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 Application
Claim(s) 1-22 are pending and under examination
The following Office Action is in response to Applicant's communication dated 07/20/2026.
Applicant’s amendments to claims 9, 15, and 20 have overcome 112(b)/112(d) rejections previously set forth in the Non-Final Office Action mailed May 26th, 2026.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 25 line 19. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Suggested Amendments
To ensure standard claims language, applicant is suggested to replace “Process for” with “A method for” in claims 1 and 4 and make corresponding changes in the dependent process claims.
For consistency, Applicant is suggested to label providing, isolation/amplification, creation steps as (a), (c), and (d) in claim 4, respectively, consistent with the specification [¶¶0028-0034 and ¶¶0125-0131 of the published application U.S. PGPub 2023/0374492 A1].
Claim Interpretation
Claim 4 does not limit the specific inducer(s) or expressly require an inducer distinct from ATP or Mg2+, which are required elements for Rho factor to efficiently unwind nucleic acid duplexes [Applicant’s specification ¶0084, 0106]. Hence, ATP and/or Mg2+ are not excluded from the scope of “inducer” given that the selected nucleic acid satisfies the claimed function of triggering helicase activity in response to presence of inducer. Under this interpretation, claim 1 and 4 may overlap insofar as an ATP-dependent selection process satisfies both claim 1’s aptamer substrate limitation and claim 4’s inducer responsive switch limitation.
Claim 12 and 13 recite isolated aptamer/switch by process used to obtain it. These claims constitute product-by-process claims. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) See MPEP § 2113.
In another word, the limitation being examined is the claimed product (aptamer and switch) and its recited structural characteristics. Consistent with interpretation of claim 4 above, claims 12 and 13 may encompass the same isolated nucleic acid where its functions include modulating helicase activity in response to ATP and/or Mg2+. For such product, the different selection processes do not, by themselves, establish structural function distinction.
Claim Rejections - 35 USC § 112(a)
Claims 1 and 4 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for selecting RNA aptamers and RNA switches, does not reasonably provide enablement for the full scope of the claimed process, including selection of DNA:DNA duplex aptamers and/or DNA switches that serve as helicase substrates under claim 1 and 4 scope. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. The reasons supporting this rejection are set forth below, with reference to the relevant undue experimentation factors identify in In re Wands 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988); and see also MPEP § 2164.01(a). Wands factors include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
(A) The breadth of the claims;
Claim 1 encompasses selection of DNA aptamers (e.g. DNA:DNA duplexes, where a randomized DNA strand is annealed to a complement DNA strand) that function as helicase substrates. Independent claim 4 additionally encompasses selection of DNA switches that stimulate helicase activity in response to an inducer. Neither claim limits the selected functional strand to RNA or the helicase to Rho. Hence, the scope of claims extend beyond obtaining RNA:RNA and RNA:DNA duplex library substrates of the helicase, it includes obtaining DNA:DNA duplex library substrates.
(C) The state of the prior art;
The following literatures identify two distinct contributions of RNA’s 2′-OH groups: stabilization of folded structure and participation in interaction with Rho helicase.
Liu et al. (Rna 13.2 (2007): 200-210) experimentally show that removing specific 2′-OH groups impair folding of kink turn RNA motif. Replacing the L1 ribose 2′-OH with hydrogen prevented metal-ion-induced folding of tested motif. This finding shows the importance of specific hydrogen bond interaction in stabilizing folded conformation [pages 200-210].
Similarly, Paladino et al. (J. Chem. Theory Comput. (2013) 9 (2): 1214–1221) uses molecular dynamics simulations to compare an RNA hairpin with an analogue containing deoxyribose (DNA) in the loop. Their results attributes increased RNA hairpin stability to hydrogen bonds between 2′-OH and surrounding bases, sugar, and phosphates, “Our results contribute to the notion that one of the important roles of the ribose sugars in RNA is to facilitate hairpin formation.”. The reference further supports structural trade off of replacing RNA’s 2′-OH groups with hydrogen in examined motif.
Homan et al. (Biochemistry. 2014;53(43):6825-6833.) further shows bulky modification at 2′-OH position disrupts tertiary folding, including in thiamine pyrophosphate and B. subtilis M-Box riboswitches. This provides additional evidence that chemical environment at 2’ position affect riboswitch folding although the experiments did not replace 2′-OH with 2′-H.
