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 .
This action is in response to the amendment, filed 07/06/2026, in which claim 8 was amended, claim 36 was canceled and claim 53 was newly added. Claims 27 and 28 are currently withdrawn due to an election/restriction requirement in a previous office action. Claims 8, 9, 26, 31-35 and 37-53 are currently under examination.
Applicant’s arguments have been thoroughly reviewed but are not persuasive for the reasons that follow. Any rejections and objections not reiterated in this action have been withdrawn.
This action is FINAL.
Priority
Acknowledgment is made of applicant' s claim for priority based on a provisional application filed as 62/832,171 on 04/10/2019.
All claims are given the priority date of 04/10/2019.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 8, 9, 26, 31-35 and 37-53 are rejected under 35 U.S.C. 103 as being unpatentable by Afonin et al (Nucleic Acids Research, Volume 42, Issue 3, 1 February 2014, Pages 2085–2097; Cited in a prior Office Action) in view of Santangelo et al (Nucleic Acids Research, 2004, Vol. 32, No. 6 e57; Pgs. 1-9; Supplemental Material Pages 1/22-22-22; Cited in a prior Office Action) and Shapiro et al (WO 2013/075132 A1; Cited in previous office action) as evidenced by O’Leary et al (Cancer Res 2018;78(13 Suppl): Abstract nr 5104; Cited in a prior Office Action). This is a Rejection made in the Office Action mailed on 04/09/2026 and re-written to address the amendment to the claims filed on 07/06/2026.
Regarding claim 8, Afonin teaches a DNA/RNA hybrid nucleic acid nanoparticle comprising:(a) at least one trigger toehold, wherein the at least one trigger toehold comprises DNA and/or RNA; and(b) at least one single stranded RNA output strand, wherein no portion of the at least one trigger toehold hybridizes to any portion of the at least one output strand, the at least one trigger toehold is complementary and hybridizes to a first target sequence when the DNA/RNA hybrid nucleic acid nanoparticle is in the presence of the first target sequence, further wherein the DNA/RNA hybrid nucleic acid nanoparticle comprises a sense construct and an antisense construct, wherein the sense construct and the antisense construct are not connected to each other, and wherein the at least one output strand separates from the DNA/RNA hybrid nucleic acid nanoparticle when the at least one trigger toehold hybridizes to the first target sequence, wherein the sense construct comprises a first trigger toehold and a first output strand, the antisense construct comprises a second trigger toehold and a second output strand, and the first trigger toehold and wherein the sense construct comprises a first DNA strand comprising a sequence that is complementary to the first output strand and the antisense construct comprises a second DNA strand comprising a sequence that is complementary to the second output strand, wherein the first DNA strand is connected to the first trigger toehold and the second DNA strand is connected to the second trigger toehold (Page 2086, Figure 1).
Afonin does not teach the DNA/RNA hybrid nucleic acid nanoparticle does not contain target sequence and where the target sequence is in a target RNA.
Shapiro teaches hybrid nucleic acid nanoparticle comprising single stranded sense and antisense strand where the sense strand has a sequence complementary to the antisense strand and the antisense strand is complementary of the target RNA in order to hybridize with the target RNA (Page 13, Lines 2-12; Page 17, Paragraphs | and 2). Shapiro teaches the therapeutic RNA switch, or tswRNA, is an RNA molecule or RNA containing molecular complex that has at least one region that is complementary to a trigger sequence such as the recognition domain (toehold in the instant claims) that can be either RNA or DNA (Page 12, Lines 26-29). Shapiro teaches upon binding to the trigger sequence, the tswRNA goes through a conformational change that allows the dicer to cleave and release the strand (Page 13, Lines 9-12). Shapiro teaches that the structure is a small hairpin RNA where it is a single stranded RNA that has self-duplexed (Page 43, Lines 18-19). Shapiro teaches the use of the nucleotide sequence encoding CTGF as a therapeutic strand (Page 5 bridging Page 6). Shapiro teaches a region of the CTGF mRNA acts as trigger (the gene CTGF is highly expressed in a variety of cancers; CTGF is also known under the synonyms CCN2 or IGFBP8) (Page 56, Lines 23-25). Shapiro teaches CTGF will trigger the active conformation of the RNA switch, leading to the formation of an siRNA targeting the anti-apoptotic gene Survivin (Page 54, Lines 28-29).
