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 .
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.
Status of Claims
Claims 1-3 and 6-22 are pending. Claims 12-22 are nonelected and withdrawn. Claims 21-22 are new. Claims 1-3 and 6-11 are under examination.
Withdrawn Objection and Rejection
In light of the amendments and the claims are legible, the previous objection is hereby withdrawn.
Election/Restrictions
New claims 21-22 are new and dependent from the non-elected inventions of Groups II and IV. Applicant has previously elected Group I. Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 21-22 are withdrawn from consideration as being dependent from the non-elected inventions. See 37 CFR 1.142(b) and MPEP § 821.03.
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.
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 1-3 and 6-11 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (US2005/0277205A1, published 12/15/2005, see 892 dated 09/25/2023) in view of Wei et al. (“Hairpin DNA-functionalized gold nanorods for mRNA detection in homogenous solution,” J. Biomed. Opt., vol. 21(9), pgs. 097001-1 to 097001-9, published September 2016, see 892 dated 04/21/2025) and Lim et al. (“Direct isolation and characterization of circulating exosomes from biological samples using magnetic nanowires”, Journal of Nanobiotechnology, vol., 17:1, pgs. 1-12, published 01/07/2019, see 892 dated 09/25/2023), as evidenced by Lin et al. (“Lab in a tube: Isolation, extraction, and isothermal amplification detection of exosomal long noncoding RNA of gastric cancer”, Talanta 225 (2021) 122090, pgs. 1-8).
With regard to claim 1, Lee teaches methods and compositions for separation of proteins with multicomponent nanorods for biomolecular separations of proteins (see abstract). Lee teaches the multifunctional nanorod is gold-nickel-gold nanorods (see para. [0073]). Figure 7 shows the segmented nanorod has biotin tagged at the end portions and His tagged protein at the center for magnetic separation. Lee further teaches purifying proteins and other molecules (e.g., antibodies, ligands, lipids, nucleic acids) utilizing multifunctional nanorods and exploit binding interactions between protein affinity tags and functional groups on nanorods (see paras. [0022] and [0071]). Lee teaches the nanorods are magnetic and thus, an appropriately applied magnetic field is used to evoke separation of the protein-rod complex from a multicomponent solution and the separation of nanorods by magnetic fields provides a simple inexpensive method of separating the nanorods from a cellular lysate (see para. [0068]). Lee further teaches in Fig. 10 shows that the nanorods of gold-nickel-gold (Au/Ni/Au) immobilized histidine antibodies to the nickel (center portion). Lee teaches that the multicomponent nanorods comprising two or more binding domains and the two or more proteins of interest are fused to protein affinity tags that are specific for different binding domains of the nanorods (see paras. [0007]-[0008]). Fig. 3 shows fluorescence spectra before and after separation of a mixture of Alexa-488-labeled anti-human IgG and Alexa-568-labeled (see para. [0013]). Lee teaches optical image and fluorescence images were obtained (see para. [0091]). Lee teaches test compound and candidate compound are any chemical entity (see para. [0058]).
Lee does not explicitly teach at least one detectably labeled nucleic acid wherein the detectably labeled nucleic acid is 6-10 nm in length, labeled with a fluorophore and comprises a portion that is complementary to a target nucleic acid, and portions that are complementary to one another, wherein the target nucleic acid is contained in or on the surface of the extracellular vesicle (claim 1) and wherein the fluorophore is 5(6)-carboxyfluorescein (FAM) (claim 6).
Noted the recitations of a target nucleic acid and the target nucleic acid is contained in or on the surface of the extracellular vesicle are directed to the intended use of the nanorod. A recitation of the intended use of the claimed product must result in a structural difference between the claimed nucleic acid that comprises a portion 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 product claim.
