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 .
Priority
Applicant’s claim to priority from Provisional Application No. 62/952,725 filed 12/23/2019 and PCT/US2020/066557 filed 12/22/2020 is hereby acknowledged.
Application Status
This Application is a National Stage entry application under 35 U.S.C. §371 of PCT/US2020/066557 filed 12/22/2020.
Amendments to claims filed 12/18/2025 are hereby acknowledged.
Claims 6, 8, 16, 18 and 23 are cancelled.
Claims 1, 3-5, 7, 9-12,15, 17, 19-21 and 24-25 are currently amended.
Claims 1-5, 7, 9-15, 17, 19-22 and 24-25 are currently pending.
Therefore, claims 1-5, 7, 9-15, 17, 19-22 and 24-25 are under consideration in this office action.
Any objection or rejection not reiterated herein has been overcome by Applicant’s amendments and is withdrawn. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/30/2022 is hereby acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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, or have been submitted on an IDS, they have not been considered.
Claim Objections
Claim 25 is objected to because of the following informalities: the claim recites:
“(c) TFEC and USF1, TFEC and GATA3, TFEC and RBFOX2, or TFEC and SALL2”. There is no “;” at the end of the sentence and one should be inserted.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 4, it recites “The method of claim 1, wherein increasing and/or decreasing expression of the one or more transdifferentiation determinants in the glioblastoma cells results in reduced growth rate of the glioblastoma cells”. The claim recites an end-result. There is no additional limitation on elements of claim 1, since there is no additional active step for the method of treating glioblastoma.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Arguments
Applicant's arguments filed 12/18/2025 have been fully considered but they are not persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “increasing and/or decreasing expression of one or more of the transdifferentiation determinants can induce an immune response against a glioblastoma”; “ a positive regulator of transdifferentiation, when expressed in a glioblastoma cell can also reduce growth of the glioblastoma cell”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The following rejections are newly added as necessitated by Applicant’s amendments:
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. 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, 5, 7, 9, 11-15, 17, 19, 21-22 and 24 are rejected under 35 U.S.C. §103 as being unpatentable over Ribeiro Lemos Pereira (Ribeiro Lemos Pereira, C.F. et al. WO 2018/185709 A1, published October 11, 2018; previously cited), in view of Zhang ( Zhang, Y. et al. "A 63 signature genes prediction system is effective for glioblastoma prognosis". International Journal of Molecular Medicine, Vol. 41 (2018), pp: 2070-2078) and Tsui (Tsui, C. et al. "Protein kinase C-B dictates B cell fate by regulating mitochondrial remodeling, metabolic reprogramming, and heme biosynthesis". Immunity, Vol. 48 (2018), pp: 1144-1159).
Regarding claims 1 and 12, Ribeiro Lemos Pereira teaches a method of treating a subject in need of treatment using a composition for reprogramming cells into dendritic cells or antigen presenting cells (see title and abstract). Ribeiro Lemos Pereira teaches the isolation of transcription factors that can reprogram or induce differentiated cells into dendritic cells, i.e. transdifferentiation determinants (see [0008]). Ribeiro Lemos Pereira teaches the transdifferentiation of cancer cells, among other cancers, glioblastoma (see [0071], [0084], [00229], [00240]). Ribeiro Lemos Pereira teaches Spi-1 proto-oncogene (PU.1) as one determinant among others, used in composition to transdifferentiate cancer cells into antigen presenting cells (see [00198] and page 92, claims 1-5).
Ribeiro Lemos Pereira also teaches that IKZF1 negatively impact the number of induced dendritic cells generated (see [00163]).
Ribeiro Lemos Pereira teaches that one, two, three, four, five, six, seven, eight or more dendritic cells-inducing factor genes, SPI1 (PU.1), IRF8 and IKZF1 among others, can be encoded and expressed in one or more expression vectors to prepare the induced dendritic cells (see [00251]).
Ribeiro Lemos Pereira teaches the expression of PRKCB as one of the top 500 genes that are differentially expressed in induced dendritic cells. Ribeiro Lemos Pereira teaches that the expression of PRKCB is down regulated in induced dendritic cells at day 9 (see Table 5, [00183], page 54).
