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 .
Application Status
This action is written in response to applicant’s correspondence received 05/17/2024. Claims 1-20 are currently pending and are examined herein.
Information Disclosure Statement
The listing of references in 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(b)
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 and 15 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 the term “the engineered marker”. There is insufficient antecedent basis for this limitation in the claim, which only recites a “synthetic marker”. Amending the claim to recite “the synthetic marker” would obviate this rejection.
Claim 15 is unclear over recitation of “the synthetic marker”. This language is considered to be indefinite because it lacks antecedent basis in claims 14 and 8, upon which claim 15 depends. Claims 8 and 14 recite a marker, which is generic and encompasses both natural and synthetic markers. The claims do not recite a synthetic marker. Amending the claim to recite “the marker” would obviate this rejection.
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:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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, 7-11, 13-18 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 11,400,168 B2 to Shapiro (hereinafter ‘Shapiro’) in view of Pacia (Pacia et al. Sonobiopsy for minimally invasive, spatiotemporally-controlled, and sensitive detection of glioblastoma-derived circulating tumor DNA. heranostics. 2022 Jan 1;12(1):362-378.).
Regarding claim 1:
Shapiro teaches a method comprising causing selective genetic expression of a synthetic marker within a cell type or region of a brain of a subject, and selectively applying focused ultrasound to a blood-brain barrier of the subject to deliver the synthetic marker to a cell type or region of a brain of the subject, wherein the synthetic marker crosses the blood-brain barrier during and/or after application of the focused ultrasound:
The method also comprises before, simultaneously, in combination with, or after applying focused ultrasound, systemically administering to the individual an effective amount of an expression vector configured to enter the brain at the transient blood-brain barrier opening and to specifically deliver and express in the target brain cells a gene encoding a chemogenetic protein under control of a promoter configured to be active in the target brain cell (col 2 ln 15-25)
methods and systems herein described and related approach, herein also indicated as acoustically targeted chemogenetics (ATAC) combines focused-ultrasound blood-brain barrier opening (“FUS-BBBO”) employed for spatially targeting a specific region in the brain, expression vectors for the delivery of genes of interest to specific cell types in a target region, and chemogenetic receptors for modulation of targeted neurons upon activation by a chemogenetic receptor (col. 43 ln 50-60)
Shapiro further teaches that the synthetic markers (chemogenic proteins) used in the method comprise receptors that activate gene expression:
chemogenetic proteins that can be used in methods and systems of the disclosure and related vectors and compositions comprise protein receptors that activate downstream signaling in the cells or gene expression (col 15 ln 55-60).
Shapiro further teaches several alternative cell-specific promoters for causing genetic expression of a marker, “ under control of one or more regulatory sequence regions in a configuration allowing to express chemogenetic proteins encoded by the polynucleotide in presence of suitable cellular transcription and translation factors.”.
Shapiro further teaches quantifying expression of the synthetic marker using a protein measurement technique (immunostaining, col. 41 ln 25-65).
Shapiro differs from the instant claims in that they do not teach selectively applying focused ultrasound after causing selective genetic expression of the synthetic marker, and do not teach obtaining a blood sample or quantifying the synthetic marker in the blood sample. Instead, Shapiro uses the ultrasound step to deliver a vector for transducing the target cells and expressing the marker, as described above, and measures gene expression histologically, also as described above.
Pacia teaches sonobiopsy, which is a “minimally invasive” (Title) method using, “uses focused ultrasound (FUS) in combination with microbubbles to disrupt the BBB and enhance the release of tumor-derived biomarkers from the FUS-targeted brain location into the blood circulation.”. This method is a form of blood-based liquid biopsy (LBx), i.e., a method comprising obtaining a blood sample from a subject and measuring biomarkers in the blood sample (p. 363). Markers detected (i.e., measured) have included protein biomarkers enhanced green fluorescent protein (eGFP) and brain-specific proteins such as glial fibrillary acidid protein (p. 364). Pacia further notes that, “preliminary clinical evidence that FUS-induced BBB disruption increased the concentrations of circulating biomarkers” including “brain-specific protein”, i.e., that the proteins may not only be detected qualitatively but may be quantified using a protein-based assay.
Pacia further teaches that this method of BBB disruption, “enables “two-way trafficking” between the brain and the bloodstream…While circulating agents can be allowed to enter the brain using FUS-mediated BBB disruption, brain tumor-derived biomarkers can also be released into the blood circulation to improve the sensitivity of blood-based LBx” (p-. 363-364).
