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 Interpretation
Regarding Claims 5 and 6, is it is noted that Claim 6 states “said one or more neuronal factors comprise the NeuroD1 polypeptide, the Neurog2 polypeptide, and the Ascl1 polypeptide. However, it is noted that Claim 5, of which Claim 6 depends, states “said one or more neuronal transcription factors further comprise one or more selected from the group consisting of Neurog2 and Ascl1. Therefore, the limitations of Claim 5 are inherent to Claim 6 and Claim 6 will be interpreted as requiring Neurog2, NeuroD1, and Ascl1.
Regarding Claims 11 and 13, it is noted that Claim 11 states “wherein said one or more transcription factors further comprises one or more liver transcription factors”. Claim 13 states “one or more liver transcription factors comprises a HNF4A polypeptide, a Foxa2 polypeptide, and a GATA4 polypeptide. However, As Claim 13 depends on Claim 11 and inherits the limitations of Claim 11, Claim 13 will be interpreted as requiring HNF4A, Foxa2, and GATA4 polypeptides.
Claim Rejections - 35 USC § 102
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 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)(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 1, 2, and 17-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Glorioso (US 20160153000A1).
Glorioso et al. discloses a herpes simplex virus (HSV) vector which does not express toxic native HSV genes and is able to persistently express a transgene. (0041) The inventive vector may include one or more operably linked transgenes (0048) which can be linked with insulator sequences close to the transgene (0050) which results in the expression of the desired transgene within a nucleated cell. (0074) The disclosed invention is able to infect a wide variety of mammalian cells (0061) in vivo and in vitro (0075) including humans to deliver therapeutic transgenes. (0079)
Regarding claim 1: Glorioso et al. discloses a method of the invention to be used in vitro or in vivo to express therapeutically relevant transgenes by way of infecting cancerous cells. (0075-0076) In an embodiment of the invention, Glorioso describes the invention infecting cancerous cells and expressing transgenes which can encode an agent such as tumor necrosis factor (TNF) which results in the killing of the cancer cells, thus treating the disease. (0076) This reads on the claimed method of treating a mammal having a cancer, wherein said method comprises administering nucleic acids encoding transcription factors to cancer cells within said mammal and the number of cancer cells is reduced within said mammal. Glorioso also discloses multiple suggested transgenes to use with their claimed invention, including NeuroD1. (0077) Since transgenes are what codes for the production of transcription factors, this reads on the claimed method of the one or more transcription factors of the claimed invention comprising NeuroD1.
Regarding Claim 2: Glorioso discloses that the invention is able to infect a wide variety of mammalian cells (0061) in vivo and in vitro (0075) including humans to deliver therapeutic transgenes. (0079) This reads on the claimed method of said mammal being a human.
Regarding Claim 17: Glorioso discloses a herpes simplex virus (HSV) vector which does not express toxic native HSV genes and is able to persistently express a transgene. (0041) This reads on the claimed method of said nucleic acids encoding one or more transcription factors administered to said cancer cells in the form of a viral vector.
Regarding Claim 18: Glorioso discloses an example of the invention which uses a retroviral vector to generate U2OS-ICP4/27 cell lines. (0143-0145, Example 12) This reads on the claimed method of the viral vector being a retroviral vector.
Regarding Claim 19: Glorioso discloses use of lentiviral vectors to engineer a source cell type to contain expression constructs encoding the HSV proteins and other proteins of interest. (0067) This reads on the claimed method of use of a lentiviral vector.
Regarding Claim 20: Glorioso discloses the inventive vector may have at least one transgene which is under the control of the promotor which includes the operable connection to insulator sequence(s). (0058) This reads on the claimed method of the nucleic acids being operably linked to a promotor sequence.
Regarding Claim 22: Glorioso discloses a method of parenteral administration, which is known in the art to mean drugs given by routes other than the digestive tract. (0072) Glorioso also discloses a method of injection directly into the hippocampus (0139, Example 10) into a rat. This reads on the claimed method of the administration of said nucleic acids being injected via intraperitoneal, intramuscular, intravenous, intrathecal, intracerebral, intraparenchymal, intratumoral, intranasal, or orally.
Regarding Claim 23: Glorioso discloses a method of the invention to be used in vivo to infect and destroy cancer cells with transgenes such as TNF which enhance tumor killing activity. (0075-0076) This reads on the claimed method of identifying a mammal as having cancer prior to administering the claimed invention.