Wei teaches a fluorescent probe for mRNA detection that consists of a gold nanorod (GNR) functionalized with fluorophore-labeled hairpin oligonucleotides (hpDNA) that are complementary to the mRNA of a target gene wherein the fluorophore is 6-carboxyfluorescein (FAM) (see abstract; Fig. 1; and pg. 097001-3, left col., para. 1 of section 2.4). Wei further teaches that compared to AuNS, gold nanorods exhibit excellent shape-dependent optical properties and by varying the aspect ratio, the longitudinal plasmon band of GNR can be finely tuned from visible to near-infrared regions (see pg. 097001-1, right col., para. 2). Wei teaches that considering the unique properties of GNR, it is expected that GNR coupled with hairpin oligonucleotides will offer great opportunity in mRNA detection and imaging and the hairpin structure on the quenching efficiency of the energy transfer pair of GNR and Cy5 (see pg. 097001-2, left col., para. 2). Wei teaches that GNR-hpDNA conjugates are highly sensitive probes for mRNA detection with high signal-to-background ratio (see pg. 097001-2, left col., middle of para. 2). Wei teaches a thiolated hairpin DNA (hpDNA) with a 6-carboxyfluorescein (FAM) and with -TTTTT GCGAGTTGGTGAAGCTAACGTTGAGGCTCGC- which has about 19-35 bases and designed to recognize a 21-nucleotide region of c-myc mRNA (see pg. 097001-3, left col., para. 1 of section 2.4).
Lim teaches isolated exosomes were characterized based on size and concentration using nanoparticle tracking analysis and exosomes are for the analysis of protein, lipid, mRNA, and miRNA (see abstract and conclusion under abstract). Lim teaches the elongated magnetic nanowires (MNWs) doped with a large amount of magnetic nanoparticles and biotin moieties are capable of conjugating with diverse exosome-specific antibodies such as anti-CD9, anti-CD63, and anti-CD81 via streptavidin-biotin interaction (see pg. 2, left col., bottom of para. and Fig. 1a). Lim further teaches the ability to detect and isolate tumor-derived exosomes may facilitate researchers to explore intracellular signals between cells and analyze functional molecular components (proteins, mRNA, and microRNA), which may provide crucial information about cancer diagnosis and prognosis (see pg. 2, left col., top portion of para. 1). Lim teaches evaluating the expression levels of exosomal miRNA after extraction from the plasma of healthy controls and lung cancer patients by Abs(antibodies)_MNWs indicated that distinct exosomal miR-21 signatures were observed in lung cancer patients (see pg. 4, right col., middle of para. 2; and Fig. 4d). Lim teaches that Abs_MNWs treatment resulted in a high yield and purity of isolated exosomes (see pg. 4, left col., top of para. 1). Lim teaches that a magnetic field was applied on the sample tubes to efficiently remove the supernatant and collect the captured exosomes (see pg. 10, left col., top of para. 1). Lim teaches highly efficient technique for the isolation and identification of exosomes from biological samples may provide critical information about exosomes as biomarkers and improve our understanding of their unique role in cancer research (see background of abstract). Lim teaches the approach of efficient extraction and quantification of exosomes without the need for expensive instruments and complex sample preparation (see pg. 2, left col., last sentence – right col., para. 1).
Even though a target nucleic acid and wherein the target nucleic acid are intended use limitations, Lim does teach the isolated exosomes the target nucleic acid is contained in or on the surface of the exosome. The evidentiary teachings of Lin et al. indicate in Fig. 1 that nucleic acids are located in or on the surface of the exosome.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have used the multicomponent nanorods of Lee with antibodies for exosomes of Lim and the hairpin oligonucleotides of Wei because: 1) Lee teaches that the purpose of the multicomponent (gold and nickel segments) nanorod is to exploit binding interactions with different conjugated functional groups on a single multicomponent nanorod for isolation of different targets with optical detection, 2) Lim teaches using nanorods to engage in surface interaction to isolate exosomes for identifying exosome RNA components for crucial information about cancer diagnosis and prognosis, and 3) Wei teaches that hairpin oligonucleotides conjugated to gold nanorods produce highly sensitive probes for mRNA detection with high signal-to-background ratio. Because multicomponent nanorods of gold and magnetic material are recognized for isolating different targets on a single nanorod of Lee and recognized by Lim that surface molecular components of exosomes are proteins, mRNA, and microRNA, it would be obvious to have incorporated gold segments on the ends of nanorod of Lim or used the multicomponent nanorods of Lee for the purpose of increasing the effectiveness in isolating exosomes by the ability to engage with more exosome’s surface functional molecular components.
Furthermore, Lim teaches evaluating the expression of exosomal RNA through the efficiency of isolating exosomes by attaching to surface molecular components on exosomes and said surface molecular components of exosomes are proteins, mRNA, and microRNA. Thus, the artisan would have been motivated to combine antibodies of Lim with hairpin oligonucleotides of Wei on a multicomponent nanorod for isolation because it would be desirable to increase the likelihood of binding to surface molecular components of exosomes for isolation and having the ability to sensitively detect the presence of RNA targets on said nanorod.
