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 .
Election/Restrictions
Applicant’s election without traverse of Group and the species elections of the combination of SEQ ID NOs: 2, 7, 8, & 10 in claim 7 and of SEQ ID NO: 33 in claim 8 in the reply filed on 11/17/2025 is acknowledged. Group II, claims 10-13, is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
A first office action on the merits of claims 1-9 & 14-18 is set forth herein and claims 10-13 are withdrawn from consideration.
Priority
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/977,454, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The provisional application, 62/977,454, does not have support of all of the limitations in claims 7 & 8 of the instant application. The provisional application, 62/977,454, does not provide support for the transmembrane nanosensor of claim 1 comprising one or more of SEQ ID NOs: 1-26 and does not provide support for wherein the hairpin loop is selected from the group consisting of SEQ ID NO: 31-34. Accordingly, claims 7 & 8 are not entitled to the benefit of the prior applications. Therefore, claims 7 & 8 are given a priority date of filing 02/17/2021.
Information Disclosure Statement
The listing of references in the specification, from pages 40-47, is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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 3-9 & 14-18 are 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.
Regarding claims 3-9 & 14, the claims recite the limitation “the transmembrane nanosensor” in line 1 of claims 3-9 and line 3 in claim 14. There is insufficient antecedent basis for this limitation in the claims and it is unclear if “the transmembrane nanosensor” is referring to “a transmembrane nanosensor device” of claim 1, from which claims 3-9 & 14 directly or indirectly depend from, or if “the transmembrane nanosensor” is referring to a different transmembrane nanosensor.
Claims 15-18 are rejected due to their dependence on claim 14.
Claim Rejections - 35 USC § 103
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.
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, 2, 4, & 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zheng (Zheng et al.; Analytical Chemistry, Vol. 90 , pages 13459-13466, October 2018), as cited on the IDS dated 02/29/2024, in view of Liu (Liu et al.; Nature Communications, Vol. 4, pages 1-5, July 2013), as cited in the IDS dated 02/29/2024.
Regarding claim 1, Zheng teaches a DNA tweezer that comprises two arms to switch between “open” and “closed” states, a pair of FRET fluorophores (a FRET pair), and a cholesterol to anchor the DNA tweezer nanosensor into the cell membrane (a lipid conjugated DNA tweezer) (abstract lines 3-9; pg. 13459-13460 paragraph bridging pg. 13459 & 13460 lines 1-13; pg. 13460 column 1 1st full paragraph lines 1-19; pg. 13461 column 1 1st full paragraph lines 1-14).
Zheng does not teach that the DNA tweezer comprises a hairpin loop complementary to a target polynucleotide trigger strand.
Liu teaches a DNA tweezer nanostructure that transitions between open and closed states in which the DNA tweezer nanostructure comprises two arms and an oligomer that connects the ends of the tweezer arms and has a ‘GCG’ stem-loop hairpin structure that holds the two arms of the tweezer close together and then transitions to an open state when a complementary target strand is hybridized to the hairpin (a hairpin loop complementary to a target polynucleotide trigger strand) (abstract lines 1-4; pg. 2 column 1 3rd full paragraph lines 1-17). Liu also teaches that this method enables real-time monitoring of the opening and closing of the tweezers by labeling the tweezer arms with a FRET pair and that this hairpin structure enables the DNA tweezer nanostructure to switch between open and closed states while maintaining its structural integrity (pg. 3-4 paragraph bridging pg. 3 & 4 lines 3-10).
Zheng and Liu are considered to be analogous to the claimed invention because they are all in the same field of DNA tweezer nanostructures. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the transmembrane DNA nanosensor device in Zheng to incorporate a hairpin loop structure that holds the two arms of the tweezer close together and is complementary to a target polynucleotide trigger strand as taught in Liu because Liu teaches that doing so would maintain the DNA tweezer nanostructures structural integrity when transitioning to and from open and closed states while enabling real-time monitoring of the open and closed states of the nanosensor with a FRET pair.
