DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. Applicant’s election without traverse of Group I (claims 1-8) in the reply filed on June 23, 2026 is acknowledged.
3. Claims 1-23 are pending.
Claims 9-23, drawn to non-elected inventions are withdrawn from consideration.
Claims 1-8 are examined on the merits.
Claim Rejections - 35 USC § 112
4. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
5. Claims 1-8 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims read on a method of measuring binding of a drug to target molecules in a subject that has been treated with a drug over a treatment period comprising contacting a probe with extracellular vesicles (EVs) from subject’s sample at different times points of the treatment period, wherein the probe is capable of competing with the drug in binding to the target molecules in the EVs and detecting the binding of the probe to the target molecules in the EVs, wherein a decrease in the binding of the probe to the EVs as treatment period progresses indicates an increase in the binding of the drug to the target in the subject.
Moreover, the EVs contacted with the probe, are further contacted with a sensor, wherein the EVs are captured to the sensor and the said captured EVs contacted with the probe and the probe binds to target molecules on the EVs results in either signal P or signal M. Binding of the probe to the target molecules results in signal P, in situ enzymatic amplification of signal corresponding to the binding of the probe to the target molecules. Signal M is rendered when contacting the EVs with the sensor.
In conclusion, binding of the drug to the target is determined at different time points in the treatment period utilizing a probe, reference probe and drug occupancy index and the EVs are further captured by one or more capture agents immobilized on the sensor and subpopulations are differentiated based on distinct capture agents with a statistical techniques.
The written description in this instant case does not set forth a plethora of molecules that can be regarded as probes, sensors and capture agents. The Specification cites several non-limiting and different probes, sensors and capture agents, as well as the instant claims, see entire document. The Specification and claims characterize these molecules by function with no structure.
The state of the art provides that many molecules fall under the umbrella of probes, magnetic labeling probes, radioactive labeling probe, optical labeling probe and metal labeling probes, see Hu et al. (Coordination Chemistry Reviews 534: 1-18, available online 10 March 2025) and in particular, segments 4-7 spanning pages 4-14; and Shao et al. (Chem. Rev. Author manuscript pages 1-83, 2018 August 28) in its entirety. Furthermore, there are many subtypes cited within the four types listed.
Additionally, the state of the art also provides that sensor or biosensors are also numerous comprising distinct sensing mechanisms able to detect a wide range of EVs, see Shao, segment 5.3 spanning pages 12-16 and Table 3 on page 81; and Hu in its entirety. Likewise, capture agents embody a host of binding molecules, including antibodies, aptamers, as well as peptides, see Hu and Shao in their entireties. Applicant has not evidenced they are in possession of the countless members of these substances regarded as probes, sensors and capture agents as the claims read on.
The instant application does not provide sufficient guidance as to the nexus or correlation between the structure and function of the undefined probes, sensors and capture agents that places the skilled artisan in possession of the genera of inhibitors in scope with the claimed invention.
In Abbvie v. Centocor (Fed. Cir. 2014), the Court held that a disclosure of many different antibodies (in that case neutralizing antibodies to IL-12 with a particular binding affinity) was not enough to support the genus of all IL-12 neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
“A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69.
Vas-Cath Inc. V Mahurkar, 19 U5PQ2d 1111, clearly states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 115).
The skilled artisan cannot envision the detailed structure of the broad class of probes; broad class of sensors; and broad class of capture agents, therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and a reference to a potential method of isolating it. The polypeptide itself is required. See Fiers v. Revel, 25 U5PQ 2d 1601 at 1606 (CAFC1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Lts. 18 U5PQ2d 1016.
Furthermore, In The Reagents of the University of California v. Eli Lilly (43 U5PQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that while Applicants are not required to disclose every species encompassed by a genus, the description of a genus is achieved by the recitation of a representative number of DNA molecules, usually defined by a nucleotide sequence, falling within the scope of the claimed genus. At section B(l), the court states that "An adequate written description of a DNA...'requires a precise definition, such as by structure, formula, chemical name, or physical properties', not a mere wish or plan for obtaining the claimed chemical invention".
At the time the application was filed Applicants do not seem to be in possession of all the members of the genus of probes, sensors and capture agents that are required for the claimed method. Applicant did not have possession of the breadth of the three sets of molecules.
The USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018. See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf.
The Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies, including the following.
“In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”.