With respect to the detectably labeled nucleic acid 6-10 nm in length, even though Wei teaches a thiolated hairpin DNA (hpDNA) having a sequence with about 19-35 bases (see above), Wei does not explicitly teach that the detectable molecule is a detectably labeled nucleic acid that has range of 6-10 nm in length. However, it has been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum length for a result-effective variable to specifically hybridize a target sequence length while activating fluorescent signals of carboxyfluoresceins (FAMs) on nanorods. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation" Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In the absence of unexpected results, it would have been obvious to the person of ordinary skill to discover the optimum length of the detectable molecule to hybridize to a specific target sequence while producing a desirable fluorescent signal of carboxyfluoresceins (FAMs) through routine experimentation because Wei teaches the length of the hairpin oligonucleotides is by the design to recognize a specific target sequence (see para. 1 of section 2.4) and activates FAM from quenched (Fig. 1).
The artisan would have had a reasonable expectation of success in using a multicomponent nanorod to conjugate antibodies and hairpin oligonucleotides because it has been well understood by Lim, Wei, and Lee to use nanorods for separation and isolation and Lee teaches combining gold and magnetic nanorods as a single multicomponent nanorod to isolate different targets.
With regard to claims 2-3, Lee teaches the multifunctional nanorod is gold-nickel-gold nanorods (see Fig. 6 and para. [0073]).
With regard to claim 6, Lee does not teach fluorophore is 5(6)-carboxyfluorescein. Wei teaches the length of the hairpin oligonucleotides is by the design to recognize a specific target sequence (see para. 1 of section 2.4) and activates FAM from quenched (Fig. 1). As stated above, it would have been obvious to have detected the presence of the target molecule on the nanorod.
With regard to claim 7, Wei does teach a thiolated hairpin DNA (hpDNA) having a sequence of about 19-35 bases (see para. 1 of section 2.4). However, the references do not explicitly teach the detectably labeled nucleic acid is 8.5 nm in length. As stated above, it has been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum length for a result-effective variable to specifically hybridize a target sequence length while activating fluorescent signals of carboxyfluoresceins (FAMs) on nanorods. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation" Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In the absence of unexpected results, it would have been obvious to the person of ordinary skill to discover the optimum length of the detectable molecule to hybridize to a specific target sequence while producing a desirable fluorescent signal of carboxyfluoresceins (FAMs) through routine experimentation because Wei teaches the length of the hairpin oligonucleotides is by the design to recognize a specific target sequence (see para. 1 of section 2.4) and activates FAM from quenched (Fig. 1).
With regard to claims 8-10, Lee does not teach a detectably labeled nucleic acid specifically binds the target nucleic acid(claim 8), wherein the extracellular vesicle is an exosome (claim 9) and wherein the target nucleic acid comprises an miRNA (claim 10). Lim teaches isolated exosomes were characterized based on size and concentration using nanoparticle tracking analysis and exosomes are for the analysis of protein, lipid, mRNA, and miRNA (see abstract and conclusion under abstract). Wei teaches a fluorescent probe for mRNA detection that consists of a gold nanorod (GNR) functionalized with fluorophore-labeled hairpin oligonucleotides (hpDNA) that are complementary to the mRNA of a target gene wherein the fluorophore is FAM (see abstract and Fig. 1). Thus, it would have been obvious to have combined the isolating steps of exosomes and miRNAs of exosomes on a single multicomponent nanorod because the multicomponent nanorod contains material compositions of gold and nickel segments which possess the ability to conjugate antibodies and hairpin oligonucleotides, as Lim recognizes the efficiency of using cylindrical nanoparticles to isolate exosomes and miRNAs from exosome are critical information in establishing the roles of the exosomes and Wei teaches that RNA hybridization to the hairpin oligonucleotide is detectable on gold segments with activated carboxyfluorescein (FAM), as the hairpin oligonucleotide is designed for specific target sequence.
With regard to claim 11, the references do not employ the specific terminology of a “kit” in describing the invention and instructions. However, as noted above, the references teach the claimed elements of the nanorod, which are the constituent reagents of the kit. In addition, the recitation of “instructions for use” is not found to be limiting in such a case as this; where the only difference between prior art references and the claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004). See MPEP 2112.01(III).
