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 .
Claim Objections
Claims 1-10 are objected to because of the following informalities: micro RNA is abbreviated in claim 1 as riRNA. It should be miRNA. Appropriate correction is required. As all claims depend ultimately from claim 1, they are objected to for the same reason.
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 1-10 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 1 concludes with “where the early detection leads to early treatment of the deep lung pathology and can lead to an improved health outcome for the subject.” This renders the claim unclear, as it cannot be determined whether the claim requires such treatment and such improved health outcome. As all claims ultimately depend from claim 1, they are rejected for the same reason.
Claims 1-10 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 1 recites “for early detection”, “the early detection” and “early treatment”. “Early” is a relative term which renders the claim indefinite. The term “early” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
As all claims ultimately depend from claim 1, they are rejected for the same reason.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. It does not appear that claim 4 is further limiting upon claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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.
Claim(s) 1-4 and 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Spivack1 ([online] 1 May 2022 [retrieved on 15 June 2026] retrieved from https://academic.oup.com/ajrccm/article/205/Supplement_1/A4661/8542894) in view of Mitchell (J. Extracell. Vesicles 10:e12110 (2021), IDS ref), Adachi (US 2025/0011839) and Elliot (US 2023/0147720).
Spivack disclosed:
sampling deep lung tissue of the subject at risk2 of the deep lung pathology by isolating micro RNA (miRNA) cargo of lung tissue origin in exhaled extracellular vesicles (EVs) purified from exhaled breath condensates (EBCs) of the subject;
purifying exhaled extracellular vesicles in exhaled breath condensate by antibody capture of the exhaled EVs
“We have developed a method for enriching and precisely evaluating deep lung tissue microRNA (miRNAs) signals contained in exhaled breath condensate (EBC)…Eighteen individuals…had non-invasive upper airway specimens (…EBC) collected…Exosome isolations from…EBC samples were performed using a novel ultra-sensitive antibody-based exosome purification assay (EV-CATCHER)…Total RNA from…exhaled exosomes from the same EBC samples…were subjected to…small-RNA sequencing…Exosome isolation from whole EBC biofluids increased the sequencing depth of EBC miRNA reads by 10-fold (p<0.01), and highest miRNA expression correlation between exhaled exosomes and deep lung specimens and deep lung specimens…Exhaled miRNAs encapsulated within exosomes non-invasively provide a representation of deep lung tissue processes, and offer a novel avenue for discovery of biomarker associated with lung pathologies.”
Regarding claim 7, Spivak disclosed: “…highest miRNA expression correlation between exhaled exosomes and deep lung specimens (BAL and BrBr).”
Spivack did not disclose whether the purified EVs were “lung-specific”. Although they were purified from exhaled breath condensates (EBCs), and purified using an antibody capture technique, Spivack is silent on whether the antibody targeted a “lung-specific” marker, as opposed to a generic EV marker that might capture EVs derived from, e.g., the trachea or the mouth, which might also be present in the EBCs.
In addition, Spivak did not disclose comparing the miRNA profile in the EBC EVs to the profile in EBC EVs from a healthy subject.
Mitchell disclosed the principle of the EV-CATCHER system (used by Spivak), noting that while they used antibodies targeting generic small EVs (anti-CD63, -CD9, -CD81; last paragraph of section 1), the system was amenable to modification in order to isolate specific sub-populations of EVs using appropriate antibodies:
Section 3.4: “Finally, we sought to determine if we could specifically select a sub-population of small-EVs from a biofluid using EV-CATCHER. For these experiments we chose to spike human plasma with commercial mouse RAWS264.7 small-EVs (SBI). We customized the EV-CATCHER assay with an antimouse CD63 antibody, without cross-reactivity to human CD63, and carried out the purification of CD63+ mouse small-EVs from human plasma.”
Section 4 (first indented paragraph): “…we demonstrated the specificity of EV-CATCHER, for purifying species-specific small-EVs, by sequencing total RNA extracted from mouse CD63+ small-EVs selectively purified from human plasma that was initially spiked with mouse RAWS264.7 total small-EVs.”