Shapiro does not teach the first trigger toehold, and the second trigger toehold is complementary to adjacent positions within the first target sequence.
Santangelo teaches 2'-deoxy-oligonucleotide probes designed to detect mRNA, featuring a stem-loop structure with a fluorophore at the 5' end and a quencher at the 3' end, utilizing a Dual FRET (Förster Resonance Energy Transfer) mechanism to minimize false positives (Page 1, Column 1 bridging Column 2). Santangelo teaches that the dual FRET molecular beacons showed a significant increased detection of the mRNA KRAS target sequence as compared to the single molecular beacons (Page 4, Column 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Afonin to include the first trigger toehold and the second trigger toehold are complementary to adjacent positions within the first target sequence as taught by Shapiro and Santangelo because Afonin teaches it is within the ordinary skill in the art to use a RNA/DNA hybrid complex that comprising (a) at least one trigger toehold, wherein the at least one trigger toehold comprises DNA; and (b) at least one single stranded RNA output strand, Santangelo teaches increased biostability and detection using dual molecular beacon probes for targeting adjacently to a KRAS mRNA target site as compared to the single molecular beacons and Shapiro teaches the use of the DNA/RNA hybrid switches in order to modulate expression levels of other genes, such as CTGF, for the purpose of treatment and the gene CTGF is highly expressed in a variety of cancers.
One would have been motivated to make such a modification in order to receive the expected benefit of specificity in the treatment of CTGF related treatments such as inhibition leading to reduction in downstream expression leading to treatment of tumor formation and/or growth as taught by Shapiro as well as increased biostability and detection of the mRNA KRAS target sequence as taught by Santangelo.
Regarding claim 9, Afonin teaches the DNA sense construct trigger toehold is within 10 nucleotide bases from the sequence complimentary to the Malachite Green sequence (denoted mg1; is directly next to the DNA sense trigger toehold in the sequence denoted DNA for H1 (mg1_s_s)) which can be considered the first output sequence as well as the DNA antisense construct trigger toehold is within 10 nucleotide bases from the sequence complimentary to the Malachite Green sequence (denoted mg2; directly next to the DNA sense trigger toehold in the sequence denoted DNA for H1 (mg2_a_a)) which could be considered the second output strand (Page 2086, Figure 1; Supplemental Page 2, Malachite green (MG) aptamer split in two RNA strands and Page 4, Hybrids designed to release MG aptamer and two siRNAs). Afonin teaches the DNA toeholds capable of interacting with each other are 100% complementary to each other as shown in the supplemental information (Supplemental Page 4; sequences denoted DNA for H1 and DNA for H2 under Hybrids designed to release MG aptamer and two siRNAs).
Regarding claim 26, Afonin teaches that the nanoparticle is a therapeutic pharmaceutical composition (Page 2085, Abstract and Page 2095, Column 2).
Regarding claims 31 and 32, Afonin does not teach wherein the first target sequence is part of a naturally occurring mRNA.
Santangelo teaches that the dual FRET molecular beacons showed a significant increased detection of the mRNA KRAS target sequence as compared to the single molecular beacons (Page 4, Column 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Afonin to include the first trigger toehold and the second trigger toehold are complementary to adjacent positions within the first target sequence as taught by Santangelo because Afonin teaches it is within the ordinary skill in the art to use a RNA/DNA hybrid complex that comprising (a) at least one trigger toehold, wherein the at least one trigger toehold comprises DNA; and (b) at least one single stranded RNA output strand and Santangelo teaches increased biostability and detection using dual molecular beacon probes for targeting adjacently to a KRAS mRNA target site as compared to the single molecular beacons.
One would have been motivated to make such a modification in order to receive the expected benefit of increased biostability and detection of the mRNA KRAS target sequence as taught by Santangelo.