Regarding claims 1 and 12, Ribeiro Lemos Pereira does teach PRKCB as a gene with a difference in expression when comparing naïve dendritic cells to the induced dendritic cells (see page 54, Table 5, [00182]). However, Ribeiro Lemos Pereira does not teach PRKCB as one of the determinant of transdifferentiation, which expression needs to be modulated, either increased or decreased by contacting the glioblastoma cells with specific nucleic acid for said effect.
However, Zhang established an effective prognostic prediction system and validated its performance for glioblastoma multiforme using PRKCG, PRKCB and CAMK2A as prognostic factors (see page 2077, right column, last paragraph). Zhang teaches that PRKCB is a tumor promoter gene that modulates the rate of autophagy, which serves as a pro-death or pro-survival mechanism. Therefore, Zhang teaches that PRKCB participates in the regulation of cell survival and apoptosis and is aberrantly expressed in Glioblastoma multiforme, its upregulation being beneficial for patient survival (see page 2077, right column, second paragraph).
Tsui teaches that PRKCB dictates B cell fate (see title) and that lack of PRKCB undermined antibody production and antigen presentation (see abstract). Tsui teaches that transgenic PRKCB-/- mice are severely immunodeficient, with less germinal center B cells, less splenic T cells and plasma cells, compared to wild type mice (see abstract and Figure 1). Tsui teaches that PRKCB instructs plasma cell differentiation in B cells (see page 1147, right column, and Figure 3).
Therefore, it would have been obvious to one with ordinary skills in the art, before the effective filing date, to have combined the teachings of Ribeiro Lemos Pereira with the teachings of Zhang and Tsui, and combined SPI1 or (PU.1) and IKZF1 as taught by Ribeiro Lemos Pereira, with PRKCB as taught by Zhang and Tsui, as transdifferentiation determinants necessary to transform glioblastoma multiforme cells into immune cells/antigen presenting cells. One with ordinary skills in the art, motivated in ensuring that the glioblastoma cells dedifferentiate and enter an immune cell differentiation program, could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Regarding claim 2, Ribeiro Lemos Pereira teaches glioma and glioblastoma (see [0071], [0084], [00240] and Table 2). However, Ribeiro Lemos Pereira does not specify which glioma/glioblastoma.
Examiner interprets that Ribeiro Lemos Pereira teaches all species in the larger genus “Glioblastoma”.
Regarding claim 3, Ribeiro Lemos Pereira teaches overexpression of transdifferentiation determinants such as SPI1 (PU.1) (see [00155], [00160], [00162], [00261]).
Regarding claims 5, 7, 9 and 11, Ribeiro Lemos Pereira teaches one, two, three, four, five, six, seven, eight or more dendritic cells-inducing factor genes, SPI1 (PU.1), IRF8 and IKZF1 among others, encoded and expressed in one or more expression vectors to prepare the induced dendritic cells (see [00251]).
Ribeiro Lemos Pereira teaches BATF3 as one of the determinants encoded by nucleic acids of the invention ([00197], [00251]). Ribeiro Lemos Pereira teaches BCL11A , ID2 , RUNX3, as genes to be expressed in induced dendritic cells ([00251]).
Ribeiro Lemos Pereira teaches a change in expression of some genes such as STAT6 (see [00174], [00180], and Figure 23).
Regarding claim14, Ribeiro Lemos Pereira teaches a method of transdifferentiating cancer cells into antigen presenting cell that are dendritic cell-like cells, comprising administering to the cancer cells one or more nucleic acids, i.e. constructs, that increase or decrease expression of one or more cancer determinant of transdifferentiation ( see [00193]-[00195], [00197]-[00200]).
Regarding claim 13, Ribeiro Lemos Pereira teaches glioma and glioblastoma (see [0071], [0084], [00240] and Table 2). However, Ribeiro Lemos Pereira does not specify which glioma/glioblastoma.
Examiner interprets that Ribeiro Lemos Pereira teaches all species in the larger genus “Glioblastoma” and “glioma”.
Regarding claim 15, 17, 19 and 21, Ribeiro Lemos Pereira teaches one, two, three, four, five, six, seven, eight or more dendritic cells-inducing factor genes, such as IRF8 among others, encoded and expressed in one or more expression vectors to prepare the induced dendritic cells (see [00251]).
Ribeiro Lemos Pereira teaches BATF3, BCL11A , ID2 , RUNX3, as genes to be expressed in induced dendritic cells ([00251]).
