DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-8) and the species of (a) CD81 and (b) CD9 in the reply filed on 5/12/2026 is acknowledged.
Claim Status
Claims 1-16 are pending.
Claims 9-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/12/2026.
Claims 1-8 are being examined on the merits.
Drawings
The drawings are objected to because the sequence identification labels in Figure 35 are non-compliant. In Figure 35, the SEQ ID NOs are notated as “SEQ ID NO. X” and should be “SEQ ID NO: X”. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Abstract
The abstract of the disclosure is objected to because there is a typo in the first sentence. The first sentence reads “Method and system for detecting disease in blood sample is described” and should read “Method and system for detecting disease in a blood sample is described” to be grammatically correct. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Specification
The disclosure is objected to because of the following informalities:
Paragraph [0019] reads “As used herein, “RT-RPA” refers but not limited to reverse transcription and recombinase polymerase amplification (RPA) reaction” and should read “As used herein, “RT-RPA” refers to, but is not limited to, reverse transcription and recombinase polymerase amplification (RPA) reaction” to be grammatically correct.
Paragraph [0019] reads “Any nucleic acid amplification method applied to this method, such as PCR, RT-PCR, LAMP, RT-LAMP, RCA, EXP AR, WGA, SDA, HAD, NASBA etc.”. It appears that a word is missing from the sentence, and as it is currently written it does not make sense. It seems like the sentence is trying to convey that any nucleic acid amplification method can be applied to this method. If that is the case, the sentence should be edited to convey this thought.
Paragraph [0024] reads “lipid bilayer-delimited particles that are naturally released from a cell, bacterial” and should read “lipid bilayer-delimited particles that are naturally released from a cell[[,]] or a [[bacterial]]bacteria” to be grammatically correct.
Paragraph [0029] reads “In another aspect of this disclosure, a non-immobilized method of process liposome and EV is can be applied.” It is unclear what this sentence is trying to say. Please clarify.
Paragraph [00110] refers to Figure 35 as an “Oligonucleotide list”. However, SEQ ID NO: 4 is not an oligonucleotide, it is a polypeptide (as evidenced by the Sequence Listing). As presented in the specification it appears to be an oligonucleotide with a poly-T sequence, but in the Sequence Listing it appears that the Ts refer to Thr.
This is not an exhaustive list of typos/grammatical errors throughout the specification. Please read through carefully.
Appropriate correction is required.
The use of the terms “FAM” (paragraph [0023, 00126]), “Nanosight” (paragraph [00126, 00129-00130, 00132]), “Tween” (paragraph [00128]), and “Graphpad Prism” (paragraph [00146]), which are trade names or marks used in commerce, have been noted in this application. These terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The examples above are not an exhaustive list of unmarked trade names or marks used in commerce throughout the specification. Please carefully read through and properly notate each instance.
Claim Objections
Claim 8 is objected to because of the following informalities: claim 8 currently reads “wherein the bodily fluid is blood” and should read “wherein the bodily fluid sample is blood” to maintain consistent claim terminology. Additionally, claim 8 does not have a period at the end the sentence. Appropriate correction is required.
Claim Rejections - 35 USC § 112b - Indefiniteness
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 2-7 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.
Claim 2 is directed to the method of claim 1 “wherein said disease-specific protein is selected from the group consisting of: CD81, PDCD6TP, HSPA8, ACTB, ANXA2, CD9, PKM, HSP90AA1, ENOl, ANXA5, HSP90AB1, CD63, YWHAZ, YWHAE, etc. as well as the antibody against LprG, LpqH, Alpha-crystallin (HspX), DnaK, GroEL2, KatG, SodA, and GlnA.”. There are two aspects that make this claim indefinite. First, the inclusion of “etc.” within the group of disease-specific proteins makes the scope of the claim indefinite, in that it is unclear what is included within the scope of “etc.”. Is this all proteins? All proteins associated with a disease? Second, the phrasing “as well as the antibody against”. Does this mean that the disease-specific protein could also be an antibody against the listed proteins? Or is “the antibody” referring to “the first antibody” of claim 1 which is used for extracting the EVs? Clarification is required on both counts. For the purposes of examination, the only species being considered is CD81, which is consonant with the species election.
Additionally, claim 2 recites the limitation "the antibody" in line 3. There is insufficient antecedent basis for this limitation in the claim. It is unclear if this is a new antibody, separate from “a first antibody” described in claim 1, from which this claim depends.
Claim 3 is directed to the method of claim 1 “wherein in step a) the EVs are enriched by using a detecting antibody that is specific to an antigen”. It is unclear when this is occurring in relation to the extracting of the EVs in step (a) of claim 1. Is the extracting happening first with the first antibody and then enriching is performed after with a detecting antibody? Are both the first antibody and detecting antibody binding to EVs at the same time? Further clarification is required. For purposes of examination, it is being interpreted that the first antibody is used for capture of the exosome and the second antibody (detection antibody) is used for labeling after capture of the exosome with the capturing antibody. This is consonant with the example in paragraph [00147] of the specification that states that EVs were captured with a CD81 antibody and then labeled with a detection antibody of anti-CD9.