Regarding claim 33, Afonin teaches the output strands were not modified at the 2’ nucleotides (Page 2086, Figure 1 and Supplemental information Page 4; sequences denoted DNA for H1 and DNA for H2 under Hybrids designed to release MG aptamer and two siRNAs).
Regarding claim 34, Afonin does not teach wherein the first target sequence comprises a portion of nucleotides encoding KRAS.
Santangelo teaches that the dual FRET molecular beacons showed a significant increased detection of the mRNA KRAS target sequence as compared to the single molecular beacons (Page 4, Column 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Afonin to include the first trigger toehold and the second trigger toehold are complementary to adjacent positions within the first target sequence as taught by Santangelo because Afonin teaches it is within the ordinary skill in the art to use a RNA/DNA hybrid complex that comprising (a) at least one trigger toehold, wherein the at least one trigger toehold comprises DNA; and (b) at least one single stranded RNA output strand and Santangelo teaches increased biostability and detection using dual molecular beacon probes for targeting adjacently to a KRAS mRNA target site as compared to the single molecular beacons.
One would have been motivated to make such a modification in order to receive the expected benefit of increased biostability and detection of the mRNA KRAS target sequence as taught by Santangelo.
Regarding claim 35, Afonin and Santangelo do not teach the use of CTGF as the target for modulation of expression.
Shapiro teaches the use of RNA switches comprising several adjacent regions that can bind to a trigger sequence as well as sense and antisense sequences that can form an siRNA-like structure (Page 2, Lines 1-11). Shapiro teaches the use of the nucleotide sequence encoding CTGF as a therapeutic strand (Page 5 bridging Page 6). Shapiro teaches a region of the CTGF mRNA acts as trigger (the gene CTGF is highly expressed in a variety of cancers; CTGF is also known under the synonyms CCN2 or IGFBP8) (Page 56, Lines 23-25). Shapiro teaches CTGF will trigger the active conformation of the RNA switch, leading to the formation of an siRNA targeting the anti-apoptotic gene Survivin (Page 54, Lines 28-29).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Afonin and Santangelo to include the modulation of expression of CTGF as taught by Shapiro because Afonin teaches it is within the ordinary skill in the art to use a RNA/DNA hybrid complex that comprising (a) at least one trigger toehold, wherein the at least one trigger toehold comprises DNA; and (b) at least one single stranded RNA output strand, Santangelo teaches increased biostability and detection using dual molecular beacon probes for targeting adjacently to a KRAS mRNA target site as compared to the single molecular beacons and Shapiro teaches the use of the DNA/RNA hybrid switches in order to modulate expression levels of other genes, such as CTGF, for the purpose of treatment and the gene CTGF is highly expressed in a variety of cancers.
One would have been motivated to make such a modification in order to receive the expected benefit of specificity in the treatment of CTGF related treatments such as inhibition leading to reduction in downstream expression leading to treatment of tumor formation and/or growth as taught by Shapiro.
Regarding claim 36, Afonin teaches wherein the first trigger toehold and the second trigger toehold hybridize to each other than the first output strand hybridizes to the second output strand and forms a double stranded output strand that separates from the nanoparticle
Afonin does not teach wherein the first trigger toehold and the second trigger toehold hybridize to adjacent positions within the first target sequence.
Santangelo teaches 2'-deoxy-oligonucleotide probes designed to detect mRNA, featuring a stem-loop structure with a fluorophore at the 5' end and a quencher at the 3' end, utilizing a Dual FRET (Förster Resonance Energy Transfer) mechanism to minimize false positives (Page 1, Column 1 bridging Column 2). Santangelo teaches that the dual FRET molecular beacons showed a significant increased detection of the mRNA KRAS target sequence as compared to the single molecular beacons (Page 4, Column 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Afonin to include the first trigger toehold and the second trigger toehold are complementary to adjacent positions within the first target sequence as taught by Santangelo because Afonin teaches it is within the ordinary skill in the art to use a RNA/DNA hybrid complex that comprising (a) at least one trigger toehold, wherein the at least one trigger toehold comprises DNA; and (b) at least one single stranded RNA output strand and Santangelo teaches increased biostability and detection using dual molecular beacon probes for targeting adjacently to a KRAS mRNA target site as compared to the single molecular beacons.