Section 4 (end of second indented paragraph): “These evaluations would suggest that the detection of low abundance biomarkers will require; 1- the use of more cell-specific antibodies for the selective enrichment of small-EV sub-populations…”.
Section 4 (last paragraph): “…the 96-plex format of our assay, may allow streamlined automation for the purification and evaluation of diverse sub-populations of circulating small-EVs (based on the specific antibodies)…”.
Adachi disclosed (paragraph [0007]): “If purification of extracellular vesicles according to the tissue from which they are derived is possible, it is considered to increase diagnostic accuracy and to be useful in treatment too. Establishment of a marker for purifying tissue-specific extracellular vesicles, a method for identification thereof, and/or a method for purification thereof will allow us to diagnose diseases with high accuracy.”
To that end, Adachi disclosed (paragraph [0021]): “…a method for selecting a marker for isolating tissue-specific extracellular vesicles.” In addition, Adachi disclosed (paragraph [0046]): “A method for purifying lung tissue-specific extracellular vesicles using a specific reagent that binds to…SFTPB…”. Adachi disclosed (paragraph [0079]): “Such a tissue-specific extracellular vesicle may be isolated and/or purified using a specific reagent that recognizes the marker, such as an aptamer or an antibody…”.
Elliot disclosed the idea of comparing miRNA in exosomes purified from a sample from a subject to that in a healthy control in order to diagnose the patient with lung disease; see paragraph [0132]: “…wherein expression of the two or more microRNAs, compared to a healthy control, comprises a signature of a fibrotic lung disease…”.
It would have been prima facie obvious to one of ordinary skill in the art to modify the method for purifying EVs from EBCs disclosed by Spivack by using an antibody specific for lung-derived EVs, such as antibody for SFTPB, as suggested by Adachi, because Mitchell indicated the EV-CATCHER technique, which Spivack used, could be tailored to purify specific sub-populations of exosomes by using appropriate antibodies, and because Adachi provided a motivation to purify tissue-specific EVs in order “to increase diagnostic accuracy”.
It would also have been obvious to compare the levels of miRNAs in EVs from patients undergoing diagnostic testing with levels from healthy controls as disclosed by Elliot, as Spivak suggested the use of miRNA cargo in isolated EVs as diagnostic markers for lung pathology, and comparing miRNA biomarker levels in patients and controls was an established practice in making such diagnoses, as shown by Elliot.
Claim(s) 8 and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Spivack ([online] 1 May 2022 [retrieved on 15 June 2026] retrieved from https://academic.oup.com/ajrccm/article/205/Supplement_1/A4661/8542894) in view of Mitchell (J. Extracell. Vesicles 10:e12110 (2021), IDS ref), Adachi (US 2025/0011839) and Elliot (US 2023/0147720) as applied to claims 1-4 and 7 above, and further in view of Xie (Technology in Cancer Research & Treatment 19:1-8 (2020), IDS ref).
The teachings of Spivack, Mitchell, Adachi and Elliot have been discussed. While Spivack disclosed the prospect of miRNAs in EVs from EBCs as biomarkers for lung pathologies, Spivack did not disclose any particular miRNA associated with any particular lung pathology.
Xie disclosed that miR-186 was greatly reduced in EBC and serum in patients with non-small cell lung cancer, whether early or late stage, and that detection of miR-186 in both EBC and serum showed higher diagnostic efficacy than detection of either alone (abstract).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to apply the method suggested by the combined disclosures of Spivack, Mitchell, Adachi and Elliot to the detection of miR-186 in lung-specific EVs isolated from EBCs, since Xie indicated this miRNA as correlating with non-small cell lung cancer, and Spivack indicated that purifying EVs from EBCs “increased the sequencing depth of EBC miRNA reads by 10-fold”, which indicates a more sensitive assay that using miRNA from bulk EBC. In addition, Adachi disclosed that purification of extracellular vesicles according to the tissue from which they are derived would allow diseases to be diagnosed with high accuracy. It is noted that cancer is a lung pathology due to smoking.