Regarding claim 2, Zheng teaches the DNA tweezer is anchor to the cellular membrane with cholesterol (lipid conjugated DNA tweezer is integrated into a lipid bilayer) (pg. 13461 column 1 1st full paragraph lines 1-14).
Regarding claim 4, Zheng teaches a DNA tweezer that comprises two arms comprising DNA (pg. 13460 column 1 1st full paragraph lines 1-19).
Liu teaches a stem-loop hairpin structure that holds the two arms of the tweezer close together and then transitions to an open state when a complementary target strand is hybridized to the hairpin comprises DNA (the target polynucleotide trigger strand is a DNA polynucleotide) (pg. 2 column 1 3rd full paragraph lines 1-17).
Regarding claim 6, Zheng teaches the DNA tweezer is anchor to the cellular membrane with cholesterol (lipid is a cholesterol molecule) (pg. 13461 column 1 1st full paragraph lines 1-14).
Claim(s) 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zheng (Zheng et al.; Analytical Chemistry, Vol. 90 , pages 13459-13466, October 2018), as cited on the IDS dated 02/29/2024, and Liu (Liu et al.; Nature Communications, Vol. 4, pages 1-5, July 2013), as cited in the IDS dated 02/29/2024 as applied to claims 1, 2, 4, & 6 above, and further in view of Langecker (Langecker, Arnaut, List, & Simmel; Accounts of Chemical Research, Vol. 47, pages 1807-1815, May 2014), as cited on the IDS dated 02/29/2024.
The teachings of Zheng and Liu with respect to claims 1 & 2 are discussed above.
Regarding claim 3, Zheng and Liu does not teach that the lipid bilayer is an exosome membrane.
Langecker teaches DNA nanotechnology and interactions of this DNA nanotechnology with lipid membrane structures to form DNA-lipid hybrid assemblies in which DNA nanostructures attached to or embedded within lipid membranes including in micelles and vesicles (lipid bilayer is an exosome (extracellular vesicle)) (abstract lines 1-20; pg. 1807 column 2 1st full paragraph lines 1-5; pg. 1808 paragraph bridging column 1 & 2 lines 1-25; Figure 2). Langecker also teaches that hybrid assemblies made from DNA nanostructures and lipid bilayer membranes have potential in improving efficiency of DNA-based delivery systems, becoming versatile membrane biosensors, etc. (pg. 1813 column 1 2nd full paragraph lines 1-4; pg. 1813 column 2 1st full paragraph lines 1-13).
Zheng, Liu, and Langecker are considered to be analogous to the claimed invention because they are all in the same field of DNA tweezer nanostructures. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the transmembrane DNA nanosensor device integrated into a lipid bilayer in Zheng to incorporate integration into an exosome membrane lipid bilayer as taught in Langecker because Langecker teaches that doing so would have potential in improving efficiency of DNA-based delivery systems and in becoming versatile membrane biosensors.
Claim(s) 5 & 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zheng (Zheng et al.; Analytical Chemistry, Vol. 90 , pages 13459-13466, October 2018), as cited on the IDS dated 02/29/2024, and Liu (Liu et al.; Nature Communications, Vol. 4, pages 1-5, July 2013), as cited in the IDS dated 02/29/2024 as applied to claims 1, 2, 4, & 6 above, and further in view of Sӧderberg (WO 2015/118029 A1).
The teachings of Zheng and Liu with respect to claims 1 & 4 are discussed above.
Regarding claims 5 & 9, Zheng and Liu does not teach that the target polynucleotide trigger strand is a microRNA (miRNA) (see claim 5) or that the transmembrane nanosensor comprises an initiator sequence (see claim 9).
Sӧderberg teaches a system comprising proximity probes that interact to from a hairpin structure when the probes are bound in proximity to a target in which one probe may be labelled with a FRET pair such that when bound to a complementary target the FRET pair generates a signal (pg. 4 lines 25-35; pg. 5 lines 1-14; pg. 38 lines 27-34). Sӧderberg also teaches the system comprising the hairpin structure undergoes a chain reaction of hybridization events when a probe comprising an “initiator” nucleic acid molecule enables an open conformation (pg. 4 lines 25-35; pg. 5 lines 1-14 & 19-25; pg. 6 lines 5-17). Sӧderberg also teaches that the analyte may be miRNA (pg. 22 lines 7-10). In addition, Sӧderberg teaches that this system is robust, simple, and easy to use yet is specific and sensitive system to detect analytes with hybridization chain reaction (pg. 4 lines 6-13).
