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 biomarker: cancer and disease: cancer in the reply filed on 6 August 2026 is acknowledged. However, during examination of the elected species, the non-elected species was found as well. As a result, the requirement for a species is withdrawn.
Information Disclosure Statement
The information disclosure statement filed 21 December 2023 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. The deficiency is as follows: non-patent literature document C1 is improperly cited and a duplicate of C8. Document C1 has not been considered; however, all other references disclosed were considered by the Examiner.
Claim Interpretation
Claim 59 states “…wherein the human patient is…at risk for developing a cancer or neurodegenerative disease.” All human patients are at some non-zero risk of developing cancer or neurodegenerative disease. Therefore, this limitation does not meaningfully narrow the claimed patient population and, under the broadest reasonable interpretation, reads on any human patient.
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 47, 78, and 122 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 47 recites the limitation "…the neurodegenerative disease" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 78 recites the limitation “…at least one…regions of the brain contemporaneously” in the last line. This is indefinite as it is unclear what event or region the application of the ultrasound beam to at least one region is contemporaneous with, particularly as ‘at least one’ permits application to only a single region.
Claim 122 recites the limitation “…the diagnosing…” in line 2. Ther is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 4, 8, 13, 26, 36, 47, 59, 72, 78, 86, 95, 106, 122, 127, and 149 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Leuthardt [US 20190323086 A1, IDS Reference].
Leuthardt discloses a method for non-invasively diagnosing a brain disease using an ultrasound beam to release brain-derived biomarkers across the blood brain barrier (BBB) of a subject to include human subjects [0006-0010, 0083]. An exemplary embodiment of this method involves applying a focused ultrasound to the brain or brain region such that the BBB is disrupted so that a detectable quantity of biomarker is released across the BBB. A biological sample, which includes blood, cerebral spinal fluid, interstitial fluid, serum, and plasma sample, is obtained from the subject. Using this sample, the biomarker is detected [0011], [0012].
They further state that this method can be used to diagnose, treat, or formulate a personalized treatment for a subject suffering from various central nervous system (CNS) diseases including CNS cancers and tumors, and neurological or neurodegenerative diseases, disorders, or conditions including Alzheimer’s disease and Parkinson’s disease. Additionally, this method can be used to detect already known biomarkers or discover new biomarkers in subjects diagnosed with said disease [0096-0098, 0105, 0109].
As is apparent from the biomarker/disease list below, the detected biomarkers relate to mutations or differential methylation patterns which are specific for different disease sub-types (i.e., astrocytoma is a sub-type of glioma). Therefore, by detecting the biomarker using Leuthardt’s method, the skilled artisan would also be determining the sub-type or mutational basis of said disease.
An exemplary, non- exhaustive list of biomarkers taught as detectable by Leuthardt’s method, and their corresponding disease(s), include: (1) MGMT promoter methylation (glioblastoma, anaplastic astrocytoma), (2) 1p/19q co-deletion (oligodendroglioma), (3) IDH 1/2 mutations (oligo- and astrocytoma WHO grade II and III, secondary glioblastoma), (4) EGFRvIII (glioblastoma), (5) TERT mutation (glioma), (6) ATRX mutation (glioma), (7) TP53 mutation (astrocytoma), (8) BRAF V600 mutation (PXA, pilocytic astrocytoma, gangliogliomas), (9) BRAF/KIAA1549 fusion (pilocytic astrocytoma), (10) H3.3 histone (pediatric HGG), (11) SHH pathway mutations, including MYCN amplification, GLI2 amplification, and TP53 mutations (medulloblastoma), (12) WNT pathway mutations (medulloblastoma), (13) MYC (medulloblastoma), (14) neuronal proteins including AR, tau, phosphorylated tau (Alzheimer’s disease), and (15) alpha-synuclein (Parkinson’s disease) [0102, 0105].
Detection of the biomarker can occur by genetic testing or sequencing [0020]. In Leuthardt’s Example 1, they performed quantitative PCR (qPCR) to determine the relative circulating levels of eGFP A mRNA and eGFP B mRNA (which collectively constituted the target biomarker) in blood serum using two primer pairs [0141]. These primer pairs are akin to the detection agent of the instant application and the qPCR detection method is considered to be a primer-based, PCR detection method.
Regarding claims 36, 47, and 59, this method is capable of detecting biomarkers specific for different diseases or disorders in individuals having or suspected of having said disease or disorder. A non-exhaustive list of these diseases and disorders includes brain cancers (as noted above), neurodegenerative diseases, generalized alcoholism, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, epilepsy, multiple sclerosis, dementia, and cognitive dysfunction [0109, 0120-0121].
Regarding claim 72, the ultrasound beam used to disrupt the BBB is a high-resolution MRI guided focused ultrasound (FUS) [0006]. Additionally, the application of the FUS can be targeted to a specific region by first scanning the subject’s head with an MRI and stereotactically coregistering the subject’s head [0018].
Regarding claim 78, the FUS can be applied while the subject is wearing a helmet which allows for targeting of different brain regions [0074], with a pulse repetition frequency ranging from 0.1Hz to
Regarding claim 86, this method can be used to diagnose lesions and detect biomarkers in areas of the brain or CNS that are typically not available for biopsy or surgery, such as the brain stem [0109].
Regarding claim 122, detection of the biomarkers can be used to monitor a course of treatment for response and efficacy, as well as to monitor disease progression. As an example, MGMT promoter methylation is described as a prognostic and predictive marker in glioblastoma [0100-0101, 0109].
Regarding claim 149, this method also includes administering microbubbles to a subject in an amount sufficient to disrupt the BBB upon application of the FUS [0027]. These microbubbles are comprised of a gas surrounded by a shell that is composed of polymers, lipids, etc. and are administered intravenously [0089-0090]. A commercially available example are Definity® microbubble which are perflutren lipid microspheres composed of octafluoropropane in a lipid shell [0093].
Claims 37, 39, 40, 42, and 43 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Leuthardt, as applied to claims 4 and 36 above, as evidenced by Roswell Park [Roswell Park. “Specific Types of Brain Tumors and Disorders”. Available: 2021 Oct 17. Obtained from the WayBack Machine on 9/10/2026. https://web.archive.org/web/ 20211017093025/https:/www.roswellpark.org/cancer/brain/about/types-brain-tumors-and-disorders].
Leuthardt is applied to the relevant teachings of claims 4 and 36 as discussed above and is incorporated herein by reference.
Regarding claims 37, 39, 40, 42, and 43, a non-exhaustive list of the CNS cancers/tumors which can be detected by Leuthardt’s method includes glioblastoma (i.e., a primary, glial brain tumor per Roswell Park p3), a metastatic brain tumor, and meningioma (i.e., a non-glial tumor per Roswell Park p4) [0115].
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kara N Kovach whose telephone number is (571)272-8134. The examiner can normally be reached Monday - Friday, 9am - 3pm.
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/K.N.K./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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