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
A Group election was not required.
Election without traverse of the following species on the reply filed on 08/25/2025 is acknowledged:
1) a progenitor cell
2) a glial progenitor cell and PDGFRα
Claims 61, 63 and 65 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species (differentiated cell), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/25/2025.
Claims 1, 31, 33, 35-37, 39, 40, 41-43, 54-56, 58, 61-63, 65, and 67 are pending.
Claims 1, 31, 33, 35, 37, 39, 40, 41-42,49, 54, 58, 62-63, 65, and 67 are newly amended
Claims 2-30, 32, 34, 38, 44-48, 50-53, 57, 59-60, 64, 66, and 68 are canceled
It is noted that claim 40 is listed as canceled in the Remarks filed 10/10/2025, and identified as “currently amended” in the instant claim set. A phone conversation with a representative of the Applicant (Sarah Pollock 610 397 7960) on 01/14/2026 confirmed that claim 40 is currently amended in the instant claims set and shall be examined herein.
Claims 1, 31, 33, 35-37, 39, 40, 41-43, 54-56, 58, 61-63, 65 and 67 are examined on the merits.
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.
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, 31 39-43, 54-56, 58 and 61-63 are rejected under 35 U.S.C. 103 as being unpatentable over Yoon et al (Molecular Therapy (2014)1:14016; 1-9; as cited in the IDS filed 11/24/2025) in view of O’Rourke et al (PLOSone (2016) 11:9;1-19) and as evidenced by Husain et al (Gene Therapy (2009) 16;1-6).
Regarding claims 1 and 39-41, 54-56, 58, 61-63: The claim is drawn to a product (a system).
The claim recites “a preparation of cells”. The instant specification is silent on an explicit definition of the term. The broadest reasonable interpretation of “a preparation of cells” is any cells that have been prepared; that is any type of cell that has undergone any sort of treatment or manipulation.
The claim recites “implantation”. The instant specification is silent on an explicit definition of this term. Oxford Languages defines the term “implant” as “a thing implanted in something else, especially a piece of tissue, prosthetic device, or other object implanted in the body”.
Thus the broadest reasonable interpretation of the term “implanting” includes an implanted embryo, cells injected into an organism and a cell that is attached to another cell within an organism.
The claims are interpreted as discussed supra.
Yoon (2014) teach in vivo imaging to monitor therapy in the brain (abstract). Yoon teach a PET reporter gene system comprising D2R80, a signaling incompetent form of a dopamine receptor (p1 col2 ¶1) expressed in an AAV vector system using the human GUSB promoter (regulatory sequence) (p7 col1 ¶5). Yoon teach D2R80 is cloned into the AAV packaging plasmid pZac2.1 and is under the control of the human GUSB gene promoter (p4 col1 ¶1). As evidenced by Husain, the transgene is 3’ to the hGUSB promoter (Figure 1).
Yoon teach intraventricular injection of the vector into mice resulted in transduction of target cells in the neocortex, entorhinal cortex and hippocampus (p2 co1 ¶2), therefore Yoon teach a preparation of cells wherein the cells are stably transduced with the genetic construct. The cells are located in the neocortex, entorhinal cortex and hippocampus, thus the cells are implanted into a subject. The imaged cells are the cells from the treated individual and thus read on autologous.
Thus Yoon teach a population of target cells comprising a recombinant genetic construct (AAV vector). The cells are imaged by PET with the radiolabeled binding molecule [18F]-fallypride (p2 col1 ¶2). Mice are injected with , which reads on administering the one or more radiolabeled binding molecules (p7 col2 ¶4). Figure 1 shows imaging (detecting) the implanted cells using PET to detect the radiolabeled molecules bound to the cognate cell surface binding molecule (p2 Fig 1).
While Yoon teach the regulatory sequence GUSB, Yoon do not teach the regulatory sequence drives target cell-type specific gene expression and is from Pdgfrα.
