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 .
Claims 1, 5, 8, 13-16, 18, 22, 24, 25, and 28-30 have been amended.
Claims 1, 3, 5-9, 12-16, 18, 22, 24-25 and 28-30 are pending.
Claims 2, 4, 10, 11, 17, 19-21, 23, 26-27, and 31 are cancelled.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn. The following rejections or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/01/2025 has been entered.
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 14-16, 18, 22, 24, 25, and 28-30 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.
Applicant’s claim 13 recites “further comprising measuring an additional biomarker”, wherein Applicant removed the plural biomarkers (see amended filed on 10/01/2025). The Examiner interpret “an” and the removal of “s” as require only one additional biomarker. However, claim 14 depends on claim 13 and recites “wherein the biomarkers are MLH1, MSH2, PD-L1, and IL-12”, which are four biomarkers. This is confusing, because is only one additional biomarker required or all four biomarkers required? For compact prosecution purposes, the Examiner will interpret the claim reading as only one additional biomarker is required in the Markush group. Note, these issues are also seen in claims 15, 16, 18, 22, 24, 25, and 28-30.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The 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.
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.
Claims 1, 3, 5-7, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over LEE (WO 2017/132564 A2) in view of CARIS (WO 2015/116868).
Regarding claim 1, LEE teaches a method for monitoring the effectives of a treatment (abstract), such as for cancer (page 5, paragraph 1). The method comprises:
providing a bodily fluid sample (claim 16), such as urine (claim 28), that comprises extracellular vesicles (claim 21), such as exosomes (claim 22), which reads on providing a bodily fluid sample from a subject, wherein the bodily fluid sample comprises extracellular vesicles;
the sample was incubated with magnetic beads (page 45, paragraph 2) that are mixed with antibodies (page 46, paragraph 2 and claim 16), which reads on incubating the sample with a capture molecule that binds to the extracellular vesicles in the sample;
the analytes of interest are concentrated near the probe (page 11, paragraph 3), which reads on concentrating the extracellular vesicles.
the samples were analyzed using an integrated magnetic-electrochemical exosome system (iMEX) (Page 40, paragraph 3), which reads on the samples were analyzed with analyzing the sample extracellular vesicles using an integrated magnetic-electrochemical sensing system;
the target analyte was measured and determined (claim 16) for various biomarkers, such as EGFRv3 (claim 23), which reads on determining measuring an amount of a biomarker associated with the extracellular vesicles,
the results are compared to a reference/control (claim 24), which reads on calculating a score based on the expression level of one or more measured biomarkers, wherein an alteration in the score relative to a control is indicative of the effectiveness of the cancer immunotherapy (Note. “calculating” is also a mental step).
LEE does not teach analyzing Interleukin-6 (IL-6), Programmed Death Ligand 1 (PD-L1) and MutL Homolog 1 (MLH1) as biomarkers.
Regarding claim 1, CARIS teaches a method for predicting effectiveness of checkpoint inhibitor immunotherapy (Page 193, paragraph 00423). This method includes providing a bodily fluid sample from a subject (CARIS claim 38), such as urine (claim 38) which has microvesicles (CARIS claim 37); which reads on, extracellular vesicles. CARIS teaches analyzing the sample with detectable labels, such as magnetic beads (Page 19, paragraph 0077, line 3). CARIS also teaches determining a molecular profile for at least one sample from the subject by assessing a plurality of biomarkers (CARIS claim 1), such as EGFRv3, MLH1, PD-L1 (table 6), and IL-6 (page 75, paragraph 1).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate MLH1, PD-L1 and IL-6. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because EGFRv3, MLH1, PD-L1 and IL-6 are functional equivalents of biomarkers to be analyzed using a diagnostic method for cancer, using a bodily fluid, such as urine, comprising extracellular vesicles, that is labeled with magnetic beads and multiple biomarkers can be detected by the method in LEE (page 36, paragraph 3).