One would have been motivated to make such a modification in order to receive the expected benefit of increased biostability and detection of the mRNA KRAS target sequence as taught by Santangelo.
Regarding claims 37 and 38, Afonin teaches the entire length of the hybrid sequences designed to release a MG aptamer and two siRNA strands (which would then hybridize to each other creating a double stranded siRNA structure) are 83 nucleic acids long (Supplemental material Page 4, Hybrids designed to release MG aptamer and two siRNAs). Therefore, the first DNA strand of the sense construct comprises from about 1 to about 100 nucleic bases between the first trigger toehold and the sequence that is complementary to the first output strand and the second DNA strand of the antisense construct comprises from about 1 to about 100 nucleic bases between the second trigger toehold and the sequence that is complementary to the second output strand.
Regarding claims 39-44, Afonin does not teach that the DNA/RNA hybrid comprises a hairpin loop and further wherein the hairpin loop comprises from about 12 to about 20 base pairs.
Santangelo teaches the sequences of the donor molecular beacon and acceptor molecular beacon where the stem sequence is underlined, and the loop sequence comprises 16 to 17 nucleic acids in length (Page 2, Table 1). Santangelo teaches the hairpin structure also acts as an adjustable energy penalty for beacon opening which improves probe specificity (Page 1, Column 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Afonin to include the hairpin loop structures as taught by Santangelo because Afonin teaches it is within the ordinary skill in the art to use a RNA/DNA hybrid complex that comprising (a) at least one trigger toehold, wherein the at least one trigger toehold comprises DNA; and (b) at least one single stranded RNA output strand and Santangelo teaches the hairpin structure also acts as an adjustable energy penalty for beacon opening which improves probe specificity.
One would have been motivated to make such a modification in order to receive the expected benefit of the hairpin structure also acts as an adjustable energy penalty for beacon opening which improves probe specificity as taught by Santangelo.
Regarding claim 45-47, Afonin teaches that when the first trigger toehold hybridizes to the second trigger toehold, the first output strand and second output strand are released and capable of hybridizing together (Page 2086, Figure 1).
Afonin does not teach wherein when the first trigger toehold hybridizes to the first target sequence, the hairpin loop is disrupted and wherein when the second trigger toehold hybridizes to the first target sequence, the hairpin loop is disrupted.
Santangelo teaches the donor molecular beacon and acceptor molecular beacon are both a hairpin loop structure and when introduced to the target binding site, hairpin loops are disrupted and the DNA sequences bind adjacently to each other on the mRNA target sequence (Page 2, Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Afonin to include the hairpin loop structures as taught by Santangelo because Afonin teaches it is within the ordinary skill in the art to use a RNA/DNA hybrid complex that comprising (a) at least one trigger toehold, wherein the at least one trigger toehold comprises DNA; and (b) at least one single stranded RNA output strand and Santangelo teaches the hairpin structure also acts as an adjustable energy penalty for beacon opening which improves probe specificity.
One would have been motivated to make such a modification in order to receive the expected benefit of the hairpin structure also acts as an adjustable energy penalty for beacon opening which improves probe specificity as taught by Santangelo.
Regarding claims 48-50, Afonin teaches that the double stranded RNA output is an siRNA (Page 2086, Figure 1).
Regarding claims 51 and 53, Afonin teaches the DNA/RNA hybrid switch system for use in treating breast cancer.
Afonin does not teach the specific target sequence and biomarkers associated with that target sequence.
Santangelo teaches a region of the KRAS mRNA target sequence for DNA dual FRET molecular beacons to bind to the KRAS gene sequence (Page 2, Column 1 bridging column 2 and Table 1). O’Leary is cited only as evidence to show that KRAS is highly expressed in a variety of cancers, specifically in breast cancer with known biomarkers including prolactin (Page 1, Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Afonin to include the first trigger toehold and the second trigger toehold are complementary to adjacent positions within the first target sequence as taught by Santangelo because Afonin teaches it is within the ordinary skill in the art to use a RNA/DNA hybrid complex that comprising (a) at least one trigger toehold, wherein the at least one trigger toehold comprises DNA; and (b) at least one single stranded RNA output strand and Santangelo teaches increased biostability and detection using dual molecular beacon probes for targeting adjacently to a KRAS mRNA target site as compared to the single molecular beacons.
