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 .
DETAILED ACTION
Election/Restrictions
1. Applicant's election of Group II, claims 6-8 and 23-30, without traverse, filed August 24, 2026 is acknowledged and has been entered. Claims 1-5 and 9-22 have been cancelled. Accordingly, claims 6-8 and 23-30 are pending and are under examination.
Priority
2. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Based on the Filing Receipt, the present application claims the benefit of priority of Provisional Application Number 63/447,539 filed on 02/22/2023. Accordingly, the effective filing date of this application is February 22, 2023 which is the filing date of Provisional Application Number 63/447,569 from which the benefit of domestic priority is claimed.
Information Disclosure Statement
3. The listing of references in pages 33-37 of the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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.
4. Claims 6-8 and 23-30 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 6 lacks antecedent basis in reciting “the level.”
Claim 6 is ambiguous in reciting “measuring the level of the at least one vesicle in the biological sample” in all occurrences within the claim because as recited, the term “level” relative to “at least one vesicle” is a subjective term lacking a comparative basis for defining its metes and bounds. It is specifically unclear what is encompassed in the term “level” in relation to “one vesicle” which appears to imply the presence of one vesicle. Does Applicant intend a specific type of vesicle or exosome such as astrocyte-derived exosome (ADE) vesicle type relative to other brain-derived vesicles such as neuron-derived exosomes (NDE) or oligodendrocyte-derived exosomes (ODE)? Same analogous comments and problems apply to the recitation of “a control level of the at least one vesicle in a control biological sample.” See the Abstract and paragraphs [0066, 0089-0090, 0092-0093] of the specification.
Same analogous comments and problems in claim 6 supra apply to claims 23 and 27 regarding the recitation of “at least one vesicle” obtained from the biological sample and the specific type of vesicles encompassed in the control biological samples recited in claims 23 and 27. See the Abstract and paragraphs [0066, 0089-0090, 0092-0093] of the specification.
Claim 6 is vague and indefinite in reciting, ”comparing … to a control … in a control biological sample” in all occurrences within the claim because it is unclear what Applicant intends to encompass in the recitation of “control” as used in the claim. In particular, the term “control” is a subjective term lacking a comparative basis for defining its metes and bounds. Does Applicant intend a normal control sample comprising vesicles from a subject who does not have hemorrhagic transformation which appears to be encompassed in the claimed invention?
Claim 23 is vague and indefinite in reciting, “obtaining a biological sample comprising at least one vesicle from the subject” and “measuring the level of one or more biomarkers in the biological sample” because it is unclear what is encompassed in the recitation of “one or more biomarkers” in relation to the “at least one vesicle” or the “biological sample.” Does Applicant intend for the one or more biomarkers to be soluble biomarkers in the biological sample, or should they be expressed on the surface of the at least one vesicle and should the at least one vesicle be of a specific type of vesicle or exosome such as ADE vesicle type relative to other brain-derived vesicles such as NDEs or ODEs?
Claim 23 is vague and indefinite in reciting, “preparing a control biological sample that comprises vesicles” and ”comparing … to a control … in a control biological sample” in all occurrences within the claim because the term “control” is a subjective term lacking a comparative basis for defining its metes and bounds. Does Applicant intend a normal control sample comprising vesicles from a subject who does not have hemorrhagic transformation which appears to be encompassed in the claimed invention?
Claim 24 is indefinite in reciting, “L1CAM”, “EAAT1”, “EAAT2” and “MOG.” Acronyms or abbreviations should be fully defined and recited at least one time in a given set of claims.
Claim 27 is vague and indefinite in reciting, “obtaining a biological sample comprising at least one vesicle from the subject” and “measuring the level of one or more biomarkers in the biological sample” because it is unclear what is encompassed in the recitation of “one or more biomarkers” in relation to the “at least one vesicle” or the “biological sample.” Does Applicant intend for the one or more biomarkers to be soluble biomarkers in the biological sample, or should they be expressed on the surface of the at least one vesicle and should the at least one vesicle be of a specific type of vesicle or exosome such as ADE vesicle type relative to other brain-derived vesicles such as NDEs or ODEs?
Claim 27 is vague and indefinite in reciting, “preparing a control biological sample that comprises neural cell type vesicles” and ”comparing … to a control … in a control biological sample” in all occurrences within the claim because the term “control” is a subjective term lacking a comparative basis for defining its metes and bounds. Does Applicant intend a control sample comprising neural cell type vesicles from a subject who does not have hemorrhagic transformation which appears to be encompassed in the claimed invention?
Claim 28 is indefinite in reciting, “L1CAM”, “EAAT1”, “EAAT2” and “MOG.” Acronyms or abbreviations should be fully defined and recited at least one time in a given set of claims.
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.
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.