Regarding claim 3, LEE teaches the bodily sample can be urine (claim 28).
Regarding claim 5, note the step of “calculating a score comprises using a SingleMarkerScore method, a CategoryScore method, a RegressionScore method, a DecisionTreeScore method, or a NeuralNetworkScore method” is a mental step.
Regarding claim 6, CARIS teaches determining a molecular profile for at least one sample from the subject by assessing a plurality of biomarkers (CARIS claim 1), such as EGFRv3, MLH1, and PD-L1 (table 6).
Regarding claim 7, LEE teaches using this method for ovarian cancer (page 40, paragraph 2).
Regarding claim 13, CARRIS teaches using MLH1 as a biomarker (table 6).
Claims 1, 3, 5-7, 13-16, 18, 22, 24, 25, and 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over LEE (WO 2017/132564 A2) and CARIS (WO 2015/116868) in view of GRABE (US 2013/0330325 A1).
LEE and CARIS teach Applicant’s invention as discussed above.
LEE and CARIS do not teach using IL12, TCF7, and perforin as biomarkers.
GRABE teaches a method of determining treatment efficacy prediction using various biomarkers (abstract). GRABE discloses several biomarkers including but not limited to: IL12 (in the form of its two subunits IL12A and IL12B), TCF7, CD47, Perforin (Page 18-19, paragraphs 0281-0288), IL2, and IL6 (Page 18-19, paragraphs 0281-0288).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate IL12, TCF7, CD47, and Perforin as biomarkers. The person of ordinary skill in the art would have been motivated to make those modifications for the purpose of developing a broad application of methods for various types of cancer immune therapy using various biomarkers, and reasonably would have expected success because multiple biomarkers can be detected by the method in LEE (page 36, paragraph 3).
Regarding claims 14, 18, 22, 24, 25, 28-30, CARRIS teaches MLH1 as a biomarker (table 6) and GRABE teaches IL12 as a biomarker (Page 18-19, paragraphs 0281-0288).
Regarding claim 15, CARRIS teaches MLH1 as a biomarker (table 6) and GRABE teaches TCF7 as a biomarker (Page 18-19, paragraphs 0281-0288).
Regarding claim 16, CARRIS teaches MLH1 as a biomarker (table 6) and GRABE teaches Perforin as a biomarker (Page 18-19, paragraphs 0281-0288).
Claims 1, 3, 5-7, 13-16, 18, 22, 24, 25, and 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over LEE (WO 2017/132564 A2) and CARIS (WO 2015/116868) in view of GRABE (US 2013/0330325 A1) in view of BAGAEV (P.N US 2018/0358132 A2).
LEE and CARIS teach Applicant’s invention as discussed above.
LEE and CARIS do not specifically teach the mental step of calculating a score comprising using a RegressionScore method.
BAGAEV teaches a method to determine a “therapy score” to predict therapeutic efficacy. A "therapy score" may be calculated using multiple normalized biomarker scores in various ways including as a weighted sum (e.g., in a regression model) (Page 16, paragraph 0141), which reads on a RegressionScore Method. This “therapy score” can be taken before and after a treatment (Page 1, paragraph 0004) and can determine the effect of a treatment. Correctly selecting one or more effective therapies for a subject (e.g., a patient) with cancer or determining the effectiveness of a treatment can be crucial for the survival and overall wellbeing of that subject (Page 1, paragraph 0007).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a regression score method to help predict therapeutic effect using data analytics. The person of ordinary skill in the art would have been motivated to make those modifications to developing a broad application of methods for various types of cancer immune therapy and to determine if therapeutics are having an effect and can be crucial for the survival and overall wellbeing of a patient and reasonably would have expected success because analyzing data from the invention listed in CARIS and LEE would not alter the invention but rather apply it further.
Claims 8, 9 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over LEE (WO 2017/132564 A2) in view of CHEN (LIN28/let-7/PD-L 1 Pathway as a Target for Cancer immunotherapy. Cancer Immunology Research. January 16, 2019).