O’Rourke (2016) teach PDGFRα is expressed exclusively by oligodendrocyte progenitor cells, making the PDGFRα promoter ideal for directing transgene expression in this cell type (abstract).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Yoon drawn to a system of in vivo tracking of target cells by using the PDGFRα promoter to drive the reporter gene (D2R80) as taught by O’Rourke.
One of ordinary skill in the art would have been motivated to modify the reporter system for in vivo tracking of target cells as taught by Yoon to for the purposes of tracking an oligodendrocyte progenitor cell population as taught by O’Rourke.
One would have had a reasonable expectation of success because O’Rourke teach the high specificity of PDGRα expression makes the PDGRα gene promoter an ideal tool to manipulate gene expression exclusively in OPCs (p2 ¶2) and one of ordinary skill in the art would understand that exchanging functional components in a transgene expression system is a standard molecular biology method that is well known in the art.
Regarding claim 31: The teachings of Yoon are discussed supra. Yoon teach the radiolabeled binding molecule is labeled with [18F]-fallypride (p2 col2 ¶2). Fallypride is a well-known high-affinity dopamine receptor ligand.
Regarding claim 42: The teachings of Yoon are discussed supra. Yoon teach PET signal in the mouse cortex, demonstrating mouse brain cells express the reporter construct (Fig 1). As discussed supra, a preparation of cells is broadly interpreted to encompass cells that have been manipulated (prepared). Thus mouse brain cells expressing the genetic construct of Yoon read on a preparation of mammalian cells as required by the claim limitations per the claim interpretation.
Regarding claim 43: The teachings of Yoon are discussed supra.
While Yoon teach the PET ligand [18F]-fallypride is widely used in animals and humans and is approved for human use which facilitates future clinical usage of the genetic construct comprising D2R80A, Yoon do not explicitly teach a preparation of human cells.
It would have been obvious to one of ordinary skill in the art to adapt the methods of Yoon and O’Rourke, drawn to a system of in vivo tracking of target cells by using the PDGFRα promoter to drive the reporter gene (D2R80) for use in human cell preparations, also taught by Yoon (p5 col2 ¶4). Clinical use is widely understood to refer to use of a product in humans.
One of ordinary skill in the art would have been motivated to modify the reporter system for in vivo tracking of target cells as taught by Yoon for the use in cell populations because Yoon teach in vivo imaging of vector transgene expression would be particularly valuable for repetitive monitoring of therapy in the brain (abstract).
One would have had a reasonable expectation of success because Yoon teach the dopamine receptor is relatively conserved in mammals and there was not evidence of an immune response to rat D2R80A in mice or cats (p7col1 ¶2).
Thus the invention as claimed is rendered obvious by the teachings of Yoon and O’Rourke.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Yoon et al (Molecular Therapy (2014)1:14016; 1-9; as cited in the IDS filed 11/24/2025) in view of O’Rourke et al (PLOSone (2016) 11:9;1-19 ) as applied to claim 1, 31 39-43, 54-56, 58 and 62-63 above, and further in view of Goldman (Prog Brain Res (2017) 231;1-24; as cited in the IDS filed 06/09/2023).
Regarding claim 49: The teachings of Yoon are discussed supra. Yoon do not teach the human cells are oligodendrocyte progenitor cells.
Goldman teach human glial progenitor cells, also called oligodendrocyte progenitor cells or NG2 cells, are promising reagents to restore myelin to demyelinated regions of diseased or injured CNS (p2 ¶1). Goldman further teach pluripotent stem cells are a feasible source of transplantable myelinogenic glial progenitor cells (p3 ¶3). Goldman teach myelination in vivo has been achieved by transplantation of hESC derived oligodendrocytes, but that the animals were not followed over time frames to ensure stability of engrafted cells because there may be a potential for undesired expansion after implantation (p3 ¶3).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Yoon drawn to a system of in vivo imaging by using oligodendrocyte-biased progenitor cells as taught by Goldman. Goldman discloses human embryonic stem cells are a feasible source of transplantable myelinogenic oligodendrocyte progenitor cells.