Zheng, Liu, and Sӧderberg are considered to be analogous to the claimed invention because they are all in the same field of DNA sensor detection systems. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the transmembrane DNA nanosensor device in Zheng to incorporate an initiator sequence and the target polynucleotide trigger strand comprising miRNA as taught in Sӧderberg because Sӧderberg teaches that doing so would provide a simple and easy to use yet specific and sensitive system to detect analytes of interest.
Claim(s) 14-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zheng (Zheng et al.; Analytical Chemistry, Vol. 90 , pages 13459-13466, October 2018), as cited on the IDS dated 02/29/2024, in view of Liu (Liu et al.; Nature Communications, Vol. 4, pages 1-5, July 2013), as cited in the IDS dated 02/29/2024, Langecker (Langecker, Arnaut, List, & Simmel; Accounts of Chemical Research, Vol. 47, pages 1807-1815, May 2014), as cited on the IDS dated 02/29/2024, and Yokota (Yokota et al.; PLOS One, Vol. 14, pages 1-13, October 2019).
Regarding claim 14, Zheng teaches a DNA tweezer that comprises two arms to switch between “open” and “closed” states, a pair of FRET fluorophores (a FRET pair), and a cholesterol to anchor the DNA tweezer nanosensor into the cell membrane (a lipid conjugated DNA tweezer) (abstract lines 3-9; pg. 13459-13460 paragraph bridging pg. 13459 & 13460 lines 1-13; pg. 13460 column 1 1st full paragraph lines 1-19; pg. 13461 column 1 1st full paragraph lines 1-14).
Zheng does not teach that the DNA tweezer comprises a hairpin loop complementary to a target polynucleotide trigger strand or exosomes bound to a solid surface.
Liu teaches a DNA tweezer nanostructure that transitions between open and closed states in which the DNA tweezer nanostructure comprises two arms and an oligomer that connects the ends of the tweezer arms and has a ‘GCG’ stem-loop hairpin structure that holds the two arms of the tweezer close together and then transitions to an open state when a complementary target strand is hybridized to the hairpin (a hairpin loop complementary to a target polynucleotide trigger strand) (abstract lines 1-4; pg. 2 column 1 3rd full paragraph lines 1-17). Liu also teaches that this method enables real-time monitoring of the opening and closing of the tweezers by labeling the tweezer arms with a FRET pair and that this hairpin structure enables the DNA tweezer nanostructure to switch between open and closed states while maintaining its structural integrity (pg. 3-4 paragraph bridging pg. 3 & 4 lines 3-10).
Langecker teaches DNA nanotechnology and interactions of this DNA nanotechnology with lipid membrane structures to form DNA-lipid hybrid assemblies in which DNA nanostructures attached to or embedded within lipid membranes including in micelles and vesicles (lipid bilayer is an exosome (extracellular vesicle)) (abstract lines 1-20; pg. 1807 column 2 1st full paragraph lines 1-5; pg. 1808 paragraph bridging column 1 & 2 lines 1-25; Figure 2). Langecker also teaches that hybrid assemblies made from DNA nanostructures and lipid bilayer membranes have potential in improving efficiency of DNA-based delivery systems, becoming versatile membrane biosensors, etc. (pg. 1813 column 1 2nd full paragraph lines 1-4; pg. 1813 column 2 1st full paragraph lines 1-13).
Yokota teaches immobilizing extracellular vesicles (exosomes) on a surface to generate a high-density nanoarray in which the nanoarray (exosomal nanoarray) enables the ability to investigate extracellular vesicles inherent properties and morphology (abstract lines 1-7 & 13-17).