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 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Glorioso (US 2016O153000A1) in view of Lacomme et al. (NEUROG2 Drives Cell Cycle Exit of Neuronal Precursors by Specifically Repressing a Subset of Cyclins Acting at the G1 and S Phases of the Cell Cycle, 2012)
The teachings of Glorioso are described above. Glorioso teaches use of a HSV vector (0041) which may include one or more operably linked transgenes (0048) which has the ability to infect mammalian cells, including human cells to deliver therapeutic transgene(s). (0079) Glorioso fails to teach use of a NeuroD1 and Neurog2 and Ascl1 polypeptides.
Lacomme et al. teaches the role of Neurog2 as it relates to cell cycle arrest of spinal progenitors and that repression of Neurog2 prevents S phase entry of neural cells and that Neurog2 coordinates cell cycle exit and neuronal differentiation. Lacomme also teaches that Ascl1 sequentially activates cell cycle regulators and therefore controls cell cycle progression. (Pg 2597, Introduction)
Regarding Claims 5 and 6: Glorioso discloses an embodiment of the invention to be used in vitro to cause transgene expression via the HSV vaccine and lists several possible therapeutic transgenes to be delivered, including Ascl1 and NeuroD1. (0058) Glorioso fails to disclose use of Neurog2 as a neuronal transcription factor. Lacomme et al. teaches use of a gain of function strategy via in ovo electroporation in chick neural tubes to identify overall Neurog2 early response genes. (Pg 2598, Results) It was shown that Neurog2 downregulates expression of cell proliferation transcription factors (including MYCN and FOXM1) and that Neurog2 expression results in repression of cell proliferation. (Pg 2600-2601, Results) Lacomme also teaches that Ascl1 sequentially activates both positive and negative cell cycle regulators and therefore manipulation of Ascl1 can impact rate of cellular proliferation through downstream cell cycle regulators. (Pg 2597, Introduction)
It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to use the inventive method of an injectable HSV vaccine to deliver therapeutic transgenes to a subject with the specific transgenes NeuroD1 and Ascl 1 as taught by Glorioso with the transgene Neurog2 taught by Lacomme. One would have had motivation to do so and a reasonable expectation of success due to the teachings of Lacomme, who details that Ascl1 sequentially activates both positive and negative cell cycle regulators and that Neurog2 controls cell cycle regulation through suppression of cell cycle proliferation factors.
Claims 3, 7-8, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Glorioso (US 2016O153000A1) in view of Lang et al. (Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma), 2018) and Chen et al. (FOXG1 Expression is Elevated in Glioma and Inhibits Glioma Cell Apoptosis, 2018).
The teachings of Glorioso are described above.
Lang et al. teaches a method of using a single intratumoral injection of DNX-2401 (a tumor-selective adenovirus) to treat recurrent high-grade gliomas. (Pg 1419, Abstract) Injection of DNX-2401 resulted in tumor necrosis and infiltration of T cells and reduction of tumor size. Injecting intratumorally also allowed for localization of the viral replication and infection process. (Pg 1426, Discussion)
Chen et al. teaches the significance of FoxG1 expression in glioma and its ties to apoptosis in glioma cells. (Pg 778, Abstract) Glioblastoma cells were cultured and transfected via lentivirus with FoxG1 plasmids (Pg 779, Plasmid construction) and subjected to a proliferation assay, apoptosis assay, Western blotting, and real-time PCR. (Pg 779, Materials and Methods)
Regarding Claim 3: Lang et al. teaches treatment of recurrent high-grade gliomas.
Regarding Claims 7, 8, and 21: Glorioso and Lang fail to teach the claimed invention to be injected directly into an environment comprising FoxG1 positive neurons that are non-cancerous. Chen et al. teaches that FoxG1 is elevated in many human glioma tissues (Pg 778, Introduction) and that FoxG1 is elevated in gliomas and negatively regulated glioma cell apoptosis. (Pg 780, Results) Chen also teaches that FoxG1 is known to be a regulator in neural progenitor cell differentiation and regulates regional patterning of the mammalian forebrain. (Pg 778, Introduction) Lang et al teaches a method of direct injection into a glioma tumor to deliver a tumor-selective adenovirus. (Pg 1420, Study Design)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the invention taught by Glorioso of an HSV vector to deliver a therapeutic transgene (such as NeuroD1 or Ascl1) with the teachings of Chen and Lang of intratumoral injection into an environment consisting FoxG1 positive forebrain neurons. One would have been motivated to do so and had a reasonable expectation of success due to the teaching of Lang (which states that injecting intratumorally allows for localized viral delivery) and Chen (which states that FoxG1 is present in neural progenitor cell differentiation and regional patterning in the mammalian forebrain).