There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of said molecules essential to the claimed invention to demonstrate possession that fulfill the requirements of a structure-function relationships of written description. Also, see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017).
“When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), the following is noted.
To show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358).
The instant disclosure, including the claims fail to disclose a representative number of species falling with the scope of the genera and/or structural common to the members of the genera so the one of skill in the art can visualize or recognize the members of the cited genera.
Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361).
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Here, Applicant’s claims include molecules that encompass various structural, specificities and functional attributes to fulfill the requirements of a structure-function relationships of written description, but does not describe the structure-identifying information about the probes, sensors and capture agents, nor describe a representative number of species falling with the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual said probes, sensors and capture agents.
A skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus that exhibit this functional property.
The specification does not evidence the possession of all the said probes, sensors and capture agents that are undefined and uncharacterized falling within the potentially large genus to establish possession. Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 U5PQ2d 1398.
The full breadth of the claims do not meet the written description provision of 35 U.S.C. 112, first paragraph.
6. 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.
7. Claims 1-8 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.
a. Claim 1 recites target molecules and a target. It is not clear if they are one and the same or are the target molecules are a unit of components or compounds, whereas the target is a selected space or place. The metes and bounds cannot be determined.
b. Claim 1 cites measuring binding of a drug to target molecules in a subject that has been treated with a drug over a treatment period, wherein a probe with extracellular vesicles (EVs) from samples taken from subject at different time points of the treatment period. The probe bound to the target molecules in the EVs are detected and evaluated to assess whether or not the probe competed with the drug in binding to the said target molecules in the EVs, wherein decreased probe-EVs binding as treatment period progresses is indicative of the binding of the drug to the target.
However, it is not clear what disease/disorder the subject is afflicted with, nor what type of biological samples and how many should be obtained from the subject and assayed for what target molecules in EVs. EVs are art known to comprise a vast number of proteins, nucleic acids, fragments of organelles, lipids, as well as other accessory molecules and compounds. Nor, is it clear what is the probe that is capable of competing with the unnamed drug that treats an unidentified malady.
Furthermore, claim 2 recites contacting the probe with EVs from subject’s samples, wherein each sample is further contacted with a sensor and captured by said sensor and utilizing the probe to contact the captured EVs on the sensor with the probe binding to target molecules on the EVs that are not already bound by the drug. It is not clear if the probe that contacted the EVs from the sample is the same probe that contacts the EVs captured on the sensor.
It is not clear if the sensor is sample-type dependent or is the same sensor able to function in each and every sample. Likewise, it is not clear if the probe is able to bind the numerous target molecules on and in the EVs.
c. The reading of claim 2 includes contacting sample EVs with a sensor and captured to the sensor, wherein a probe is contacted with the sensor EV captured. The probe binds target molecules in the EVs results in a signal P. Claim 3 reads on EVs contacted with the sensor results in signal M. However, this last contact step was cited in claim 2. Hence, it would seem signal M would also be emitted at claim 2. It is not clear if signal M is also emitted when the probe does not bind target molecules. Accordingly, the metes and bounds cannot be determined.
d. Based on the reading of claim 7, EVs are captured by binding to one or more capture agents immobilized on the sensor. It is not clear what these capture agents are. Accordingly, the metes and bounds cannot be determined.
8. Claim 1 and claim 4 recite the limitation "the target" in line 8 and line 3, respectively. There is insufficient antecedent basis for this limitation in the claims.
9. Claim 8 recites the limitation "the captured EVs" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 101
10. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
11. The claimed invention (claims 1-8) is directed to judicial exception without significantly more. The claim(s) recite(s) a method of measuring binding of a drug to target molecules in a subject that has been treated with a drug over a treatment period, comprising contacting a probe with extracellular vesicles (EVs) from samples obtained from the subject at different time points of the treatment period, wherein the probe is capable of competing with the drug in binding to the target molecules in the EVs, and detecting the binding of the probe to the target molecules in the EVs, wherein a decrease in the binding of the probe to the EVs as treatment period progresses indicates an increase in the binding of the drug to the target.
Moreover, the EVs contacted with the probe, are further contacted with a sensor, wherein the EVs are captured to the sensor and the said captured EVs contacted with the probe and the probe binds to target molecules on the EVs, not already bound by the drug results in either signal P or signal M. Binding of the probe to the target molecules on EVs not already bound by the drug, results in signal P, in situ enzymatic amplification of signal corresponding to the binding of the probe to the target molecules.
