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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 1/7/2026 has been entered.
Status of Claims
Claim 40 has been amended. Claims 44-49 are newly added. Claims 40 and 44-49 are pending and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn. The previous rejection has been modified in view of Applicant’s arguments and further consideration of the claim limitations. New grounds of rejection are set forth herein. The Examiner’s response to Applicant’s arguments is incorporated below.
Claim Rejections - 35 USC § 112
Claim 46 is 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. The claim is dependent upon claim 43, which is a cancelled claim. Accordingly, the metes and bounds of the claim have not been clearly set forth and the scope of the invention cannot be distinctly ascertained.
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.
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (US 2015/0037818) in view of Bhana et al. (J. Colloid and Interface Sci., 2016, 469, p. 8-16), in further view of Zong et al., Anal. Methods, 2016, 8, 5001.
The instant claim is directed to a method of characterizing biomarkers on an exosome, the method comprising (a) contacting the exosome with a nanotag comprising a plasmonic nanoparticle, a 16-mercaptohexadecanoic acid-linked polyethylene glycol covalently bound at the thiol terminal to a surface of the nanoparticle, an antibody bound to the PEG thiol with the thiol terminal bound to a surface of the nanoparticle, and a Raman reporter that is incorporated into the MHDA pocket on the surface of the nanoparticle, wherein an antibody present on the nanotag binds an antigen present on the exosome; (b) exposing the exosome to a light source and acquiring an image of the exosome, wherein the image serves as a mask to localize the exosome; (c) exposing the exosome to a wavelength sufficient to elicit a signal from the nanotag; (d) detecting the signal using Raman spectroscopy, and (e), characterizing the biomarker on the exosome with the mask image and the Raman signal.
Huang teaches anisotropic magnetic-optical iron oxide-gold core-shell nanoparticles which exhibit surface plasmon absorption between about 550 nm-900 nm. An anisotropic iron oxide-gold core-shell nanoparticle can be surface-modified or derivatized with a material capable of binding to an analyte, antigen, cell or other moiety. For example, an anisotropic iron oxide-gold core-shell nanoparticle can be conjugated to an antibody capable of specific binding to an antigen, including cell-surface antigens. Thus, an anisotropic iron oxide-gold core-shell nanoparticle can be targeted to specifically bind to an analyte or cell type, which permits separation of the analyte and detection of the present or absence of the analyte (e.g., Example 2) (paragraph 0050).
Dye-adsorbed metal NPs, referred to as surface enhanced Raman scattering nanoparticles (SERS NPs), have emerged as a new type of biological labels for cancer detection during the last decade. The rationale is that SERS NPs have exceptional detection sensitivity and specificity. The enhancement of the Raman signals of the dye by the supporting metal NPs can be as much as 1014 to 1015, thus facilitating the detection down to the single molecule or single particle level (paragraph 0055).
In Example 2, antibody conjugated IO-Au SER NOVs are prepared. QSY21 (i.e. Raman reporter) was added to IO-Au nanoovals (NOVs). The mixture was vortexed… to allow the adsorption of the dye onto the NPs. This was followed by addition of carboxy-poly(ethylene)-thiol (HOOC-PEG-S, MW 5000). The bifunctional PEG was attached to the NPs via Au--S bonds. Anti-epithelial call adhesion molecules (anti-EpCAM) or anti-human epidermal growth factor receptor (anti-HER) monoclonal antibodies to the IO-Au SERS NOVs (paragraphs 0091-0099).
Cellular binding was examined by dark field imaging with an Olympus IX71 inverted microscope. Specific cellular bindings of the conjugated nanoovals were confirmed by the presence of dense nanoparticles on and/or in the cells, which in turn confirmed the successful ligand conjugation to the nanoparticles. Dark field images of cancer cells incubated with the antibody-conjugated nanoovals and unconjugated nanoovals, which meets the limitation of the instant step wherein membrane bound vesicles are exposed to a light source and imaged (paragraph 0099).
Further, SK-BR-3 cells were dispersed in PBS and labeled with a cocktail of anti-EpCAM/QSY21/IO-Au NOVs and anti-HER2/QSY21/IO-Au NOVs and SERS measurements were performed, which meets the limitation wherein membrane bound vesicles were exposed to a wavelength sufficient to elicit a signal from the nanotag and detection using Raman spectroscopy (see paragraphs 0099-0105).