Schwartz et al. (Nat Struct Mol Biol 16, 1309–1316 (2009), disclosed in IDS) shows that RNA track’s 2’-OH groups participate in step wise activation of Rho helicase during RNA-DNA duplex unwinding [abstract]. The finding identifies additional obstacle to transferring Rho helicase system to binding DNA-DNA substrates.
Dehghani-Tafti (Nucleic Acids Res. 2017;45(12):7354-7366) discloses Human UPF1 (hUPF1) is able to unwind dsDNA in an ATP dependent process.
(F) The amount of direction provided by the inventor
FIG. 3 diagram illustrating the steps of the helicase SELEX process for selecting DNA aptamers [¶0044-0045]. Specification further discloses library of nucleic acid duplex constructs contains double stranded nucleic acid molecules, consisting of DNA/DNA duplexes [¶0092]
(G) The existence of working examples
Working examples shows selections of RNA-DNA duplexes including serotonin responsive RNA switches. DNA only serve as template or complementary strand [Examples 1-3].
Specification lacks selections of DNA-DNA embodiments, which limits the experimental support for extending RNA embodiment to DNA scope.
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Although Dehghani-Tafti and Applicant’s Fig.3 shows UPF1 able to unwind DNA-DNA substrates, such disclosures does not teach how to configure a DNA-DNA library so that the randomized DNA strand forms structurally functional aptamers or switches suitable for screening.
Liu and Paladino demonstrate specific RNA folds depend on stabilizing interactions involving 2’-OH groups , while Homan demonstrates modification of such involving 2’-OH groups can disrupt tertiary folding. These findings highlight uncertainty in assuming that the demonstrated RNA structure and functions will transfer simply to DNA. Additional experiments may be needed to determine whether randomized DNA strands able to form functional aptamers and/or switches within DNA-DNA constructs under the disclosed screening conditions.
Claims 2, 3, 5-8, 10, 11, 16, and 18-20 are also rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because their scope comprise the DNA-DNA selection embodiment address above. The additional limitations: rounds of selection and sequencing (claim 2); immobilizing (claim 3); and automation (claims 11 and 19) do not resolve the identified deficiency in selecting functional DNA aptamer or switches. The inducer limitation of claims 5, 6, and 20 and selection/counter selection of claim 7 maintain the requirement to obtain functional DNA switches. Claims 8 and 16 specify Rho or UPF1 helicases, which also do not resolve the identified deficiency of obtaining DNA candidates to be screened. Claim 10 and 18 claiming DNA complementary strand alternative without restricting the randomized functional strand RNA.
Claim Rejections - 35 USC § 112(b)
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.
Claim(s) 10, 15, 18 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.
Claim 15 recites a method for detecting a compound of interest, “using the genetic construction of claim 14”, but does not recite what steps must be performed to carry out the method. The statement of “the switch is responsive to the presence of said compound of interest.” only describe what a generic construction can do. It does not identify a procedure of detection process. “Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph” (see MPEP § 2173.05(q)).
Claims 10 and 18 recite “2′-alkyl-RNA strand”, which does not clearly identify the chemical modification required. It fails to because it fails to clarify whether the alkyl group replaces the entire 2′-hydroxyl group (-OH) to form a direct carbon-carbon bond on the ribose ring (2′-C-alkyl RNA), or if it is attached via an ether linkage to the oxygen atom (2′-O-alkyl RNA). These alternatives identify chemically distinct structures. Applicant’s specification ¶0102 repeated the term without defining the structure. It is also unclear if the term requires modification of every nucleotide in the strand or encompasses strands having only selected modified nucleotide. For these reasons, one of ordinary skill in the art cannot determine with reasonable certainty the scope of protection, the metes and bounds of the claim are unascertainable.
Applicant(s) is/are required to clarify the attachment chemistry of the modification. Any amendment must be supported by the original application filed. Clarification introducing structure or modification that was not expressly disclosed would raise a separate issue of new matter or lack of written descriptin support.
Claim Rejections - 35 USC § 101
Claims 12 and 13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to product of nature without additional element amount to significantly more than judicial exceptions as per MPEP 2106.04(b)(II).
Step 1: Claims 12 and 13 recite isolated nucleic acid product and thus fall within statutory category of composition of matter.