Pacia further notes that the method can detect synthetic or engineered markers:
sonobiopsy enriched blood specimens with enhanced green fluorescent protein
(eGFP) mRNA, the expression of which had been caused by transduction of glioblastoma cells (p. 364)
In summary, Shapiro teaches methods of delivering gene therapy vectors across the blood-brain barrier using FUS to disrupt the BBB, and Pacia teaches that the same method is two-way, i.e., causes measurable release of biomarkers into the blood across the BBB, including synthetic biomarkers expressed by transduced cells, such as GFP.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of delivering a synthetic marker (such as eGFP or a transgene fused to eGFP, as taught by Pacia) across the BBB to a cell or tissue in the brain of a subject, using FUS to temporarily open the BBB, as taught by Shapiro, to include an additional step of using FUS to detect expression of the marker, as taught by Pacia. As a matter of common sense and sound scientific reasoning, the ordinary artisan would have been motivated to confirm expression of the marker. Based on Pacia’s teachings, the ordinary artisan would have had a reasonable expectation that the FUS-BBBO method could be applied two-way, i.e., both to deliver a transgene to a target site in the brain and to measure expression of said transgene to confirm its successful transduction and expression, in a minimally invasive way.
Regarding claim 8, Shapiro teaches a method of measuring neuronal activity by causing expression of a marker by neurons in one or more brain regions of a subject, wherein the marker is indicative of endogenous neuronal activity (see e.g. Table 2 and activity-dependent promoters such as the c-fos promoter; see also the description for FIG. 6, which notes that activated cells are c-Fos-positive, i.e., that c-Fos-positive results indicate that a cell has been activated). It would have been obvious to adapt the method of using Pacia’s two-way sonobiopsy to measure expression of a marker in a blood sample, as discussed above and applied to claim 1, to measure neuronal activity by causing expression of a marker (such as eGFP) under control of a promoter which responds to neuronal activity, such as a c-Fos promoter, for the same reasoning as described above, mutatis mutandis.
Regarding claim 16: Shapiro in view of Pacia teaches the method for determining the success of a gene therapy delivery, as recited in claim 16, for the same reasons already discussed above.
Regarding claim 2, Shapira teaches wherein the cell type comprises neurons, as described above.
Regarding claim 3, Pacia teaches that the two-way FUS-BBBO technique can be applied to secreted proteins (i.e., detects circulating tumor-derived biomarkers, e.g., protein; p. 363).
Regarding claim 7, Shapiro in view of Pacia renders obvious the method of determining success of the gene delivery efficacy, as described above.
Regarding claims 9 and 20, Shapiro teaches wherein the marker is transduced into one or more brain regions, as described above.
Regarding claim 10, Shapiro teaches wherein the marker is transduced using an AAV, as described above.
Regarding claims 11 and 17, Shapiro teaches that the marker is under the control of a genetic circuit that responds to c-Fos when activated by heightened neuronal activity (see above and Table 2, which lists a c-Fos responsive promoter).
Regarding claim 13, insofar as Shapiro in view of Pacia teach causing expression of a genetic marker that responds to neuronal activity, they teach diagnosing neurological diseases such as localized brain damage, i.e., localized neuronal cell death.
Regarding claims 14, 15 and 18, Shapiro in view of Pacia teaches determining the success of a gene therapy delivery/efficacy, as described above.
Claim 4, 12 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Shapiro and Pacia as applied to claims 1-3, 7-11, 13-18 and 20, further in view of Hosseini (Hosseini et al. Enzyme-linked Immunosorbent Assay (ELISA): From A to Z. (2017). Springer Publishing Company, Incorporated. 1st edition.).
Shapiro and Pacia render obvious the methods of 1, 8 and 16, from which the instantly rejected claims depend, as described above.
Shapiro and Pacia do not teach wherein the method of protein quantification is ELISA.
Hosseini teaches that ELISA is an immunoassay (Title) which is a widely used technique to measure protein concentrations in the areas of food industry, vaccine development, immunology, diagnosis, toxicology, drug monitoring, pharmaceutical industry, and transplantation (p. 19 § 2.1).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the generic method as taught by Shapiro and Pacia to comprise measuring the protein using the ELISA technique. The ordinary artisan would have been motivated to do so, and have had a reasonable expectation of success, based on Hosseini’s teachings that ELISA was a widely used and effective protein measurement technique applicable to various industries and areas of research.
Claim 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Shapiro and Pacia as applied to claims 1-3, 7-11, 13-18 and 20, further in view of Ronald (Ronald et al. Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker. Proc. Natl. Acad. Sci. U.S.A. 112 (10) 3068-3073.)
Shapiro and Pacia render obvious the method of measuring gene expression, comprising causing selective genetic expression of a marker within a cell type or region of a brain of a subject, selectively applying focused ultrasound to a blood-brain barrier of the subject, wherein the marker crosses the blood-brain barrier during and/or after the application of the focused ultrasound, obtaining a blood sample, and quantifying the marker in the blood sample, of claim 1, from which the instantly rejected claims depend, as described above.