Claims 4-7 recite the limitation "the disease". There is insufficient antecedent basis for this limitation in the claim. Each of these claims depends from claim 1, where no disease has been defined. Clarification is required.
Claim 5 recites that “the disease…is a viral infection” and then recites possibilities such as TB, HIV, and influenza as the “disease”. TB is tuberculosis, which is a disease but is not a viral infection. Tuberculous is caused by Mycobacterium tuberculosis, which is not a virus but a pathogenic bacterium. Additionally, HIV is a virus but is not a disease in and of itself. The inclusion of options which are not diseases and which are not viral diseases makes the scope of this claim indefinite and clarification is required.
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.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Klass (Klass et al., US 2010/0184046 A1; cited on IDS of 5/13/2025) in view of Gao (Gao et al., Angewandte Chemie 2019; cited on IDS of 5/13/2025) and Sabeti (Sabeti et al., WO 2022/051667 A1, EFD of 9/3/2020).
Claim 1: Klass teaches a method of detecting the presence of a disease-specific protein in a bodily fluid sample, and specifically teaches isolating extracellular vesicles (exosomes) by binding with a capture agent (an antibody) specific to disease-specific proteins on the surface of said extracellular vesicles (paragraphs [0010, 0106, 0129, 0170, 0779]). Klass teaches that an exosome can be analyzed through detecting, quantitatively or qualitatively, the biomarker or bio-signature of said exosome (paragraph [0114]). Klass et al. teaches that this detection can be achieved with fluorescent detection systems (paragraph [0140, 0268, 0702]).
Klass teaches lysing the exosomes to release and analyze contents of said exosome such as nucleic acids (paragraph [0697]). Klass et al. does not teach that reagents for analysis of nucleic acids within the exosomes are delivered via liposome fusion probes. However, use of liposome fusion probes for delivery of reagents to exosomes for analysis is known in the art, as taught by Gao.
Gao teaches a method of analyzing exosomal miRNAs in which virus-mimicking fusogenic vesicles (Vir-FVs) are used to specifically target exosomes and deliver reagents to the exosomes upon fusion to allow miRNA detection (Vir-FV reads on liposome fusion probe; Abstract, Figure 1).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Klass with the liposome fusion probes as taught by Gao. One would be motivated to do so given the assertion by Gao that analyzing the nucleic acids within the exosomes by delivery of reagents through fusion can "avoid the occurrence of degradation and contamination". One would have a reasonable expectation of success given that Gao uses this technology to detect nucleic acids within exosomes, the same type of extracellular vesicle as studied by Klass.
Klass in view of Gao do not teach that the liposome fusion probes deliver reagents including reverse transcriptase (RT), recombinase polymerase amplification (RPA), and CRISPR/Cas12a reagents to enable the detection of nucleic acids. However, usage of these reagents for detection of nucleic acids in a sample is known in the art, as taught by Sabeti.
Sabeti teaches a CRISPR effector system for detection of nucleic acids (Abstract). Sabeti teaches that the CRISPR effector system uses a Cas12a protein (paragraph [0037]). Additionally, Sabeti teaches using RT-RPA to amplify and detect RPA targets (paragraph [0108] and Figure 1A).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Klass and Gao with the CRISPR/Cas effector system as taught by Sabeti. One would be motivated to do so given the assertion by Sabeti that this detection system is “robust” and provides “attomolar sensitivity” (paragraph [0138]). One would have a reasonable expectation of success given that Sabeti teaches that this methodology can be used to analyze RNA within exosomes (paragraph [0487]).
Claim 2: Klass teaches that the disease-specific protein is CD81 (consonant with the election; paragraphs [0126, 0779, 0910] and Figure 68D).
Claim 3: Klass teaches that a detecting antibody that is specific to an antigen on the surface of the exomsome can be used in addition to the capture antibody (paragraph [0683]). Klass teaches that a detecting antibody can be specific to CD9 (paragraph [0683, 0910] and Figure 68).
Claim 4: Klass teaches that the disease can be cancer (paragraph [0096]).
Claim 5: Klass teaches that the disease can be a viral infection (paragraph [0100]).
Claim 6: Klass teaches that the disease can be a bacterially induced disease (paragraph [0100]).
Claim 7: Klass teaches that the disease can be brain damage (“brain trauma”, paragraph [0099]).
Claim 8: Klass teaches that the bodily fluid sample is any bodily fluid (blood, serum, sputum, urine, or saliva; paragraph [0106]).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILEY E CASH whose telephone number is (571)272-0971. The examiner can normally be reached Monday-Friday 8:30am-6pm ET.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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