FIG. 12 shows (A) Schematic illustration of the preparation of antibody-conjugated IO-Au SERS NOVs; (B) Dark field image of SK-BR-3 cells incubated with a cocktail of anti-EpCAM/IO-Au SERS NOVs and anti-HER2/IO-Au SERS NOVs; and (C) Dark field image of SK-BR-3 cells incubated with unconjugated IO-Au SERS NOVs. The data show specific binding of antibody-conjugated IO-Au NOVs, but not the unconjugated ones, to the cancer cells.
See also Figures and description of Figures 13, and 14 including detection of prelabeled SK-BR-3 cells spiked into whole blood. (A) SERS spectra from different number of SK-BR-3 cells; (B) Plot of SERS signal intensity at 1496 cm−1 versus the number of SK-BR-3 cells; (C) Comparison of SERS signals from 10 pre-labeled SK-BR-3 cells in the blood and signals from the blood only (the negative control). The calculated LOD was less than 1 cell/mL blood.
Accordingly, Huang meets the limitations of the instant nanotags and methods, including a providing a plasmonic nanoparticle (IO-Au NOV), an antibody bound to the PEG thiol with the thiol terminal bound to the surface of the nanoparticle and a raman reporter (QSY21), and methods of exposing a cell to a light source and acquiring an image of a cell, i.e. wherein the image serves to localize the cell which is consistent with a mask according to the instant claims; exposing the a cell to a wavelength sufficient to elicit a Raman signal from the nanotag; and characterizing a biomarker on a cell, such as the presence of a cell surface antigen.
Huang teaches characterizing a biomarker on a cell, but does not specifically teach 16-mercaptohexadecanoic acid linked polyethylene glycol covalently bound at the surface of the nanoparticle and does not teach characterizing biomarkers on an exosome.
Bhana teaches a sub-100 nm nanosystem for simultaneous near infrared photodynamic and photothermal cancer therapy. The nanosystem was formed by adsorption of silicon 2,3-naphthalocyanine dihydroxide (i.e. Raman reporter) onto gold nanorod followed by covalent stabilization with alkylthiol linked polyethylene glycol. The effects of alkylthiol chain length on drug loading, release and cell killing efficacy were examined using 6-mercaptohexanoic acid, 11-mercaptoundecanoic acid and 16-mercaptohexadecanoic acid. We found that the loading efficiency of silicon 2,3-naphthalocyanine dihydroxide increased and the release rate decreased with the increase of the alkylthiol chain length (abstract).
Nanoparticles were prepared, and SiNC was loaded onto Au NRs via electrostatic adsortion followed by covalent stabilization with AT–PEG. SiNC adsorption was characterized by Raman measurement. Fig. 3A shows the surface enhanced Raman scattering (SERS) spectra of MHA–PEG/SiNC/Au NRs, MUA–PEG/SiNC/Au NRs and MHDA–PEG/SiNC/Au NRs, in comparison to the Raman spectrum of pure SiNC.All three nanocomplexes showed strong SERS signals from SiNC, confirming the adsorption of SiNC onto Au NRs (page 10).
It was demonstrated that the number of adsorbed SiNC increases as the number of carbon in AT segment increases. This is probably because the longer AT forms a larger hydrophobic pocket than the shorter AT on the surface of Au NR (Fig. 3D). As a matter of fact, previous studies have shown that hydrophobic drugs can be trapped in the Au NP monolayer formed by MUA–linked tetra (ethylene glycol). It is believed that the MUA segments form the hydrophobic pocket than the shorter AT on the surface of Au NR, the ethylene glycol forms a hydrophilic external shell to stabilize the drug-loaded complex in aqueous solution. Our previous studies by high performance liquid chromatography (HPLC) have shown that such pocket can trap hydrophobic paclitaxel with ∼ 2 × 104 per Au NR. Here we used Raman spectroscopy as a simple characterization technique and found a similar loading capacity of SiNC to Au NRs covalently bound with MUA–PEG. Further, we found this drug loading capacity indeed depends on the alkanethiol chain length, with longer one leading to higher SiNC loading density. Due to the hydrophilic nature of PEG, we believe incorporation of SiNC in the PEG layer is trival (page 11).