Regarding claim 8, LEE teaches a method for diagnosing cancer (page 5, paragraph 1). The method comprises:
providing a bodily fluid sample (claim 16), that comprises extracellular vesicles (claim 21), such as exosomes (claim 22), which reads on providing a bodily fluid sample from a subject, wherein the bodily fluid sample comprises extracellular vesicles;
the sample was incubated with magnetic beads (page 45, paragraph 2) that are mixed with antibodies (page 46, paragraph 2 and claim 16), which reads on incubating the sample with a capture molecule that binds to the extracellular vesicles in the sample;
the analytes of interest are concentrated near the probe (page 11, paragraph 3), which reads on concentrating the extracellular vesicles.
the samples were analyzed using an integrated magnetic-electrochemical exosome system (iMEX) (Page 40, paragraph 3), which reads on the samples were analyzed with analyzing the sample extracellular vesicles using an integrated magnetic-electrochemical sensing system;
LEE does not teach analyzing Lin28 as a biomarker.
Regarding claim 8, CHEN teaches Lin28, which is a RNA binding protein/polypeptide, is a cancer biomarker (abstract), which reads on measuring an amount of a Lin28 polypeptide associated with the extracellular vesicles, wherein an elevated amount of Lin28 polypeptide relative to a control is indicative of a poor cancer prognosis. LIN28 is frequently dysregulated in tumor cells, and upregulation of LIN28 correlates with advanced disease and poor prognosis for many cancer subtypes (Pg. 487, right-hand column, second paragraph).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate Lin28 as a biomarker. The person of ordinary skill in the art would have been motivated to make those modifications, for the purpose of developing a broad application of methods for cancer immunotherapy using various biomarkers, and reasonably would have expected success because multiple biomarkers can be detected by the method in LEE (page 36, paragraph 3).
Regarding claim 9, LEE teaches the bodily sample can be urine (claim 28).
Regarding claim 12, LEE teaches using this method for ovarian cancer (page 40, paragraph 2).
Response to Arguments
Applicant argues, that the references do not teach that the biomarkers are associated with extracellular vesicles.
Examiner does not find this argument persuasive because LEE teaches a method for monitoring the effectives of a treatment (abstract), such as for cancer (page 5, paragraph 1). The method comprising providing a bodily fluid sample (claim 16), that comprises extracellular vesicles (claim 21), such as exosomes (claim 22) and examining various biomarkers, such as EGFRv3 (claim 23).
LEE does not teach analyzing Interleukin-6 (IL-6) as a biomarker.
CARIS teaches a method for predicting effectiveness of checkpoint inhibitor immunotherapy (Page 193, paragraph 00423). This method includes providing a bodily fluid sample from a subject (CARIS claim 38), such as urine (claim 38) which has microvesicles (CARIS claim 37); which reads on, extracellular vesicles. CARIS teaches analyzing the sample with detectable labels, such as magnetic beads (Page 19, paragraph 0077, line 3). CARIS also teaches determining a molecular profile for at least one sample from the subject by assessing a plurality of biomarkers (CARIS claim 1), such as EGFRv3, MLH1, PD-L1 (table 6), and IL-6 (page 75, paragraph 1).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate IL-6. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because EGFRv3 and IL-6 are functional equivalents of biomarkers to be analyzed using a diagnostic method for cancer, using a bodily fluid, such as urine, comprising extracellular vesicles, that is labeled with magnetic beads and multiple biomarkers can be detected by the method in LEE (page 36, paragraph 3).
Furthermore, since the bodily fluid sample contains extracellular vesicles and the biomarker is measured from the bodily fluid sample, the biomarkers are there for associated with the extracellular vesicles.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. MEJIAS whose telephone number is (703)756-5666. The examiner can normally be reached M-F.
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/S.L.M./ Examiner, Art Unit 1618 /JAKE M VU/Primary Examiner, Art Unit 1618