One of ordinary skill in the art would have been motivated to modify the system as taught by Yoon to use human oligodendrocyte-biased progenitor cells as taught by Goldman because Goldman teach there is a need for following the transplanted cell population over time to asses for undesired expansion after implantation.
One would have had a reasonable expectation of success because Yoon discloses a system for non-invasive in vivo imaging of cells and one of ordinary skill in the art would understand that genetic methods that are successful for manipulation of a cell type can be reasonably expected to be successful for an alternative cell types and the methods are well known in the art.
Thus the invention as claimed is rendered obvious by the teachings of Yoon, O’Rourke, and Goldman.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Yoon et al (Molecular Therapy (2014)1:14016; 1-9; as cited in the IDS filed 11/24/2025) in view of O’Rourke et al (PLOSone (2016) 11:9;1-19 ) as applied to claims 1, 31 39-43, 54-56, 58 and 62-63 above, and further in view of Kummer et al (Molecular Imaging (2007)6:3; 0-12).
Regarding claim 33: The teachings of Yoon and O’Rourke are discussed supra. Yoon do not teach the system comprises the reporter molecule EGFP.
Kummer(2007) teach an in vivo imaging system comprising a vector comprising D2R80A, a signaling incompetent dopamine receptor, and the eGFP reporter molecule (abstract, Fig 1A). Kummer teach use of eGFP expression as a marker gene for vector production in cell culture (p9 col2 ¶2) and use of eGFP to select for cells transduced with the vector at different expression levels (p6 col1, ¶2).
It would have been obvious to one of ordinary skill in the art to adapt the system of in vivo tracking of target cells as taught by Yoon by using an eGFP reporter molecule as taught by Kummer.
One of ordinary skill in the art would have been motivated to modify the system as taught by Yoon with the eGFP reporter as taught by Kummer for the purposes of monitoring vector production in cell culture and for the ability to sort transduced cells.
One would have had a reasonable expectation of success because Yoon and Kummer both disclose genetic methods for in vivo tracking of a target cell population and one of ordinary skill in the art would understand that one of ordinary skill in the art would understand that exchanging functional components in a transgene expression system is a standard molecular biology method that is well known in the art.
Thus the invention as claimed is rendered obvious by the teachings of Yoon, O’Rourke, and Kummer.
Claims 35 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Yoon et al (Molecular Therapy (2014)1:14016; 1-9; as cited in the IDS filed 11/24/2025) in view of O’Rourke et al (PLOSone (2016) 11:9;1-19 ) as applied to claims 1, 31 39-43, 54-56, 58 and 62-63 above, and further in view of Kummer et al (Molecular Imaging (2007)6:3; 0-12) and further in view of Addgene (Plasmids 101: Multicistronic Vectors [online]. Addgene [retrieved on 01/15/2026]. Retrieved from the Internet: <URL: Plashttps://blog.addgene.org/plasmids-101-multicistronic-vectors).
Regarding claims 35 and 36: The teachings of Kummer are discussed supra. Kummer teach the cell surface binding molecule and the reporter molecule are translated separately but use of an intervening IRES between the two coding sequences (Fig 1A).
Kummer does not teach the use of a self-cleaving peptide within the construct to separate translation of the cell surface binding molecule (D2R80A) and the reporter molecule (eGFP).
Addgene teach self-cleaving peptides in multicistronic vectors results in equimolar production of multiple gene products from the same RNA and are short (~20 bp) sequences (p3 ¶1). Addgene also teach a common self-cleaving peptide is P2A.