Au NRs as a carrier can deliver more than 104 SiNC per particle by incorporating SiNC into the hydrophobic pocket of AT–PEG on the surface of Au NRs. Through the unique formulation, both Au NR and SiNC are protected by the stealthy PEG and thus the nanocomplex will have long circulation properties in the blood stream, ensuring sufficient tumor accumulation of both Au NR and SiNC (page 15).
Zong teaches that exosomes play an important role in intercellular communications. Here, we present a surface-enhanced Raman scattering (SERS) based detection method for tumor-derived exosomes using SERS nanoprobes and magnetic nanobeads. The SERS nanoprobe has a core–shell structure, with gold core–silver shell nanorods (Au@Ag NRs) as the SERS active core, Raman molecules as the SERS reporter and a silica layer as the protecting shell. The outmost surface of the SERS nanoprobe is decorated with exosome-specific antibodies. Each magnetic nanobead is fabricated by coating Fe3O4 nanoparticles (NPs) with a silica shell and attaching specific antibodies to the silica shell. With target exosomes present, the magnetic nanobeads and SERS nanoprobes can capture the exosomes by forming a sandwich-type immunocomplex. The immunocomplex (as well as the SERS nanoprobes) can be precipitated with a magnet, and thus SERS signals can be detected in the precipitates. With no target exosomes present, no immunocomplex can be formed, and thus quite weak SERS signals will be detected in the precipitates. Hence, the SERS signal of the final magnetic separation product can be used to detect exosomes. In the experiment, using one kind of tumor cells and one kind of normal cells, we proved that the presented method can be used for both qualitative and quantitative detection of tumor-derived exosomes (abstract).
Exosomes play a vital role in intercellular communication and substance exchange. For tumor cell-derived exosomes, they are deeply involved in modulation of tumor microenvironment and metastatic niche formation. Usually, tumor cells secret more exosomes with special biomarkers on their membrane surfaces as compared with normal cells. This makes tumor-derived exosomes an important cancer biomarker. Thus detection and analysis of tumor-derived exosomes can give important insight into the pathological stages of cancerous diseases.
To determine whether the proposed method can be applied for quantitative detection of tumor-derived exosomes, exosomes in amounts of 4.88 106, 4.88 105, 4.88 104 and 4.88 103 are used. Pure PBS buffer solution is used as the blank control. After 1.5 h, the mixture is exposed to a magnet and the precipitate is collected for SERS measurements. The results are shown in Fig. 5a. First, the SERS intensity of the blank control is obviously much weaker than the SERS intensities obtained with target exosomes present. Second, the SERS intensity decreases as the amount of exosomes decreases. Fig. 5b more vividly demonstrates the concentration-dependent SERS intensity. As can be seen from the inset of Fig. 5b, the presented SERS-based method exhibits better quantitative detection ability with an exosome number of less than 105. Considering that the dynamic range of the presented method seems not so satisfactory, we are currently working on using microuidic chips and the SERS technique to get better exosome detection performance. The correlation between exosome amounts and SERS intensity can be fitted using the equation y¼ 803.8 + 472.2 lg x 33.1 lg2 x, where y represents the SERS intensity and x represents exosome numbers. The limit of detection (LOD) is defined using the equation SLOD ¼ Sblank + 3SD, where SLOD represents the signal intensity of LOD, Sblank represents the signal intensity of the blank control while SD represents the standard deviation of the blank control. The LOD of the present method is found to be approximately 1200 exosomes. Table 1 provides the analysis times and LODs different detection methods, which better exhibits the short analysis time and improved LOD of the present method. As can be seen, the LOD of the present method is obviously lower than that of many of the other reported methods. This benet arises from the high sensitivity provided by SERS. The above experi mental results prove that the proposed SERS-based method can indeed be used to detect target exosomes as well as for quantitative analysis of the target exosomes (page 5005-6).
In the present SERS-based method, by directly using the SKBR3 culture media as the analyte, we proved that the collection and identification of exosomes can be accomplished simultaneously by the magnetic nanobeads and SERS nanoprobes in one step. Thus the total analysis time is only 2 h. Besides, the SERS-based method is not solely applicable to the detection of exosomes secreted by SKBR3 cells. The detection of other kinds of exosomes, such as those secreted by breast or lung cancer cells, can be facilely realized by choosing appropriate antibodies deco rated on the magnetic nanobeads and SERS nanoprobes (page 5007).
