microRNA may be placed in the second signal circuit, as required by claims 1 and 7. While Weiss teaches one or more target sites for a set of microRNAs on the signal circuit in addition to the coding gene, Weiss does not teach that these one or more target sites for a first set of microRNAs inhibit or reduce activity of a regulatory RNA polynucleotide, rather this inhibition and reduction in RNAi activity is carried out by a second, different set of miRNA target sites (e.g., miR-FFE-3 target sites). In Weiss’s circuit, the expression of the coding sequence is inhibited or reduced by binding to target sites present on the polynucleotide of the coding sequence by a different set of microRNAs (environment miRNAs – low miRNA or high miRNA, Fig. 4).
However, Weiss teaches, see claim 1 (i) “a first sensor circuit comprising a promoter operably linked to a nucleotide sequence encoding a first activator (e.g., coding sequence of gene of interest) and one or more target sites (e.g., antagomir or sponge) for a first set of microRNAs”.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to encode a polynucleotide that inhibits or reduces activity of a regulatory polynucleotide into the first expression vector and thus recapitulate the modulation of gene expression as taught by Weiss in to a synthetic activation circuit that comprises at least 2 expression vectors. One of skill in the art would be motivated by the advantage of making a simpler circuit by substituting the first set of miRNA target sites on the vector comprising the output molecule into miRNA target sites that bind to the RNAi because it would have merely amounted to a simple combination/substitution of prior art elements according to known methods to yield predictable results and thus satisfy the claim limitations as recited in instant claims 1 and 7. One would have been motivated to do so for the advantage of simplifying the circuit and a goal of synthetic biologists is to redesign circuits for efficiency and simplicity. One of ordinary skill in the art would have reasonable expectation of success because Weiss provides the various elements to combine as well as the method steps to follow in constructing a circuit from the various parts. See MPEP 2143 (A), (B), and 2144 II.
Thus, Weiss makes obvious instant claims 1, 6-7, 9-14, and 18.
Claim(s) 23 and 24 remain rejected under 35 U.S.C. 103 as being unpatentable over Weiss (WO 2019027414) as applied to claims 1, 6-7, 9-14, and 18, above, wherein claim 18 is evidenced by Ebert (Ebert MS, Sharp PA. RNA. 2010 Nov;16(11):2043-50. doi: 10.1261/rna.2414110. Epub 2010 Sep 20. ) and further in view of Benedik (Benedik, Michael. (2019). Re: Number of same promoter in Plasmid?. Retrieved from: https://www.researchgate.net/post/Number-of-same-promoter-in-plasmid/5cfff9c10f95f125143c6dc3/citation/download), 3 pgs.).
Regarding claims 23 and 24, Weiss does not teach wherein in the synthetic a second nucleic acid sequence encoding a polynucleotide which inhibits or reduces activity of a single stranded RNA interfering (RNAi) molecule processed from a regulatory RNA polynucleotide circuit, said first promoter comprises two copies, and wherein said first nucleic acid sequence is operably linked to a first copy of said first promoter and said second nucleic acid sequence is operably linked to a second copy of said first promoter sequence rather, both the first and second nucleic acid sequences are transcribed from the same promoter.
However, before the effective filing date of instant invention, Bendik teaches that one may use two (copies of) promoters to express two output molecules in a single plasmid if one wishes to have the same number of output molecules (answer to the question, can I use two promoters to express two gRNA, pg. 1).
It would have been prima facie obvious to a person of ordinary skill in the art at the time the effective filing date to substitute the single polynucleotide under operable control of a single promoter to one where first and second nucleic acid sequences are separately under the control of same copies of different promoters, namely to arrive at the claimed invention, as redesigning of cellular circuits is a goal of synthetic biology. A person of ordinary skill in the art would be motivated to use a greater number of copies of the promoter (two copies of the same promoter as recited) in order to induce a stronger level of the expression of each of the linked nucleic acids since such substitution have been known in the art to be effective. It would be a simple substitution for one of ordinary skill in the art because it would have amounted to substitution of one known prior art element for another to obtain predictable results in the method. See MPEP 2143 I.(B). One of ordinary skill in the art would have reasonable expectation of success because both references involve common laboratory techniques.
Thus, Weiss in view of Benedik make obvious instant claims 23 - 24.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Response to Arguments
Applicant’s arguments, see Pgs. 16 - 17, filed 28th Dec 2025, with respect to rejections under 35 USC § 103 have been fully considered but are not persuasive. The previous rejection has been maintained.
In response to applicant's argument on pages 16-17 that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In the instant case, Examiner articulated an advantage to simplify the circuit of Weiss. Unlike Applicants statement, an advantage is a reasoning and not a conclusory statement. See MPEP para below that supports Examiner’s position:
2144 II. THE EXPECTATION OF SOME ADVANTAGE IS THE STRONGEST RATIONALE FOR COMBINING REFERENCES
The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983). See also Dystar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick, 464 F.3d 1356, 1368, 80 USPQ2d 1641, 1651 (Fed. Cir. 2006) ("Indeed, we have repeatedly held that an implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the ‘improvement’ is technology-independent and the combination of references results in a product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. Because the desire to enhance commercial opportunities by improving a product or process is universal—and even common-sensical—we have held that there exists in these situations a motivation to combine prior art references even absent any hint of suggestion in the references themselves.").
In response to applicant's argument on page 17, “the claimed synthetic gene expression modulation circuit achieves a specific technical effect that is not taught or suggested by the alleged prior art….that enables fold change activation”, this is not persuasive. “Fold change activation” is a feature that is not recited in the claims nor is it supported by the specification. Other than being the title of the invention, there are no examples or description of “fold change”. The term “fold change activation” encompasses any, limitless range of “fold change”, i.e., up to 1 million. This is not claimed or described.
Conclusion
Claims 1, 6-7, 9-14, 18, and 23-24 remain rejected.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/ Examiner, Art Unit 1635
/CATHERINE KONOPKA/ Primary Examiner, Art Unit 1635