It would have been obvious to one of ordinary skill in the art to adapt the system of Kummer, drawn to a genetic construct for expression of the cell surface binding molecule and the reporter molecule as separate proteins using an IRES by modifying the construct to replace the IRES of Kummer with a self-cleaving peptide encoding nucleotide sequence as taught by Addgene, such as P2A.
One of ordinary skill in the art would have been motivated to modify the genetic construct as taught by Kummer with the self-cleaving peptide sequence P2A as taught by Addgene because Addgene teach advantages of the self-cleaving peptide is that it is smaller than the IRES sequence and expresses equimolar products, in contrast to the IRES for which the downstream elements can have lower expression (p2/3 ¶ 6/1). Furthermore, Addgene teaches plasmid vectors with the P2A self-cleavage peptide are available (p4 table) and recommended instead of IRES elements (p4 ¶2).
One would have had a reasonable expectation of success because Addgene teach that scientists have adapted self-cleaving peptides to overcome some of the disadvantages of the IRES element, that the P2A sequence is recommended in place of an IRES (p3/4 ¶1/2), and one of ordinary skill in the art would understand that exchanging functional components in a transgene expression system is a standard molecular biology method that is well known in the art.
Thus the invention as claimed is rendered obvious by the teachings of Yoon, O’Rourke, Kummer and Addgene.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Yoon et al (Molecular Therapy (2014)1:14016; 1-9; as cited in the IDS filed 11/24/2025) in view of O’Rourke et al (PLOSone (2016) 11:9;1-19 ) as applied to claims 1, 31 39-43, 54-56, 58 and 62-63 above, and further in view of Philip et al (Immunobiology (2014)124-8).
Regarding claim 37: The teachings of Yoon are discussed supra. Yoon do not teach the genetic construct that comprises the inducible cell death gene caspase-9.
Philip teach that for T-cell cancer gene therapy, suicide genes would allow selective deletion of administered T cells in the face of toxicity (abstract). Philip further teach inducible caspase-9 has been tested in clinical studies (p1277 col2 ¶1).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Yoon drawn to a system of in vivo tracking of target cells by including caspace-9 as suicide gene as taught by Philip.
One of ordinary skill in the art would have been motivated to modify the reporter system for in vivo tracking of target cells as taught by Yoon to comprise a suicide gene as taught by Philip to allow selective deletion of the target cells in the face of toxicity.
One would have had a reasonable expectation of success because Philip teach caspase-9 has been tested in a clinical study. Furthermore, one of ordinary skill in the art would understand that adding functional components to a transgene expression system is a standard molecular biology practice that is well known in the art.
Thus the invention as claimed is rendered obvious by the teachings of Yoon, O’Rourke, and Philip.
Claim 65 is rejected under 35 U.S.C. 103 as being unpatentable over Yoon et al (Molecular Therapy (2014)1:14016; 1-9; as cited in the IDS filed 11/24/2025) in view of O’Rourke et al (PLOSone (2016) 11:9;1-19 ) as applied to claims 1, 31 39-43, 54-56, 58 and 62-63 above, and further in view of Riss et al (Journal of Cerebral Blood Flow and Metabolism (2011) 31;1-9), Nichols et al (Chem Rev (2008) 108;1-28) and Dunham et al (Trends Biotechnol (2009) 27:9;1-10).
Regarding claim 65: The teachings of Yoon and O’Rourke are discussed supra. While Yoon and O’Rourke teach a signal incompetent dopamine receptor, they do not teach the cells express a signal incompetent serotonin receptor or that the radiolabeled molecule is a selective serotonin agonist or antagonist.
Riss teach 18F altanserin is a selective antagonist of the 5-HT2A serotonin receptor that has been used in a considerable number of studies conducted in humans (p1 col1 ¶1). Riss do not teach the 5-HT2A receptor is signal incompetent.
Nichols teach the serotonin receptors, including 5HT2A, are a large family of G-protein coupled receptors (BPCRs) (p1 col2 ¶1). The serotonin GPCRs are classified as “type A” family, rhodopsin-like receptors and the location of highly conserved residues of these family members suggests serotonin receptors bear a high structural and functional resemblance to the other type A family members (p3/4 col 2/1 ¶5/2).