5. Claims 6-8 and 23-30 are rejected under 35 U.S.C. 103 as being unpatentable over Routenberg et al. (US 2023/0349920 A1) in view of Patabendige et al. (Astrocyte Activation in Neurovascular Damage and Repair Following Ischemic Stroke. Molecular Sciences 22 (4280): 1-22 (April 20, 2021))
Routenberg et al. disclose a method of analyzing a sample from a subject to determine disease including ischemic stroke (Abstract; [0125]). Routenberg et al. teach that extracellular vesicles (EVs) or exosomes play several roles in various central nervous system (CNS) diseases and disorders; hence EVs are emerging as useful indicators of disease including ischemia [0005, 0006, 0008]. According to Routenberg et al., these EVs or exosomes are secreted by cells in the CNS including neurons, astrocytes, and oligodendrocytes; hence, brain-derived vesicles [0005, 0121, 0125, 0126, 0129, 0130]. In study, Routenberg et al. teach obtaining CNS biological sample comprising at least one brain-derived vesicle from the subject, the brain-derived vesicle comprising neurons, astrocytes, and oligodendrocytes [0108, 0109, 0111, 0112, 0125-0132]; and measuring the concentration of the brain-derived vesicles and the level of one or more surface biomarkers expressed by the brain-derived vesicle in the CNS sample ([0126, 0127, 0129-0132, 0311-0314]; Example 28). Routenberg et al. further teach comparing the concentration of the brain-derived vesicles and the level of the biomarker(s) expressed by the brain-derived vesicle in the CNS sample from the subject to a control sample having a predetermined amount of brain-derived vesicles and/or level of the one or more biomarkers expressed by the brain-derived neural cell type EVs in a control biological sample ([0573-0576]; Example 27; Example 28; Example 29). The one or more biomarkers comprise CD9, L1CAM, CD171, EAAT1 (GLAST-1), EAAT2 (GLT-1), and MOG. Routenberg et al. found that neuron, astrocyte, and oligodendrocyte brain cells express these unique ganglioside surface biomarkers which are used to measure and isolate EVs from other CNS cell types [0126, 0127, 0129-0132, 0179-01810201, 0204].
Routenberg differ from the instant invention in failing to teach analyzing brain-derived vesicles in a biological sample to determine hemorrhagic transformation.
Patabendige et al. teach that transient or permanent loss of tissue perfusion from ischaemic stroke (after stroke) can lead to damage of the neurovasculature and disrupt brain homeostasis that cause long-term motor and cognitive deficits. Patabendige et al. study astrocytes (CNS cells) which are more resistant than other CNS cell types to stroke pathology, and exert a regulative effect in response to ischaemic stroke (Abstract). Astrocytes are glial cells that have important roles in brain homeostasis as well as in the development and maintenance of the blood–brain barrier (BBB); and can further have either protective or detrimental effects on neurons following ischaemic stroke (p. 2, 1st & 2nd full ¶s; Figure 1). Patabendige et al. teach that astrocytes are highly secretory cells in the CNS that secrete extracellular vesicles (EVs), exosomes, and microvesicles. Astrocyte-derived exosomes are being widely pursued for their abilities to cross the BBB, suppress autophagy, and ameliorate neuronal damage during ischaemic stroke (Figure 2; p. 10, 4th full ¶ to p. 12). BBB breakdown leads to cerebral oedema and haemorrhagic transformation which are common complications of ischemic stroke that can impact the outcomes of these patients with potentially serious and life-threatening consequences (p. 6 last full ¶). Patabendige et al. show that astrocytes modulate cerebral blood flow, angiogenesis and the BBB and are shown to have critical importance in upregulating many BBB features including low paracellular permeability, transporters, and enzymes. (pp. pp 5-6).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to incorporate the teaching of Patabendige in the critical role of astrocytes and astrocyte-derived vesicles in suppressing autophagy and ameliorating neuronal damage during ischemic stroke with the ability of the vesicles to cross the BBB during BBB breakdown that leads to cerebral oedema and hemorrhagic transformation into the assay method of measuring a sample for the level or amount of brain-derived vesicles as taught by Routenberg to determine hemorrhagic transformation because Routenberg taught that brain-derived vesicles express distinct specific surface antigens that can be detected and measured for use in determining the presence of disease such as hemorrhagic transformation as taught by Patabendige that presents after the incidence of stroke in a subject. One of ordinary skill would have had reasonable expectation of success in incorporating the teaching of Patabendige in the role of astrocyte-derived vesicles in hemorrhagic transformation into the method of measuring and isolating brain-derived vesicles as taught by Routenberg because Routenberg and Patabendige teach analogous art in the field of Neuropathology involving brain-derived cells and secreted vesicles therefrom.
It is proper for purposes of the obviousness rejection to interpret the "control levels” as taught by Routenberg and the comparative BBB dysfunction following ischemic stroke showing astrocyte reactivity levels as shown by Patabendige in Figure 2 to encompass the control samples and levels in the event of hemorrhagic transformation as recited in claims 6, 23, and 27 because unpatented claims are given the broadest reasonable interpretation consistent with the specification.
6. No claims are allowed.
Remarks
7. Prior art made of record are not relied upon but considered pertinent to the applicants' disclosure:
Hotta et al. (Monitoring of Post-Brain Injuries by Measuring Plasma Levels of Neuron-Derived Extracellular Vesicles. Biomarker Insights. 17: 1-9 (2022)) teach a sandwich immunoassay to measure plasma neuron-derived extracellular vesicle (NDE) using anti-neuron CD171 and anti-EV CD9 ([CD171 + CD9+]) in patients undergoing total aortic arch replacement (TAR) with selective cerebral perfusion during cardiopulmonary bypass before and after surgery (Abstract).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GAILENE R. GABEL whose telephone number is (571)272-0820. The examiner can normally be reached Monday, Tuesday, and Thursday 5:30 AM to 4:00 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory S. Emch can be reached at (571) 272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GAILENE GABEL/Primary Examiner, Art Unit 1678
September 15, 2026
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