Signal M is rendered when contacting the EVs with the sensor.
The binding of the drug to the target at different time points in the treatment period comprising determining a probe labeling index µ based on the ratio of the signal P to the signal M, normalizing the probe labeling index µ to a reference probe labeling index µ0, to produce a normalized probe labeling index µ/µ0, wherein the reference probe labeling index µ0 is determined on a control sample, wherein the control sample is obtained from a subject that has not been treated with the drug, determining a drug occupancy index based on the normalized probe labeling index.
Moreover, at the different time points are at intervals after start of the treatment period, the drug occupancy at each time point is determined, wherein if the drug is effective the drug occupancy is higher at a later time point than the drug occupancy at an earlier time point.
And captured EVs bound to one or more capture agents immobilized on the sensor to distinguish different subpopulations, wherein the method comprises calculating a composite drug occupancy based on the drug occupancies determined for the different subpopulations using a multiple linear regression model.
The judicial exception is the relationship between the binding of a drug to target molecules in a person’s biological sample containing target molecules in EVs over a course of treatment time. Differences in the binding of a drug to target molecules in EVs as determined with drug occupancy index over different time points is indicative of the effectiveness of the drug, wherein if the drug occupancy at a later time point is higher than the drug occupancy at an earlier time point, the drug is rendered to be effective. This judicial exception is not integrated into a practical application because the claims describe a law of nature, namely the relationship between target molecules in the EVs from a subject’s sample at different time points during drug treatment over a period of time, indicative of drug effectiveness and identifying different populations of EVs. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because assaying mutations does not add significantly more and is not an inventive concept.
The analysis as set forth in the 2019 Guidance is as follows:
Step 1: Yes, claims are drawn to methods which are one of the four statutory categories, a process.
Step 2A, prong 1: Yes, the claims recite/describe a law of nature or natural phenomenon. Claim 1 describes the relationship between the target molecules in the EVs and bound probe, bound sensor over the course of treatment time with or without bound drug, wherein probe bound to target molecules in EVs further contacted and captured with a sensor with the probe binds the target molecules on the EVs not already bound by the drug, wherein the binding of the probe to the target molecule yields signal P values. The EVs contacted with the sensor and captured by the sensor results in signal M.
The binding of the drug to the target is based on signal P and signal M, further determining the binding of the drug to the target at different time points in the treatment period utilizing a probe labeling index m and drug occupancy index, as well as drug efficacy and populations of EVs.
Step 2A, prong 2: No, the law of nature or natural phenomenon does not integrate into a practical application because there are no additional steps beyond the determination of a signal based on binding of target molecules on EVs to probes and/or sensors. This embodiment does not rely on or use the exception, this language does not integrate the law of nature or judicial exception into a practical application. There is observation of target(s)/target molecule(s) on/in EVs to binding molecules taken from samples over the course of treatment with a drug. In some claims thereafter, essentially there is a condition, wherein if the drug occupancy at a later time point is higher than the drug occupancy at an earlier time point is indicative of drug effectiveness. However, there is no stipulation set forth if the at a later time point, drug occupancy is lower than the drug occupancy at an earlier time point. Once one has the information regarding binding of the drug to the target, probe to EVs, probe to EVs captured on the sensor, drug occupancy at different time points, as well as determination of different subpopulations if any and/or benefit from a treatment and/or assessing the efficacy of treatment.
Step 2B: There is no inventive concept present in the claims. The steps of analyzing target(s)/target molecule(s) on EVs from biological samples with drug treatment is established by well understood, routine conventional methods, and in addition they are pre-solution activity, i.e. data gathering necessary to perform the correlation. The claims and steps inform one of ordinary skilled in the art whether or not an individual is benefiting from drug treatment and the effectiveness of the drug. The claims do not recite additional elements that amount to significantly more than the law of nature and are recited at a high level of generality, and are necessary data-gathering steps. Accordingly, these claims are not eligible under step 2A or step 2B.
Claims that describe the relation set forth a natural law. The claim limitations setting forth additional elements are insufficient to transform the identified natural law into a patentable process. The method for making such determinations were well known in the art and these activities are not sufficient to transform an unpatentable law of nature into a patent-eligible application of such law.