One would have been motivated to make such a modification in order to receive the expected benefit of increased biostability and detection of the mRNA KRAS target sequence as taught by Santangelo.
Regarding claim 52, Afonin teaches that no strands of the nanoparticle were modified at the 2’ nucleotides (Page 2086, Figure 1 and Supplementary information pages 2-5).
Response to Arguments - Claim Rejections - 35 USC § 103
The previous rejection of claims 8, 9, 26, 31-35 and 37-53 under 35 U.S.C. 103 as being unpatentable by Afonin et al (Nucleic Acids Research, Volume 42, Issue 3, 1 February 2014, Pages 2085–2097) in view of Santangelo et al (Nucleic Acids Research, 2004, Vol. 32, No. 6 e57; Pgs. 1-9; Supplemental Material Pages 1/22-22-22) and Shapiro et al (WO 2013/075132 A1; Cited in previous office action) as evidenced by O’Leary et al (Cancer Res 2018;78(13 Suppl): Abstract nr 5104) has been maintained in view of Applicant’s amendments of the claims filed 07/06/2026. Applicant’s arguments have been fully considered but have not been found to be persuasive.
Applicant addresses each reference individually. Specifically, Applicant argues that Afonin does not contain the target, comprises a sense and an antisense construct, and wherein the sense construct comprises a first trigger toehold and a first output strand, the antisense construct comprises a second trigger toehold and a second output strand, and the first trigger toehold and the second trigger toehold are complementary to adjacent positions within the first target sequence. Applicant argues that Afonin (2014) could be described as having a “target sequence”, the targets would be the single-stranded DNA toeholds of the complementary constructs. Applicant continues to argue that the constructs of Afonin (2014) necessarily contain the target sequence (i.e., each construct includes a toehold which is complementary to its target, which is contained on the other construct), which Applicant argues does not include the presently claimed feature that the nanoparticle “does not contain the target sequence”. Applicant continues to argue that in contrast with the presently claimed nanoparticle having a separate trigger, the system described in Afonin (2014) involves a two-construct strand exchange, wherein two DNA/RNA hybrids having complementary single-stranded DNA toeholds hybridize with each other, facilitating a strand exchange and release of a double stranded RNA output. Applicant argue that Afonin (2014) does not teach or suggest a nanoparticle having a sense construct and an antisense construct, wherein release of a double-stranded output occurs upon toehold hybridization to a separate target sequence. Applicant argues that the presently claimed nanoparticle is a marked improvement over such two-construct system of Afonin (2014), at least because for the presently claimed nanoparticle, a trigger of the strand exchange and double stranded output can be an external stimulus, e.g., in the presence of a particular mRNA, specifically, the nanoparticle of the presently claimed invention could be administered systemically, but strand exchange would only occur in cells where an RNA comprising a target sequence is present.