Claims 9-16 are rejected under 35 U.S.C. 103 as being unpatentable over Glorioso (US 2016O153000A1) in view of Lang et al. (Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma), 2018), Enane et al. (GATA loss of function in liver cancer impedes precursor to hepatocyte transition, 2017), Feldmann et al. (Albumin synthesis by human liver cells: its morphological demonstration, 1972), and Oh et al. (Directed Differentiation of Pluripotent Stem Cells by Transcription Factors, 2019)
The teachings of Glorioso and Lang are described above.
Enane et al. teaches use of wild-type and missense GATA4 vectors used to transfect cell populations (pg 3532, bottom paragraph and pg 3538, Methods) to show that haploinsufficiency of GATA4 is a cause of hepatocellular carcinoma (HCC) precursor phenotypes in hepatic cells and that GATA4 is a master transcription factor driver of hepatocyte differentiation. (Pg 3528, Results) A cause-effect relationship between GATA4 and HNF4A was discovered which displayed amplification of HNF4A when GATA4 was expressed in HCC cells as opposed to those with an empty control vector. (Pg 3531, Results and pg 3533, Table 5B)
Feldmann et al. teaches that it is well established that liver cells synthesize albumin. (Pg 1036, first paragraph)
Oh et al. teaches that forced induction of FOXA2 will cause hPSCs to differentiate into hepatic endoderm and that HNF4α is a key regulator of liver-specific genes. (Pg 206, Hepatocytes)
Regarding Claims 9 and 10: Enane et al. teaches use of mice which model the somatically acquired liver GATA4 haploinsufficiency of HCC. (Pg 3528, Results) This reads on the claimed method of the cancer is a liver cancer, specifically hepatocellular carcinoma.
Regarding Claims 11-13: Glorioso et al. teaches use of GATA4 as a transgene to use with their claimed invention. (0058) Glorioso fails to teach use of the claimed invention in hepatocellular carcinoma. Enane et al. teaches use of a mouse model of HCC. (Pg 3528, Results) Enane also teaches that GATA4 is a master transcription factor driver of hepatocyte differentiation and that haploinsufficiency of GATA4 is a cause of HCC precursor phenotypes in hepatic cells. (Pg 3528, Results) Enane fails to teach use of FOXA2 and HNF4α as transcription factors.
Oh et al. teaches use of forced induction of FOXA2 causes hPSCs to differentiate into hepatic endoderm and that HNF4α is a key regulator of liver-specific genes. (Pg 206, Hepatocytes) Oh also teaches delivery methods and differentiation efficiencies for said transcription factors. (See Table 4, below)
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the invention taught by Glorioso of a HSV vector expressing GATA4 as a hepatocellular carcinoma treatment method due to the teachings of Enane who shows that haploinsufficiency of GATA4 is a cause of HCC precursor phenotypes in hepatic cells and Oh, who details that FOXA2 and HNF4α are key regulators in hepatocyte differentiation. One would have a reasonable expectation of success and motivation for doing so based on the role of GATA4, FOXA2, and HNF4α as taught by Enane and Oh, which states that GATA4, FOXA2, and HNF4α all influence hepatocyte differentiation.
Regarding Claim 14: Enane et al. teaches use of a mouse model of hepatocellular carcinoma. (Pg 3528, Results) Because the mouse model is a model of HCC, it would additionally comprise normal hepatic cells found in the liver. This reads on the claimed method of the non-cancerous cells being hepatocytes.
Regarding Claims 15 and 16: Feldmann et al. teaches that it is known throughout the art (“well established”) that liver enzymes secrete albumin as part of their normal biological processes. (Pg 1036, first paragraph) This reads on the claimed method of the hepatocytes secreting a liver enzyme and that enzyme being albumin.
Response to Arguments
Examiner has clarified that claim 6, while depending from claim 5, further depends from claim 1 as claim 5 depends on claim 1. Therefore, the 35 U.S.C. 112 rejection regarding indefiniteness pertaining to the phrase “NeuroD1 polypeptide” has been overcome and the argument found persuasive.
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive. Applicant argues that Glorioso fails to disclose conversion of said cancer cells into non-cancerous cells within said mammal in vivo. This is unpersuasive. The teachings of Glorioso revolve around use of TNF and NeuroD1 to be used to transfect cancerous cells either in vitro or in vivo. As Glorioso is teaching use of the NeuroD1 peptide and the result of administration of said peptide resulting in a decrease in the number of cancerous cells within the subject, it is inherent that the mechanism of action disclosed by Glorioso is the same mechanism of action disclosed by the Applicant. As the Applicant claims use of the same transgene used in the same capacity (the reduction of cancerous cells in a subject), regardless of the method used, the mechanism of action is the same and therefore inherent to use of the transgene.