Ribeiro Lemos Pereira teaches a change in expression of some genes such as STAT6 (see [00174], [00180], and Figure 23).
Regarding claim 22, Ribeiro Lemos Pereira teaches viral vectors, including lentiviral vector (see page 94, Ribeiro Lemos Pereira’s claim 14; [0024]). Ribeiro Lemos Pereira also teaches plasmids (see [00195], [00203]).
Regarding claim 24, Ribeiro Lemos Pereira teaches a method increasing expression of one or more transdifferentiation determinants in cancer cells, which include glioma and glioblastoma cells, resulting in induction of an immune response against the cancer cells (see [0057]-[0062], [0084], [00240], [00249]-[00252] and claims 1-6).
The obviousness of the combination of references Ribeiro Lemos Pereira, Zhang and Tsui is described above, therefore the combination of references also renders elements of the depending claims 2-3, 5, 7, 9, 11, 13-15, 17, 19, 21-22 and 24 obvious.
Claims 10, 20 and 25 are rejected under 35 U.S.C. § 103 as being unpatentable over Ribeiro Lemos Pereira (Ribeiro Lemos Pereira, C.F. et al. WO 2018/185709 A1, published October 11, 2018; previously cited), Zhang ( Zhang, Y. et al. "A 63 signature genes prediction system is effective for glioblastoma prognosis". International Journal of Molecular Medicine, Vol. 41 (2018), pp: 2070-2078) and Tsui (Tsui, C. et al. "Protein kinase C-B dictates B cell fate by regulating mitochondrial remodeling, metabolic reprogramming, and heme biosynthesis". Immunity, Vol. 48 (2018), pp: 1144-1159), as applied to claims 5, 9 and 19 above and in further view of Collombet (Collombet, S. et al. “Logical modeling of lymphoid and myeloid cell specification and transdifferentiation”. PNAS, Vol. 114, No. 23 (2017), pp: 5792-5799; previously cited), Xu (Xu, W. et al. “E2A transcription factors limit expression of GATA3 to facilitate T lymphocyte lineage commitment”. Blood, Vol. 121, No. 9 (2013), pp: 1534-1542; previously cited), Rehli-1 (Rehli, M. et al. “Transcriptional regulation of CHI3L1, a marker gene for late stage of macrophage differentiation”. The Journal of Biochemical Chemistry, Vol. 278, No. 45 (2003), pp: 44058-44067; previously cited) and Rehli-2 (Rehli, M. et al. “TFEC is a macrophage-restricted member of the Microphthalmia-TFE subfamily of Basic Helix-Loop-Helix Leucine Zipper transcription factors”. The Journal of Immunology,Vol.162 (1999), pp: 1559-1565; previously cited).
The rejections of claims 5, 9 and 19 are described above. It is noted that claims 5, 9 and 19 are rendered obvious by the combination of Ribeiro Lemos Pereira, Zhang and Tsui.
Regarding claims 10 and 20, they recite “ wherein the one or more additional transdifferentiation determinants are selected from the group consisting of: CTSZ, TFEC, USF1, GATA3, RBFOX2, and SALL2.”
Regarding claim 25, it recites specific combinations of determinants:
CTSZ, TFEC, USF1, GATA3, or RBFOX2;
CTSZ and TFEC, CTSZ and USF1, CTSZ and GATA3, or CTSZ and RBFOX2;
TFEC and USF1, TFEC and GATA3, TFEC and RBFOX2, or TFEC and SALL2
USF1 and GATA3, USF1 and RBFOX2, or USF1 and SALL2; or
GATA3 and RBFOX2, or GATA3 and SALL2.
The combination of references Ribeiro Lemos Pereira, Zhang and Tsui does not render obvious the specific transdifferentation determinants CTSZ, TFEC, USF1, GATA3, RBFOX2, and SALL2.
However, regarding claims 10, 20 and 25 (a)-(c), Rehli-1 teaches that several known transcription factors are needed and specifically bind the promoter of a specific late stage marker of macrophage differentiation, CHI3L1 (see title and abstract). Rehli-1 teaches that these transcription factors are PU.1 (i.e. SPI1), Sp1, Sp3 and USF (see abstract). Rehli-1 teaches that complexes containing SP1, Sp3, USF1 and USF2a were detectable in supershift analysis (see Figure 5C and page 44063, left column).
Therefore, Rehli-1’s teachings indicate that transcription factors associated with terminal differentiation in antigen presenting cells such as macrophages include USF1.