Step 2A, Prong One: Applicant’s specification expressly contemplates aptamers are “qualified as being “natural” in the case they have been isolated from a library of natural nucleic acid fragments” [0162-0166]. Additionally, example 4 further describes naturally encoded Rut sites as aptamer that function as Rho helicase’s substrate [¶0228-0234].
Holland et al. (Proc Natl Acad Sci U S A. 2012;109(14):5376-5381, , disclosed in IDS) describes naturally occurring Salmonella mgtA leader RNA and its Mg2+ sensing regulation of Rho-dependent transcription termination. Fig. 1 and 2 provide evidence of RNA’s regulatory conformations and interaction with Rho.
Both applicant disclosure and Holland’s description of naturally occurring riboswitches support identification of corresponding natural RNA embodiment encompassed in claims 12 and 13. Hence claims 12 and 13 recite judicial exception under Step 2A, Prong One, see MPEP § 2106.04(c). The analysis proceeds to Step 2A, Prong Two to determine whether the claims integrate the exception into practical application.
Step 2A, Prong Two: The claims encompass the identified natural product themselves. Isolation and selection limitations identify how the product is obtained, and they do not require practical application integrating the product of nature into a patent-eligible invention. See MPEP § 2106.04(d).
Step 2B: Considered individually and together, the remaining limitations add no significant product characteristic or other element beyond obtaining the identified natural product. Accordingly, the claims do not amount to significantly more than the judicial exception. See MPEP § 2106.05 (b)-(c).
Claim 15 is rejected under 35 USC § 101 because the claimed invention is directed to nonstatutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because attempts to claim a process without setting forth any steps involved in the process fail to comply with 35 U.S.C. 101. Although the claim starts with “A method for detecting a compound of interest”, the remaining limitations merely identify the genetic construction to be used and its responsiveness characteristic to a compound. The phrase “using the genetic construction of claim 14” recites intended use without define the procedure by which it is performed. The “wherein the switch is responsive to the presence of said compound of interest.” simply describe the property of the switch rather than operative steps. See MPEP § 2173.05(q).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 13-14 and 21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hollands et al. (Proc Natl Acad Sci U S A. 2012;109(14):5376-5381, disclosed in IDS).
Regarding claims 12 and 13, Hollands discloses isolated mgtA as a Mg2+ responsive riboswitch. High Mg2+ promotes formation of stem-loops that enable mgtA’s interaction with helicase Rho and promotes Rho-dependent transcription termination [Figs. 1A, 2B-D, result and method sections]. Hence Hollands discloses isolated switch that modulates helicase activity in response to an inducer, Mg2+.
Regarding claims 14 and 21, Hollands further discloses genetic construction comprising the switch of claim 13 and an expression cassette, which is a reporter system comprising a reporter gene in said expression cassette. (e.g. wild-type Salmonella harboring a plasmid with a plac1–6-driven transcriptional fusion of the wild-type mgtA leader to a promoterless E. coli lacZ gene (pYS1010). LacZ serves as a reporter gene. [Fig.1 legend])
Subject Matter Free of Prior Arts
Instant claims 9, 17 and 22 are free of prior art, but objected to as being dependent upon a rejected base claim. The following references were considered as the closest prior arts:
The closest prior arts considered during examination includes Jang et al. (Biochem. Biophys. Res. Commun. 66.3 (2008): 738-744, disclosed in IDS). Jang teaches an in vitro SE LEX process for isolating
inhibitory RNA aptamers against SARS coronavirus NTPase/Helicase (nsPlO) using an RNA library having
random sequences of 40 nucleotides. Jang further teaches repeated rounds of selection, recovery, amplification, and enrichment of RNA aptamer pool inhibit helicase unwinding activity.
Regarding claim 1, Jang does not teach or suggest the claim process of claim 1. Jang's SE LEX
selection is based on affinity association of RNA molecules with helicase, where in the non-binding RNA
candidates are removed and the bound RNA candidates are recovered and amplified. Jang's helicase
unwinding assay is used to characterize the inhibitory potency of the selected candidates, not part of the selection criteria/condition. Meanwhile, claim 1 and 4 uses helicase-mediated duplex unwind/disassociation as the basis for selection and enrichment. Jang does not disclose or suggest this
activity-based selection mechanism.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Khai Quynh Tien Pham whose telephone number is (571)272-6998. The examiner can normally be reached M-T, 9-4 ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached at (571) 272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KHAI QUYNH TIEN PHAM/Examiner, Art Unit 1684
/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684