Shapiro and Pacia do not teach the method further comprising diagnosing a neurological disease or determining the success of a treatment based on the quantity of the marker.
Ronald teaches delivery of selective (tissue specific) synthetic markers (“minicircles”) for diagnosing or determining the success of a treatment based on the quantity of the marker in a blood sample from a subject:
Blood-based cancer diagnosis is highly attractive, but current strategies suffer because they rely on the detection of endogenous molecules that often are secreted into the circulation by both malignant and nonmalignant cells. One solution to this problem is to avoid nonmalignant tissue expression by artificially engineering tumor cells to express a unique reporter not normally expressed by any tissue. This study shows that systemic administration of nonviral safe vectors we call “tumor activatable minicircles” allows one to distinguish tumor-bearing from tumor-free subjects reliably and to assess tumor burden simply by measuring blood levels of such a reporter. (p. 3068)
It is relevant to note that “determining success of a treatment” is interpreted as encompassing assessing tumor burden, as taught by Ronald, during treatment, to monitor the subject for signs of decreased tumor burden as they undergo treatment.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of delivering gene therapy and releasing biomarkers into the blood by FUS-mediated BBB opening, as taught by Shapiro and Pacia, to target tumor tissues in the brain for diagnosing cancer and determining the success of treatment, as taught by Ronald.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 7-10, 13-16, 18, 20 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-8, 12-19 of U.S. Patent No. U.S. Patent No. 11,400,168 B2 in view of Pacia. Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons that follow.
Patented claim 1 recites a method to perform cell-specific control of activity of a target brain cell, the method comprising applying focused ultrasound to a target brain region to induce a transient blood-brain barrier opening, administering an AAV expression vector configured to enter the brain at the transient blood-brain barrier opening, wherein the AAV expression vector comprises a vector regulatory region in series with a target brain cell regulatory region in a configuration in which expression of the gene encoding the chemogenetic protein is performed in the presence and activity of both the vector regulatory regions and the target brain cell regulatory region independently activated (i.e., causing selective genetic expression of a synthetic marker within a region of a brain of a subject). Patented claim 1 differs from instant claim 1 insofar as instant claim 1 includes the steps of obtaining a blood sample of the subject and quantifying the selective marker, which are not included in patented claim 1. Shapiro defines “chemogenetic protein” as a protein having an operative state and inoperative state with respect to the activity of a target brain cell, including proteins such as c-fos, as described above. Those steps would have been obvious in view of Pacia, as described in the rejection of the claims under 35 U.S.C. 103 above. Pacia renders obvious two-way sonobiopsy to measure expression of biomarkers in a blood sample, including a transgene which has been transduced into target cells in the brain. Instant claim 8 also recites a method for measuring neuronal activity, and is rendered obvious in view of Pacia by the same rationale. Similarly, it would have been obvious to determine the success of the patented method by measuring the marker, as recited in instant claim 16. Regarding patented claims 16 and 17, it would have been obvious to include steps of measuring expression of the chemogenetic protein to assess the success of the gene delivery or treatment.
Regarding instant claim 2, patented claim 1 recites wherein the target cell is a brain cell, and Shapiro’s disclosure indicates that the method was performed in neurons specifically, as already described.
Regarding claims 3, 5-7, 9-10, 13-18 and 20, the patented claims either recite limitations such as transducing the synthetic marker into a brain region, or are obvious over Shapiro in view of Pacia, as already described above. Regarding claims 5-6, as the patented claims already describe methods of treatment, it would have been obvious to modify the patented methods to include steps of diagnosing a disease prior to treatment or assessing the success of the treatment during and after treatment, for the same reasons discussed above.
Claims 4, 12 and 19 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-8, 12-19 of U.S. Patent No. U.S. Patent No. 11,400,168 B2 in view of Pacia and Hosseini. Although the claims at issue are not identical, they are not patentably distinct from each other because, as already described above, Shapiro and Pacia teach the methods of claims 1, 8, and 16, and while they do not teach quantifying the protein using ELISA, Hosseini teaches that ELISA is a widely used protein quantification assay. As described in the rejections of the claims under 35 U.S.C. 103 above, it would have been obvious to quantify the expressed marker using widely used protein quantification techniques such as ELISA.
Subject Matter Eligibility Analysis
Regarding claim 1, it is noted that the claim is drawn to a method of measuring gene expression. The invention belongs to the statutory category of a process. However, it is not a judicial exception, such as a mental process, because the act of measuring cannot practically be performed in the human mind.
Conclusion
No claim is allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
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/AMANDA M ZAHORIK/Examiner, Art Unit 1636
/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636
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