Claims 1-8 are drawn to a non-statutory method having a "natural principle" as a limiting element or step without reciting additional elements/steps that integrate the natural principle into the claimed invention such that the natural principle is practically applied, and are sufficient to ensure that the claim amounts to significantly more than the natural principle itself. In the instant case, the "natural principle" is: the claims recite/describe a law of nature or natural phenomenon. The claims describe the relationship between target molecule(s)/target(s) in/on EVs within a biological sample at different drug treatment time points and effectiveness of drug treatment and identification of different EV subpopulations.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because assaying differences in target binding signals during different time points within drug treatment, drug occupancy and EV populations does not add significantly more and is not an inventive concept. Because methods for making such determinations were well known in the art, these steps simply tell researchers to engage in well-understood, routine, conventional activity previously engaged in by scientists in the field. Such activities are normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such law. Detection of target(s)/target molecule(s) has been observed by applicant but not engineered by applicant. The claims do not add significantly more to the natural phenomenon because the claims do not require a novel reagent, apparatus of incorporate a novel treatment based on the correlation.
A claim that focuses on use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, and added something significant to, the natural principle itself. See Mayo, 101 USPQ2d at 1966. Recited elements such as “measuring”, “contacting”, “detecting”, “determining” and “normalizing” based on the natural principle impose no meaningful limit on the performance of the claimed invention. As set forth the claims do not impose meaningful limits on the performance of the claimed invention. Patents cannot be obtained on subject matter identified by the courts as being exempted from eligibility (i.e., laws of nature, natural phenomenon, and abstract ideas). Further, the method steps are conventional and routine in the art for the reasons stated above and the claims do not amount to significantly more than the recited judicial exception. The claims do not "practically apply" the judicial expectation; rather, the claims "simply inform" the judicial exception to one performing routine active method steps and do not amount to significantly more than the judicial exception itself. In the instant case, the outcome of the claimed method is only a statement of the judicial exception, evaluating differences in EV populations, signals based on drug/target binding at different time periods and different samples. Thus, the invention has not been practically applied. It is concluded that the instant claims are judicial exceptions to 35 U.S.C. 101 and are therefore not patent eligible. See the 2019 Revised Patent Subject Matter Eligibility Guidance and Federal Register https://www.federalregister.gov/documents/2019/10/18/2019-22782/october-2019-patent-eligibility-guidance-update; and FDsys.gov.
Claim Rejections - 35 USC § 102
12. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
13. Claim(s) 1-8 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yan, Zhang. (Plasmonic Biosensor Platforms for Molecular Analyses of Circulating Extracellular Vesicles. Dissertation, Department of Biomedical Engineering. National University of Singapore. 158 pages. December 29, 2020). Yan discloses using small-molecule chemical occupancy and protein engagement (ExoSCOPE) to measure “…multiparametric drug dynamics (i.e., drug occupancy and protein composition) in molecular subpopulations of exosomes, from scant blood samples (5 µL of native plasma in 1 hour), detects even delicate changes of drug interaction with different mutant proteins, and provides integrative metrics that reveal real-time cellular treatment changes (i.e., drug engagement and potency), across different targeted drugs.”, see pages 31 and 32.
“ExoSCOPE is a nanotechnology platform for multiparametric, activity-based analysis of EV drug dynamics- through the simultaneous evaluation of drug-target engagement and protein expression changes in distinct subpopulations of vesicles. Named extracellular vesicle monitoring of small-molecule chemical occupancy and protein expression (ExoSCOPE), the technology utilizes bio-orthogonal probe amplification and spatial patterning of molecular reactions within plasmonic resonators to measure EV drug dynamics directly in patient blood samples.”, paragraph (para.) bridging pages 105 and 106.
“Fig. 2.7 Conventional EV protein analysis. (a) Western blotting. EV protein lysate is separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), before being transferred over to a membrane for immunoblotting of specific EV protein targets (e.g., HSP70, Flotillin-1, and CD61). (b) Enzyme-linked immunosorbent assay (ELISA). In the specific "sandwich" configuration, vesicles or lysates could be applied to a solid support that has been pretreated with an immobilized capturing antibody. Captured vesicle targets are then exposed to a detecting target antibody.”, see page 45.
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“For EV analysis, using different anti bodies to selectively capture vesicles, we developed the multiplexed ExoSCOPE workflow to measure protein composition and drug occupancy in molecular subpopulations of EVs. For cellular analysis, we used flow cytometry for cell marker gating and occupancy measurements.”, see page 129.