However, in the rejection presented above, it is acknowledged that Afonin does not teach the DNA/RNA hybrid nucleic acid nanoparticle does not contain target sequence and where the target sequence is in a target RNA. Therefore, Shapiro is relied to teach that hybrid nucleic acid nanoparticle comprising single stranded sense and antisense strand where the sense strand has a sequence complementary to the antisense strand and the antisense strand is complementary of the target RNA in order to hybridize with the target RNA (Page 13, Lines 2-12; Page 17, Paragraphs | and 2) and additionally, Shapiro teaches CTGF will trigger the active conformation of the RNA switch, leading to the formation of an siRNA targeting the anti-apoptotic gene Survivin (Page 54, Lines 28-29). It is additionally acknowledged that Afonin and Shapiro do not teach the first trigger toehold, and the second trigger toehold is complementary to adjacent positions within the first target sequence. Therefore, Santangelo is relied on for teaching 2'-deoxy-oligonucleotide probes designed to detect mRNA, featuring a stem-loop structure with a fluorophore at the 5' end and a quencher at the 3' end, utilizing a Dual FRET (Förster Resonance Energy Transfer) mechanism to minimize false positives (Page 1, Column 1 bridging Column 2). Specifically, Santangelo teaches that the dual FRET molecular beacons showed a significant increased detection of the mRNA KRAS target sequence as compared to the single molecular beacons (Page 4, Column 2). In conclusion, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Afonin to include the first trigger toehold and the second trigger toehold are complementary to adjacent positions within the first target sequence as taught by Shapiro and Santangelo because Afonin teaches it is within the ordinary skill in the art to use a RNA/DNA hybrid complex that comprising (a) at least one trigger toehold, wherein the at least one trigger toehold comprises DNA; and (b) at least one single stranded RNA output strand, Santangelo teaches increased biostability and detection using dual molecular beacon probes for targeting adjacently to a KRAS mRNA target site as compared to the single molecular beacons and Shapiro teaches the use of the DNA/RNA hybrid switches in order to modulate expression levels of other genes, such as CTGF, for the purpose of treatment and the gene CTGF is highly expressed in a variety of cancers.
Additionally, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the DNA/RNA hybrid is not a two-construct strand exchange) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Finally, in response to applicant's argument that in the presence of a particular mRNA, specifically, the nanoparticle of the presently claimed invention could be administered systemically, but strand exchange would only occur in cells where an RNA comprising a target sequence is present, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Applicant argues the teachings of Shapiro separately from Afonin. Specifically, Applicant argues that Shapiro describes a DICER-dependent “therapeutic RNA switch” which is mediated by the intracellular RNAi machinery, but wherein there is no output strand separation conditioned on the conformational change at the time when the target sequence is hybridized. Applicant continues to argue that the construct is complemented as undergoing a conformational change which does not itself result in an output but rather renders the construct competent for processing RNAi machinery. Applicant argues that this contrasts with the presently claimed nanoparticle wherein a conformational change in an antisense construct and a sense construct results in a double stranded output. Applicant argues that the example provided in the present invention shows the output strand is a double-stranded RNA is in itself an DsiRNA (Dicer-substrate iRNA), which does not require DICER to cleave from the nanoparticle, but rather is released from the nanoparticle and then can enter RNAi machinery. Applicant further argues that the construct of Shapiro does not include RNA protection advantages of the present claimed nanoparticle, specifically elements to protect the RNA construct from degradation.
Although Applicant has addressed Shapiro and its teachings individually, it is not relied on for its entirety as it is used in combination with Afonin as the primary reference and Santangelo as an additional secondary reference to teach all the limitations of the presently claimed invention. Shapiro is only recited to teach the deficiencies of Afonin, specifically Shapiro is relied to teach that hybrid nucleic acid nanoparticle comprising single stranded sense and antisense strand where the sense strand has a sequence complementary to the antisense strand and the antisense strand is complementary of the target RNA in order to hybridize with the target RNA (Page 13, Lines 2-12; Page 17, Paragraphs 1 and 2) and additionally, Shapiro teaches CTGF (the gene CTGF is highly expressed in a variety of cancers; CTGF is also known under the synonyms CCN2 or IGFBP8) will trigger the active conformation of the RNA switch, leading to the formation of an siRNA targeting the anti-apoptotic gene Survivin (Page 54, Lines 28-29). It is additionally acknowledged that Afonin and Shapiro do not teach the first trigger toehold, and the second trigger toehold is complementary to adjacent positions within the first target sequence. Therefore, Santangelo is relied on for teaching 2'-deoxy-oligonucleotide probes designed to detect mRNA, featuring a stem-loop structure with a fluorophore at the 5' end and a quencher at the 3' end, utilizing a Dual FRET (Förster Resonance Energy Transfer) mechanism to minimize false positives (Page 1, Column 1 bridging Column 2). Specifically, Santangelo teaches that the dual FRET molecular beacons showed a significant increased detection of the mRNA KRAS target sequence as compared to the single molecular beacons (Page 4, Column 2). In conclusion, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Afonin to include the first trigger toehold and the second trigger toehold are complementary to adjacent positions within the first target sequence as taught by Shapiro and Santangelo because Afonin teaches it is within the ordinary skill in the art to use a RNA/DNA hybrid complex that comprising (a) at least one trigger toehold, wherein the at least one trigger toehold comprises DNA; and (b) at least one single stranded RNA output strand, Santangelo teaches increased biostability and detection using dual molecular beacon probes for targeting adjacently to a KRAS mRNA target site as compared to the single molecular beacons and Shapiro teaches the use of the DNA/RNA hybrid switches in order to modulate expression levels of other genes, such as CTGF, for the purpose of treatment and the gene CTGF is highly expressed in a variety of cancers.