It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the bifunctional PEG-thiol which is used to bind to the nanoparticle and a target molecule (antibody) in the methods of Huang when the teaching of Huang is taken in view of Bhana. While Huang does not recite 16-mercaptohexadecanoic acid-linked polyethylene glycol bound to the nanoparticle and linked to an antibody, it is known from Bhana to vary the length of a self assembled molecule having affinity for the nanoparticle surface and which can be modified by oligoethylene glycol molecules, including use of 16-mecaptohexadecanoic acid as alkyl length. One would have found further motivation to provide a 16-mercaptohexadecanoic acid linker between the gold nanoparticle and polyethylene glycol because Bhana teaches that a hydrophobic Raman reporter molecule having a 16-mecaptohexadecanoic acid linker between gold nanoparticle and PEG allows for a hydrophobic pocket on the surface of Au NR, and results in higher loading capacity of the drug. Accordingly, with regard to the limitation wherein a Raman reporter that is incorporated into the MHDA pocket on the surface of the nanoparticle, one would have had a reasonable expectation of success that a hydrophobic Raman reporter would be present in the MHDA pocket.
It would have been further obvious to provide the particles taught by Huang and Bana for use in characterizing biomarkers, such as identification of the presence therof, on an exosome when the teachings of Huang and Bana are taken in view of Zong. For example, the anisotropic iron oxide-gold core-shell nanoparticles taught by Huang can be surface-modified or derivatized with a material capable of binding to an analyte, antigen, cell or other moiety. Zong teaches that by using SKBR3 culture media as an analyte, we proved that the collection and identification of exosomes can be accomplished, and that a SERS nanoprobe is decorated with exosome-specific antibodies. While Huang does not specifically recite exosomes, one would have been motivated to provide detection and analysis of biomarkers on exosomes using the antibody coated nanoparticles because Huang is concerned with using SERS nanoparticles as biological labels for cancer detection, and Zong teaches that detection and analysis of tumor-derived exosomes can give important insight into the pathological stages of cancerous diseases. For example, both Huang and Zong teach use of a sample comprising SK-BR-3 cell culture as an analyte.
With regard to the step of detecting the signal using Raman spectroscopy, thereby characterizing the exosome, wherein the mask image and the Raman image are analyzed to determine the expression profile of a biomarker, it is noted that step b recites exposing the exosome to a light source and acquiring an image of the exosome, wherein the image serves as a mask to localize the exosome. Accordingly, as Huang teaches both vesicle imaging (which correlates to the claimed mask to localize a vesicle according to the instant claim language) and Raman detection of analyte/antigen, which correlates to Raman image are analyzed to determine the expression profile of a biomarker, or presence of antigen, it is considered that the instant claims are rendered obvious. With regard to the newly added claims, Huang teaches that the anisotropic iron oxide-gold core-shell nanoparticles of the invention can be used for detection of analytes (including, e.g., antigens, cells, and the like) in a sample (such as a biological sample, including fluids, tissues, and the like) (paragraph 0169) and Zong teaches a limit of detection within the claimed range.
Response to arguments
Applicant argues that Applicant traverses for the reasons of record. For example, Peyman may indicate that exosomes may have been known, but that is insufficient to allege that any measurement would be applicable to exosomes with a reasonable expectation of success. For example, Huang "eliminate[s] the influence of cell debris in cell suspension by measuring Raman signals from the individual whole cell.", citing paragraph [0138]. Applicant asserts that Huang is based on not imaging "cell debris" and therefore teaches away from exosomal measurement.
Applicant’s arguments have been fully considered but are not persuasive. It is respectfully submitted that the Huang reference does not rise to the level of teaching away from exosome detection. See MPEP 2145. A prior art reference that “teaches away” from the claimed invention is a significant factor to be considered in determining obviousness. However, “the nature of the teaching is highly relevant and must be weighed in substance. A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In reGurley, 27 F.3d 551, 553, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (Claims were directed to an epoxy resin based printed circuit material. A prior art reference disclosed a polyester-imide resin based printed circuit material, and taught that although epoxy resin based materials have acceptable stability and some degree of flexibility, they are inferior to polyester-imide resin based materials. The court held the claims would have been obvious over the prior art because the reference taught epoxy resin based material was useful for the inventor’s purpose, applicant did not distinguish the claimed epoxy from the prior art epoxy, and applicant asserted no discovery beyond what was known to the art.).