Applicant further argues that Glorioso fails to disclose use of NeuroD1 for use in mammals in vivo. Glorioso states throughout the body of the document that the intended use for the disclosed invention is both in vitro and in vivo, particularly in mammals. While it is true that in the specific paragraph cited by the Applicant (0077) use of NeuroD1 is directed to cells in vitro, it is still inherent that each example disclosed by Glorioso is intended for use in vitro and/or in vivo for the reduction of the number of cancerous cells in a subject.
In addition to this, Applicant references the office action dated 06/04/2025 stating that Examiner wrote “Glorioso fails to teach use of NeuroD1 and Neurog2 and Ascl1 polypeptides.” However, Examiner clarifies that this is in reference to the 35 U.S.C. 103 rejection of claim 5, which requires use of all three polypeptides (as stated in the above Claim Interpretation section) and therefore is irrelevant to the discussion regarding the 35 U.S.C. 102(a)(1) rejections of claims 1, 2, and 17-23 and is considered unpersuasive and moot.
Based on the above discussion, the 35 U.S.C. 102(a)(1) rejections of claims 1, 2, and 17-23 are upheld.
Regarding the 35 U.S.C. 103 rejections, Applicant first argues that Lacomme fails to remedy the deficiencies of Glorioso regarding use of Neurog2 expression in cancer cells. This is unpersuasive. Lacomme teaches use of a gain of function strategy of Neurog2, which in turn downregulates cell proliferation transcription factors. Lacomme further teaches manipulation of Ascl1 impacts the rate of cell proliferation. A person skilled in the art would understand that use of these transgenes is useful in cancer biology, as manipulation of the cell cycle and proliferation transcription factors is already a strategy employed throughout the art in the field of cancer biology. Furthermore, the teachings of Lacomme are intended to be used in the context of the invention as taught by Glorioso, which as discussed above inherently relies on the same mechanism of action as claimed by the Applicant. Therefore, the rejections regarding claims 5 and 6 are upheld.
Following the discussion above, Applicant further claims that the teachings of Lang, Chen, Enane, Feldmann, and Oh fail to remedy Glorioso for their respective claims due to none of the cited prior art pertaining directly to the conversion of hepatocellular carcinoma cells into non-cancerous albumin secreting hepatocytes within a mammal. However as discussed above, Glorioso not only teaches use of the claimed invention both in vivo and in vitro, but it is inherent that the mechanism of action would be the same as Glorioso used the same transgene to target cancerous cells. Furthermore, Glorioso details an example of the invention regarding human hepatocytes and transfection of said cells in Example 8 and references use of the invention in cancerous cells in 0055, 0056, 0075 (in which Glorioso further lists a preferred embodiment of the invention to be used in liver cells), and 0076. As Glorioso inherently teaches the same method as the Applicant, the teachings of Lang, Chen Enane, Feldmann, and Oh are to be incorporated to the method as taught by Glorioso for the following reasons:
Lang teaches use of an intratumor injection which targets and treats high-grand gliomas
Chen correlates the expression of FoxG1 to apoptosis, making it a key transgene of interest in the treatment of cancers
Enane directly relates missense mutations of GATA4 as a cause of hepatocellular carcinoma, making it a key gene of interest for hepatocellular carcinoma
Feldmann teaches that albumin is inherently secreted in liver cells, rendering it relevant to claims 15 and 16 which state that the hepatocytes must secrete albumin (it is further considered inherent that the hepatocytes would secrete albumin, as it is an innate property of hepatocytes, as stated by the Applicant in the Remarks dated 12/03/2025)
Oh states that GATA4, FOXA2, and HNF4α all influence hepatocyte differentiation, rendering the aforementioned genes of interest in the treatment of hepatocellular carcinoma.
In addition to the above discussion, Examiner clarifies that the teachings of Lacomme, Lang, Chen, Enane, Feldmann, and Oh are intended to be taken in the context of Glorioso and be incorporated into the invention as taught by Glorioso, and not as standalone bodies of work. Per MPEP 2141.03.I, "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.”
Per the discussion above, the 35 U.S.C. 103 rejections regarding claims 3, 5-16, and 21 are upheld.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNA M THUESON whose telephone number is (571) 272-3680. The examiner can normally be reached M-F 7:30-5 EST. 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.
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/HANNA MARIE THUESON/ Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638