Applicant argues that nothing about Santangelo teaches or suggests toeholds, DNA/RNA hybrid nanoparticles, an antisense construct, a sense construct, a double stranded output or other features of the present claim 8. Applicant continues to argue that Santangelo does not appear to be expressly clear as to whether the beacons consist of RNA or DNA. Applicant states that it is interpreted Santangelo as describing beacons consisting of unmodified nucleotides of either DNA or RNA. Applicant, however, insists and argues that Santangelo does not disclose or suggest DNA/RNA hybrids and only discloses a general concept of two probes that hybridize to proximate portions of a target ssRNA, but does not provide any suggestion regarding the structure or function of DNA/RNA hybrid nanoparticles such as presently claimed.
Although Applicant has addressed Santangelo and its teachings individually, it is not relied on for its entirety as it is used in combination with Afonin as the primary reference and Shapiro as an additional secondary reference to teach all the limitations of the presently claimed invention. It is additionally acknowledged that Afonin and Shapiro do not teach the first trigger toehold, and the second trigger toehold is complementary to adjacent positions within the first target sequence. Therefore, Santangelo is relied on for teaching 2'-deoxy-oligonucleotide probes designed to detect mRNA, featuring a stem-loop structure with a fluorophore at the 5' end and a quencher at the 3' end, utilizing a Dual FRET (Förster Resonance Energy Transfer) mechanism to minimize false positives (Page 1, Column 1 bridging Column 2). Specifically, Santangelo teaches that the dual FRET molecular beacons showed a significant increased detection of the mRNA KRAS target sequence as compared to the single molecular beacons (Page 4, Column 2). In conclusion, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Afonin to include the first trigger toehold and the second trigger toehold are complementary to adjacent positions within the first target sequence as taught by Shapiro and Santangelo because Afonin teaches it is within the ordinary skill in the art to use a RNA/DNA hybrid complex that comprising (a) at least one trigger toehold, wherein the at least one trigger toehold comprises DNA; and (b) at least one single stranded RNA output strand, Santangelo teaches increased biostability and detection using dual molecular beacon probes for targeting adjacently to a KRAS mRNA target site as compared to the single molecular beacons and Shapiro teaches the use of the DNA/RNA hybrid switches in order to modulate expression levels of other genes, such as CTGF, for the purpose of treatment and the gene CTGF is highly expressed in a variety of cancers.
Applicant argues that because of the arguments discussed above that the combination of Afonin in view of Shapiro and Santangelo and as evidenced by O’Leary does not teach the instantly claimed invention.
However, in response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Applicant argued each reference separately and did not address the combined obviousness the prior art taught over the claimed invention. Therefore, the arguments are not persuasive as Applicant did not specifically argue how each prior art fails to remedy the deficiencies.
Finally, Applicant argues that the dependent claims comprise further limitations that distinguish the presently claimed invention from the prior art discussed and therefore renders the presently claimed invention patentable.
In conclusion, the rejection of the independent and dependent claims of the presently claimed invention are found to maintained and the arguments presented by Applicant are not found to be persuasive as outlined and detailed above.
Conclusion
No claims are allowed.
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 ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm 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, JENNIFER A DUNSTON can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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