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Clinical blood samples were obtained from “…lung cancer patients undergoing targeted treatment” and healthy controls, wherein EV protein markers and putative cancer markers where quantified, see last 6 lines on page 10; page 20, Fig. 3.42; and page 26, Fig. 4.41 and 4.42.
“Plasma samples were collected from lung cancer patients were at various time points: TO, before treatment (baseline); T1, 24 hours (day-1) after erlotinib treatment initiation; T2, 192 hours (day-8) after treatment initiation. Responder and non-responder status was clinically determined at the end of the treatment (day-21).”, see the captions for Fig. 4.45 and 4.47 spanning pages 26 and 27; page 144, Fig. 4.48; and page 24, Fig. 4.33.
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“A heterogeneous cell mixture was treated with erlotinib (1 µM) or vehicle (DMSO). Samples were obtained from the mixture at various time points during drug treatment and labeled with probe A3 (100 nM)”, wherein probe signal was observed to change during drug treatment., see page 25, Figure 4.33.
Moreover, EVs within the samples were analyzed utilizing a magnetic sensor within the micronuclear magnetic resonance (mNMR) detection system, ExoSCOPE sensors and APEX sensors, see page 13, Fig. 2.8; Fig. 3.13, 3.17, 3.18 captions bridging pages 15 and 16; page 118, 4.3.3 segment; page 137, 4.5.2 segment.
“Specifically, immuno-captured EVs that have a low drug occupancy are extensively labeled with competitive probes, whose bio-orthogonal handles enable in situ enzymatic amplification to locally deposit insoluble optical products. These optical deposits enhance plasmonic signals to generate a red shift in the transmitted light spectrum, thereby enabling multiparametric analysis of EV drug dynamics (i.e., protein composition and drug occupancy changes).”, see para. bridging pages 22 and 23.
“The system measures transmission SPR through a periodic array of plasmonic nanoholes and uses an in situ enzymatic conversion to rapidly grow an insoluble optical product over bound exosomes (Fig. 3.13).”, see page 67, segment 3.3.3.
Utilizing “APEX assay schematics...sensitive and multi-parametric profiling at the nanoscale [was performed, wherein], exosomes are first immuno-captured onto a plasmonic nanohole sensor (before amplification). Through an in situ enzymatic amplification, insoluble optical products are locally deposited onto the sensor-bound exosomes (after amplification). This deposition is spatially defined for molecular co-localization analysis, and changes the refractive index for SPR signal enhancement. Note the resultant red shift in the transmitted light through the nanosensor.”, see Fig. 3.13 on page 68. “In terms of assay technology, the APEX platform exploits a rapid, in situ enzymatic conversion to achieve a highly localized, amplified signal.”, see page 97.
“Fig. 4.18 Spatial patterning of ExoSCOPE molecular reactions within plasmonic resonators. EVs are protein-typed and probe-amplified within plasmonic nanoring gaps, to exploit local electromagnetic hotspots for sensitive detection. Specifically, immuno-captured EVs that have a low drug occupancy are extensively labeled with competitive probes, whose bio-orthogonal handles enable in situ enzymatic amplification to locally deposit insoluble optical products. These optical deposits enhance plasmonic signals to generate a red shift in the transmitted light spectrum, thereby enabling multiparametric analysis of EV drug dynamics (i.e., protein composition and drug occupancy changes)”, see Fig. 4.18 caption spanning pages 121 and 122.
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See page 123.
Yan also discloses the ability to ascertain and profile EV subpopulations based on distinct and different biophysical and/or biochemical properties, see page 10. “To evaluate molecular heterogeneity of targeted therapy, …different antibodies…” were used “…to selectively profile EV subpopulations and their respective drug occupancies.”, see page 24, Fig. 4.30; page 32; paragraph (para.) bridging pages 102 and 103; and para. bridging pages 103 and 104.
“Fig. 4.48 Multiplexed ExoSCOPE for early time point (T1) assessments. Across different EV subpopulations, we measured respective longitudinal changes (T1 with respect to T0) in EV drug occupancy (deT1) and EV protein marker (dMT1), and used the data to construct regression models for scoring drug occupancy changes (Ie) and marker composition changes (IM), respectively. Corresponding changes in plasma drug concentration is denoted dDT1.”, see pages 27, 144 and 145; and entire document.
Conclusion
14. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached on 8AM-8PM, Monday through Friday.
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, Julie Wu can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
August 3, 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643
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