Dunham teach G-protein coupled receptors are the largest class of cell surface receptors and that expression of GPCRs that traffic to the plasma membrane for ligand binding can be challenging in heterologous cells (p1 ¶1/2). Dunham further teach truncation of the c-terminus for the GPCR GABAbR1 allows for robust plasma membrane expression of a signal incompetent form of the receptor (unable to couple to G proteins) (p2/3 ¶5/1).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Yoon drawn to a method of in vivo tracking using a signaling incompetent dopamine receptor with a radiolabeled binding molecule by using a serotonin receptor with a radiolabeled binding molecule as taught by Riss. Riss discloses the in vivo imaging system using the serotonin receptor is established for a considerable number of studies and thus one would have been motivated to use the system because it is well studied and well characterized.
It would have been obvious to use signal incompetent serotonin receptor because Yoon teach a signal incompetent receptor is a desirable feature for use of a reporter gene in the brain because it is biologically inert in cells that do not normally express the receptor gene.
One would have had a reasonable expectation of success because Nichols teach the serotonin receptor 5HT2A is a GPCR for which structure and function is conserved with other GPCRs, and Dunham teach methods to generate signal incompetent GPCRs are known in the art and that deletion of the c-terminal tail improves GPCR expression and trafficking while rendering the protein signal incompetent.
Thus the invention as claimed is rendered obvious by the teachings of Yoon, O’Rourke, Riss, Nichols and Dunham.
Claim 67 is rejected under 35 U.S.C. 103 as being unpatentable over Yoon et al (Molecular Therapy (2014)1:14016; 1-9; as cited in the IDS filed 11/24/2025) in view of O’Rourke et al (PLOSone (2016) 11:9;1-19 ) as applied to claims 1, 31 39-43, 54-56, 58 and 62-63 above, and further in view of Bernau et al (Journal of Neuroscience Methods (2014) 228;1-12) and Goldman (Prog Brain Res (2017) 231;1-24; as cited in the IDS filed 06/09/2023).
Regarding claim 67: The claim is interpreted per the claim interpretation discussed supra. The teachings of Yoon and O’Rourke are discussed supra. Yoon and O’Rourke do not teach the preparation of cells are glial progenitor cells.
Bernau et al (2014) teach neural stem and progenitor cells are distinct in their ability to differentiate into cells of the neural lineage and are well-suited for cell-based treatment of neurodegenerative disorders (p2 col1 ¶1). Bernau further teach a method of in vivo noninvasive longitudinal cell tracking in clinical settings would be invaluable to allow scientists to understand cell dynamics in single subjects as well as cohorts and adapt progenitor/stem cell therapies for further studies (p2 col1 ¶2). Bernau teach tracking of neural progenitor cells, but do not explicitly teach glial progenitor cells.
Goldman et al (2017) teach exogenous glial progenitors can be therapeutic vectors for disorders of myelin (p2/3 ¶3/1).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Yoon and O’Rourke drawn to a system for in vivo tracking of target cells by using glial progenitor cells as taught by Bernau and Goldman.
One of ordinary skill in the art would have been motivated to modify the system as taught by Yoon and O’Rourke by using a preparation of glial progenitor cells because Goldman teach glial progenitors can be therapeutic vectors for disorders of myelin and Bernau teach that a noninvasive method for tracking neural progenitor cells in clinical settings would be invaluable.
One would have had a reasonable expectation of success because the disclosures are directed to in vivo tracking of neural cells and Bernau teach in vitro genetic manipulation of neuronal progenitor cells for in vivo detection (p5 col1 ¶1).
Thus the invention as claimed is rendered obvious by the teachings of Yoon, O’Rourke, Bernau and Goldman.
Conclusion
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631