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Spivack ([online] 1 May 2022 [retrieved on 15 June 2026] retrieved from https://academic.oup.com/ajrccm/article/205/Supplement_1/A4661/8542894) in view of Mitchell (J. Extracell. Vesicles 10:e12110 (2021), IDS ref), Adachi (US 2025/0011839) and Elliot (US 2023/0147720) as applied to claims 1-4 and 7 above, and further in view of Levänen (J. Allergy Clin. Immunol. 131(3):894-903 (2013)).
The teachings of Spivack, Mitchell, Adachi and Elliot have been discussed. While Spivack disclosed the prospect of miRNAs in EVs from EBCs as biomarkers for lung pathologies, Spivack did not disclose any particular miRNA associated with any particular lung pathology.
Levänen disclosed (abstract): “Significant differences in BALF exosomal miRNA was detected for 24 miRNAs with a subset of 16 miRNAs, including members of the let-7 and miRNA-200 families, providing robust classification of patients with mild nonsymptomatic asthma from healthy subjects with 72% cross-validated predictive power (Q2 5 0.72).”
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to apply the method suggested by the combined disclosures of Spivack, Mitchell, Adachi and Elliot to the detection of miRNAs associated with asthma in lung-specific EVs isolated from EBCs, since Levänen indicated a subset of miRNAs as correlating with asthma, and Spivack indicated miRNA in EVs isolated from EBCs correlated with miRNA in EVs in BAL specimens. In addition, Adachi disclosed that purification of extracellular vesicles according to the tissue from which they are derived would allow diseases to be diagnosed with high accuracy.
Claim(s) 5 and 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Spivack ([online] 1 May 2022 [retrieved on 15 June 2026] retrieved from https://academic.oup.com/ajrccm/article/205/Supplement_1/A4661/8542894) in view of Mitchell (J. Extracell. Vesicles 10:e12110 (2021), IDS ref), Adachi (US 2025/0011839) and Elliot (US 2023/0147720) as applied to claims 1-4 and 7 above, and further in view of Eitan (US 2025/0093343).
Regarding claim 5, Mitchell disclosed the details of how the EV-CATCHER system worked, including activating antibody with DBCO ester (last portion of section 2.2 on page 4; figure 1), coupling the DBCO modified antibody to a DNA linker by click chemistry (i.e. reaction between DBCO and azide on the DNA linker; last portion of section 2.2 on page 4; figure 1), binding of the antibody-DNA linker to streptavidin-coated well plates (last portion of section 2.2 on page 4) pre-treated with RNAse A (figure 2 description), releasing the captured EVs from the plate using uracil DNA glycosylase (last portion of section 2.2 on page 4).
Regarding claim 6, Mitchell disclosed the use of monoclonal antibodies in the EV-CATCHER system (Figure 1 description, e.g.) and Adachi disclosed SFTPC as a target for purifying lung-specific EVs.
Neither Spivack nor Mitchell disclosed eluting the purified EVs from the antibody as recited in claim 5.
Eitan disclosed (paragraph [0129]): “To obtain purified EVs, subsequent step(s) involving e.g. elution of the EV from the capture antibodies/beads under conditions involving e.g. elevated detergent content and/or reduced pH, is/are carried out.”
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to modify the method suggested by the combined disclosures of Spivack, Mitchell, Adachi and Elliot by eluting the captured EVs from the antibody in order to obtain more purified EVs as noted by Eitan. Such modification represents nothing more than the combination of prior art elements according to known techniques to yield predictable results (MPEP 2143-I).
Conclusion
No claims are free of the prior art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL C WOOLWINE whose telephone number is (571)272-1144. The examiner can normally be reached 9am-5:30pm.
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, GARY BENZION can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAMUEL C WOOLWINE/ Primary Examiner, Art Unit 1681
1 It is noted that Spivak has an effective date more than one year prior to the earliest date of priority for the instant application, and that both inventors are listed as authors.
2 Anyone having lungs is “at risk” of developing deep lung pathology.
Prosecution Insights