Response to Arguments
Applicant's arguments filed 08/21/2025 have been fully considered but they are not persuasive.
With respect to 35 U.S.C. 103 rejection, Applicant argues on page 7 that to advance prosecution, claim 1 has been amended. Applicant argues that there is no motivation or guidance to a person of ordinary skill in the art to streamline isolation of exosomes and detection of a target nucleic acid using a single nanorod. Applicant argues that the combination of references is based on hindsight. Lee describes a nanorod for separation of proteins and other molecules but does not suggest using the nanorod for detection. Similarly, Lim describes a nanowire for separation of exosomes, but does not suggest using the nanowire for detection. Wei describes a nanorod for mRNA detection, but does not suggest using the nanorod for isolation. Lim and Wei suggest that the functionals molecules, either for exosome isolation or for mRNA detection, should be distributed throughout the entire nanorod, indicating against the division of the nanorod for multiple uses. The further argues on page 8, para. 2, that the mere capability of the nanorod in achieving certain outcomes says nothing about the motivation to actually modify the nanorod to realize the outcomes. Meanwhile, Lim does not concern improving efficiency in miRNA detection, providing no motivation to streamline isolation with detection. Applicant further argues that there would be no reasonable expectation of success of the claimed nanorod in detection of extracellular vesicle-related nucleic acids because Lee merely describes its multi-segment nanorod can be used for separation of proteins and other molecules.
The arguments are not found persuasive for the following reasons. It is not hindsight because nanorods are recognized in the art for separation of biomolecules in a sample. In particular, Lim teaches the blueprint for isolating exosomes is through magnetically functionalized nanorods and recognizes that the efficiency of isolating is through surface binding affinity of surface molecular components (i.e., proteins, mRNA, and microRNA) on exosomes. Meanwhile, Lee recognizes that magnetic nanorods are fused with gold nanorods to form a bimetallic nanorods (gold end portions with center portion is magnetic) for different biomaterial separations in a sample. Because multicomponent nanorods of gold and magnetic material are recognized for isolating different targets of a sample as taught by Lee and Lim teaches the effectiveness of isolating exosomes is through its surface functional molecular components, it would be obvious to have incorporated gold segments on the ends of nanorod of Lim or used the multicomponent nanorods of Lee for the purpose of increasing the effectiveness and ability to engage with more exosome’s surface functional molecular components. Therefore, it is obvious to try as multicomponent nanorods having gold ends and magnetic material are recognized in the art for separation and extraction.
Moreover, Lim teaches evaluating the expression of exosomal RNA through the efficiency of isolating exosomes by attaching to surface molecular components on exosomes and said surface molecular components of exosomes are proteins, mRNA, and microRNA. Thus, the artisan would have been motivated to combine antibodies of Lim with hairpin oligonucleotides of Wei on a multicomponent nanorod for isolation because it would be desirable to increase the likelihood of binding to surface molecular components of exosomes for isolation and having the ability to sensitively detect the presence of RNA targets on said nanorod.
Applicant further argues on page 9 that the present claims achieve unexpected and superior effects. In particular, the instant Figs. 3E, 4F, 4G, and 5A-5C demonstrate numerous advantageous effect in characterizing and distinguishing cell states and cell types. Therefore, the above superior and advantageous effects achieved by the claimed nanorod cannot be expected from the teachings of Lee, Wei, and Lim.
The arguments related to unexpected/superior results are not found persuasive. To show unexpected results, the evidence must be (1) commensurate in scope with the claimed subject matter, In re Clemens, 622 F.2d 1019, 1035, 206 USPQ 289, 296 (CCPA 1980), (2) show what was expected, to "properly evaluate whether a … property was unexpected", and (3) compare to the closest prior art. Pfizer v. Apotex, 480 F.3d 1348, 1370-71, 82 USPQ2d 1321, 1338 (Fed. Cir. 2007).
In this particular case, the claimed nanorods are not commensurate in scope with the data provided in the figures. The nanorods in the instant figures are specific with the materials and the size of the nanorods, a specific fluorophore, and specific characteristics of the detectably labeled nucleic acid to provide the superior results as demonstrated in the figures. Therefore, the arguments are not found persuasive.
Conclusion
No claim is 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.
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/N.P.N/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678