Regarding claims 10, 20 and 25 (a), (c) and (d), Collombet teaches about factors important in myeloid cell specification and transdifferentiation (see title and abstract). Collombet teaches the transcription factors needed for different stages of cell lineage commitment as seen in Figure 1 and below:
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Collombet teaches that Spi1 (PU.1) and IKZF1 (Ikaros) are important determining transcription factors that are active in cell commitment towards common lymphoid progenitor cells and monocyte lineages (see above, and Figure 1A).
Collombet teaches that E2a is as important as Ikaros for commitment into common lymphoid progenitor lineage (see Figure 1A and Figure 3). Collombet teaches that E2a is known to be a master regulator of lymphoid and myeloid cell specification (see page 5798, right column, second paragraph). Collombet refers to reference #38 for this teaching; reference #38 is Xu.
Xu teaches that E2a targets GATA3 gene expression (see title). Xu teaches that overexpression of GATA3 extends the self-renewal capacity of thymocytes (DN2 cells) and increases the propensity to inhibits a T-cell lineage commitment ( see page 1535, left column, first paragraph).
Therefore, according to Collombet and Xu’s teachings, overexpression of GATA3 together with Ikaros (IKZF1) will likely block the common lymphoid progenitor (see Figure 1A) commitment towards T cell differentiation, and favor the commitment towards pre-B lineages capable of transdifferentiating into antigen presenting cells.
Collombet and Xu’s teachings also suggest that overexpression of GATA3 and Ikaros together with SPI1 will certainly redirect any transdifferentiation towards antigen presenting cells.
Regarding claims 10, 20 and 25 (a), (c),(d), Rehli-2 teaches that TFEC is a macrophage-restricted transcription factor (see title and abstract). Rehli-2 teaches that PU.1 (SPI1) is necessary for gene expression regulation of TFEC gene in macrophages. Rehli-2 teaches that TFEC might itself individually or in concert with other transcription factors in the same family play a role in macrophage-specific gene regulation (see abstract; see page 1560, left column, 4th paragraph).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the transcription factors Spi1 (PU.1) and Ikaros (IKZF1) as taught by Ribeiro Lemos Pereira, with PRKCB as taught by Zhang and Tsui, with an additional gene such as USF1 as taught by Rehli-1, or GATA3 gene as taught by Collombet/Xu, or TFEC gene as taught by Rehli-2. One with ordinary skills in the art, motivated in insuring that the cells commit to an antigen presenting cells lineage to enhance the chances of producing cells that are effective for adoptive cell transfer and immunotherapy for glioma or glioblastoma could have performed this modification with a reasonable expectation of success based on the teachings of Rehli-1, Collombet/Xu and Rehli-2. One motivated in a high rate of cell transdifferentiation into macrophages could have combined the teachings of Ribeiro Lemos Pereira modified with Zhang and Tsui, with the teachings of Rehli-1, Collombet, Xu and Rehli-2 since all the references are drawn to markers specific for cell lineage commitment and/or transdifferentiation. One with ordinary skills in the art could have used Spi1, Ikaros, PRKCB, USF1, GATA3, and TFEC genes in one or more expression vector and transformed the cancer cells into antigen presenting cells and arrived at the claimed invention.
Response to Arguments
Applicant's arguments filed 12/18/2025 have been fully considered but they are not persuasive.
In response to Applicant’s argument on page 12 of Remarks, stating “None of the cited reference disclose or suggest the combination of SP11, IKZF1, and PRKCB”, the new rejections under 35 U.S.C. §103 of claims 1-3, 7, 9, 11-15, 17, 19, 21-22 and 24 are based on a new combination of references, Ribeiro Lemos Pereira, Zhang and Tsui, that teach SPI1, IKZF1 and PRKCB. Claims 10, 20 and 25 are rejected under 35 U.S.C. §103 as unpatentable over Ribeiro Lemos Pereira, Zhang, Tsui, in further view of Collombet/Xu, Rehli-1 and Rehli-2. Thus, the newly cited references, in combination with Ribeiro Lemos Pereira, disclose the combination of SP11, IKZF1, and PRKCB. Therefore, the claims are deemed to be obvious over the new combination of references.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/A.D./Examiner, Art Unit 1636 /NANCY J LEITH/Primary Examiner, Art Unit 1636