Furthermore, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) (“a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.”) (internal quotations omitted) (quoting DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)); and Schwendimann v. Neenah, Inc., 82 F.4th 1371, 1381, 2023 USPQ2d 1173 (Fed. Cir. 2023) (“Although Oez [the prior art] used a white pigment with a cross-linking polymer, it does not discourage a skilled artisan from using the white pigment without a cross-linking polymer or lead the skilled artisan in a direction divergent from the path taken in the Appealed Patents. Thus, Oez's disclosure is substantial evidence that supports the Board's finding that Oez does not teach away from the proposed combination.”).
In the instant case, Huang specifically recites that the nanoparticles can be be surface-modified or derivatized with a material capable of binding to an analyte, antigen, cell or other moiety. The teaching as a whole is not directed solely to detection of cells, and further exosomes are not identified as cell debris.
Applicant further argues that there is no reasonable expectation that Huang or Bhana's methods had any applicability to Peyman's measurements that occur "in the subject." See claim 1. There is no basis, whatsoever, to contend that a person of ordinary skill in the art would use a technique based on measuring Raman signals from the "whole cell" and eliminating cellular debris to image exosomes (which may be characterized as "cell debris").
Applicant’s arguments have been fully considered but are not persuasive. It is respectfully submitted that the Peyman reference has been replaced by the Zong reference, which teaches in vitro analyte.
Applicant further argues that the cited references do not teach or suggest every limitation claimed. Applicant asserts that for example, step b) recites the step of exposing the exosome to a light source and acquiring an image of the exosome, wherein the image serves as a mask to localize the exosome. The Examiner alleges that, in Huang, "[c]ellular binding was examined by dark field imaging" and, therefore, "Huang teaches both vesicle imaging (which correlates to the claimed mask to localize a vesicle according to the instant claim language) and raman detection of analyte/antigen, which correlates with the Raman image. Applicant asserts Huang’s imaging is used to confirm "the presence of dense nanoparticles on and/or in the cells, which in turn confirmed successful ligand conjugation to the nanoparticles." citing [0098]. Applicant contends that Huang does not perform mask-based localization as alleged by the Examiner. Applicant argues that the cited references also do not teach or suggest the use of both Raman and localization imaging as claimed and that the present claims recite both creating a mask to localize the exosomes and performing Raman in conjunction with that mask. Applicant argues that not only are localization, mask creation, and exosomes not taught or suggested by Huang, mask creation in conjunction with Raman is also not taught or suggested by any of the references. However, as only explained in the originally filed specification, by "analyzing the dark field mask image and the SERS target image, the expression profile of targeted proteins may be obtained that informs the amount and the protein level of the exosome subpopulation positive to the targeted protein." See Originally filed specification at p. 22, Ins. 10-25.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that Huang teaches the active steps a-d according to the instant claims, including contacting, exposing to a light source, exposing to a wavelength to elicit raman response and detecting a raman response.
With regard to the assertion that Huang’s imaging is used to confirm "the presence of dense nanoparticles on and/or in the cells, which in turn confirmed successful ligand conjugation to the nanoparticles and that Huang does not perform mask-based localization, see e.g. Figure 12 of Huang, which shows dark field image of SK-BR-3 cells. It is respectfully submitted that the cells are imaged, and therefore located and Raman detection is reported. Further Bhana teaches an anisotropic iron oxide-gold core-shell nanoparticle can be conjugated to an antibody capable of specific binding to an antigen, including cell-surface antigens. Thus, an anisotropic iron oxide-gold core-shell nanoparticle can be targeted to specifically bind to an analyte or cell type, which permits separation of the analyte and detection of the present or absence of the analyte, and teaches that surface enhanced Raman spectroscopy and imaging, which enhances the molecular diagnosis of a substance attached to the surface of a metallic nanoparticle after it is exposed to the laser light energy as known in the art, etc. recorded to enhance an early disease diagnosis in vivo as set forth above. Applicant’s arguments have been fully considered but the rejection is maintained.
Conclusion
No claims are allowed at this time.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