Zheng, Liu, Langecker, and Yokota are considered to be analogous to the claimed invention because they are all in the same field of DNA and cellular analysis. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the transmembrane DNA nanosensor device in Zheng to incorporate a hairpin loop structure that holds the two arms of the tweezer close together and is complementary to a target polynucleotide trigger strand as taught in Liu because Liu teaches that doing so would maintain the DNA tweezer nanostructures structural integrity when transitioning to and from open and closed states while enabling real-time monitoring of the open and closed states of the nanosensor with a FRET pair and it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the transmembrane DNA nanosensor device integrated into a lipid bilayer in Zheng to incorporate integration into an exosome membrane lipid bilayer as taught in Langecker because Langecker teaches that doing so would have potential in improving efficiency of DNA-based delivery systems and in becoming versatile membrane biosensors and it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to integrate the transmembrane nanosensor into an exosomal nanoarray comprising exosomes bound to a solid surface as taught in Yokota because Yokota teaches that doing so would enable the ability to investigate extracellular vesicles inherent properties and morphology.
Regarding claims 15 & 16, Yokota teaches the extracellular vesicles (exosomes) are immobilized on a surface with CD81 (exosomes are bound to a solid surface by an exosome specific antibody CD81) (pg. 2-3 paragraph bridging pg. 2 & 3 lines 1-4).
Regarding claims 17 & 18, Yokota teaches that extracellular vesicles are obtained from breast cancer and kidney cell lines cultured in medium (exosomes are from human (patient) liquid biological sample) (pg. 4 3rd full paragraph lines 1-2; pg. 4 4th full paragraph lines 1-7).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6 & 9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of copending Application No. 18/296,915 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both are directed to a transmembrane nanosensor.
Regarding claims 1 & 9, the instant application claims a transmembrane nanosensor device comprising a lipid conjugated DNA tweezer comprising a hairpin loop complementary to a target polynucleotide trigger strand, a fluorophore and a quencher paired to the fluorophore, or a FRET pair, wherein the hairpin loop is bound by the target polynucleotide trigger strand, the DNA tweezer transitions from a closed conformation to an open conformation, the quencher is separated from the fluorophore, and the fluorophore fluoresces and the instant application claims that the transmembrane nanosensor device comprises an initiator sequence. Copending Application No. 18/296,915 claims a cell detection system comprising a transmembrane nanosensor comprising a lipid-conjugated DNA comprising a first hairpin stem-loop comprising a loop comprising a polynucleotide sequence which is complementary to a target polynucleotide, a stem, a fluorophore, a quencher paired to the fluorophore, and a HCR initiator domain and wherein upon the first hairpin stem-loop binding to the target polynucleotide the nanosensor transitions from a closed conformation to an open conformation exposing the initiator domain and allowing for fluorescence the fluorophore without quenching (see claim 1).
Regarding claim 2, the instant application claims wherein the lipid conjugated DNA tweezer is integrated into a lipid bilayer. Copending Application No. 18/296,915 claims wherein the lipid-conjugated DNA spans a lipid bilayer (see claim 2).
Regarding claim 3, the instant application claims wherein the lipid bilayer is an exosome membrane. Copending Application No. 18/296,915 claims wherein the lipid bilayer is a cellular outer membrane or episome (see claim 3).
Regarding claim 4, the instant application claims wherein the target polynucleotide trigger strand is an RNA or a DNA polynucleotide. Copending Application No. 18/296,915 claims wherein the target polynucleotide is an RNA or a DNA (see claim 4).
Regarding claim 5, the instant application claims wherein the target polynucleotide trigger strand in miRNA. Copending Application No. 18/296,915 claims wherein the target polynucleotide is mRNA or miRNA (see claim 5).
Regarding claim 6, the instant application claims wherein the lipid is a cholesterol molecule. Copending Application No. 18/296,915 claims wherein the lipid comprises a cholesterol molecule (see claim 6).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-9 & 14-18 are rejected. It is noted that the transmembrane nanosensor comprising SEQ ID NOs: 2, 7, 8, & 10 and the transmembrane nanosensor wherein the hairpin loop is SEQ ID NO: 33 were searched and found free of the prior art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682