DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of Group I, claims 1-18, drawn to a method of inducing apoptosis in the reply filed on 02/04/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 19-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse (see above) in the reply filed on 02/04/2026.
Claims 5, 12, and 14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse (see above) in the reply filed on 02/04/2026.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
STATUS OF CLAIMS
Claims 1-20 are pending. Claims 5, 12, 14, and 19-20 are withdrawn by the examiner as being drawn to non-elected invention(s) and/or species. Claims 1-4, 6-11, 13, and 15-18 are under examination in this office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) filed 6/21/2022 is acknowledged.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 6, 8-10, 15, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO-2020010188-A1 (provided in IDS, herein Chang), as evidenced by US-20200069818-A1 (herein Jaskula-Ranga).
Regarding claims 1-2, Chang teaches a method of inducing apoptosis in at least one cell ([0002]: alternating electric fields at these frequencies are often referred to as “tumor treating fields” or “TTFields.”” claim 23: “applying a second alternating electric field at a second frequency to the cancer cells for a second period of time, wherein the second frequency is different from the first frequency, and wherein the second alternating electric field at the second frequency reduces viability of the cancer cells.” [0047]: “the term “reducing viability” of a cell refers to reducing the growth, proliferation, or survival of the cell, or increasing cytotoxicity of the cell.” [0059]: “Annexin-V-APC binding is a signature of early apoptosis which is characterized by ruffling of the membrane.” [0094]: “72 h of TTFields exposure induced cell death with a marked proportion of Annexin V-positive cells.”), the method comprising the steps of:(1) applying an alternating electric field to the at least one cell for a period of time, wherein application of the alternating electric field downregulates at least one DNA damage repair pathway in the at least one cell (claim 23: “applying a first alternating electric field at a first frequency to the cancer cells for a first period of time, wherein application of the first alternating electric field at the first frequency to the cancer cells for the first period of time increases permeability of cell membranes of the cancer cells” and see above regarding claim 23; [0004]: “reported prolongation of DNA damage by chemotherapy or radiotherapy in conjunction with TTFields”); and (2) exposing the at least one cell to a clustered regularly interspaced short palindromic repeats (CRISPR) associated protein (CRISPR-Cas) system comprising: a single guide RNA (sgRNA) that comprises a guide sequence that hybridizes to a target DNA sequence in the at least one cell; and a CRISPR-associated endonuclease or gene encoding same (claim 23: “introducing a substance to the cancer cells, wherein the increased permeability of the cell membranes enables the substance to cross the cell membranes.” [0131]: “ techniques described herein can also be used to enable substances that ordinarily could not traverse the cell membrane to a significant extent to enter the cell. Examples of this class of substances discussed above include…(e) genome editing system including but not restricted to meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR/Cas9)…” and as evidenced by Jaskula-Ranga a CRISPR-Cas system necessarily includes at least one gRNA, see claim 1: “(a) providing a non-naturally occurring nuclease system comprising one or more vectors comprising: i) a promoter operably linked to at least one nucleotide sequence encoding a nuclease system guide RNA (gRNA), wherein the gRNA hybridizes with a target sequence of a DNA molecule in a cell of the subject, and wherein the DNA molecule encodes one or more oncogene products expressed in the cell; and ii) a regulatory element operable in a cell operably linked to a nucleotide sequence encoding a genome-targeted nuclease.”).
Regarding claim 6 and 17, Chang teaches wherein at least one of: the alternating electric field is applied at a frequency in a range of from about 100 kHz to about 10 MHz; and the alternating electric field has a field strength of at least 1 V/cm (claim 24: “the first frequency is between 250 kHz and 350 kHz, and the second frequency is between 150 kHz and 250 kHz” and claim 25: “the first frequency is between 125 kHz and 175 kHz…” and claim 26: “ … the second frequency is between 100 kHz and 300 kHz” and claim 31: “wherein the first alternating electric field has a field strength of at least 1 V/cm RMS.”); and the period of time that the alternating electric field is applied is in a range of from about 24 hours to about 72 hours (claim 49: “wherein the interval of time is between 12 and 72 hours”); and are repeated one or more times ([0101]: “application of the alternating electric fields may be repeated periodically.”).
Regarding claims 8-10, Chang teaches a method of treating or reducing the occurrence of at least one condition, disease, disorder, or infection in a subject (claim 35: “a method for treating a tumor in a subject’s body and delivering a substance across cell membranes in the subject’s body” and claim 36: “wherein the tumor comprises a glioblastoma in the subject’s brain”), the method comprising the steps of:(1) applying an alternating electric field to at least a portion of the subject for a period of time, wherein application of the alternating electric field downregulates at least one DNA damage repair pathway in at least a portion of the subject; and (2) administering to the subject a clustered regularly interspaced short palindromic repeats (CRISPR) associated protein (CRISPR-Cas) system comprising: a single guide RNA (sgRNA) that comprises a guide sequence that hybridizes to a target DNA sequence associated with the at least one condition, disease, disorder, or infection; and a CRISPR-associated endonuclease or gene encoding same (claim 35: “applying a first alternating electric field at a first frequency to the subject’s body for a first period of time, wherein application of the first alternating electric field at the first frequency to the subject’s body for the first period of time increases permeability of the cell membranes in the subject’s body; administering the substance to the subject, wherein the increased permeability of the cell membranes enables the substance to cross the cell membranes; and applying a second alternating electric field at a second frequency to the subject’s body for a second period of time that is at least one week long, wherein the second frequency is different from the first frequency, and wherein the second alternating electric field at the second frequency inhibits growth of the tumor” and [0131]: “techniques described herein can also be used to enable substances that ordinarily could not traverse the cell membrane to a significant extent to enter the cell. Examples of this class of substances discussed above include…(e) genome editing system including but not restricted to meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR/Cas9)…” and as evidenced by Jaskula-Ranga a CRISPR-Cas system necessarily includes at least one gRNA, see claim 1: “(a) providing a non-naturally occurring nuclease system comprising one or more vectors comprising: i) a promoter operably linked to at least one nucleotide sequence encoding a nuclease system guide RNA (gRNA), wherein the gRNA hybridizes with a target sequence of a DNA molecule in a cell of the subject, and wherein the DNA molecule encodes one or more oncogene products expressed in the cell; and ii) a regulatory element operable in a cell operably linked to a nucleotide sequence encoding a genome-targeted nuclease.); and wherein the CRISPR-associated endonuclease is selected from the group consisting of Cas3, Cas9, Cas12, Cas12a, Cas12b, Cas12e, Cas12f, Cas13a, Cas13b, mini-Cas9, and Cas9 nickase (nCas9), see reference to [0131] of Chang above; and wherein the at least one condition, disease, disorder, or infection is selected from the group consisting of a cancer, see reference to claim 36 of Chang above.
Regarding claim 15, Chang teaches wherein the CRISP-Cas system is administered about 24 hours to about 48 hours after application of the alternating electric field has begun ([0132: “methods described herein may be useful to deliver large molecules (which ordinarily would not pass through the relevant cell membrane) through a cell membrane…delivery of such drugs can be enhanced by applying alternating electric fields to the relevant body part for a period of time (e.g., 24 hours) prior to and during administration those drugs” and [0133]: “it may be possible to achieve localized enhancement of drug uptake in bacteria by applying alternating electric fields to the relevant body part for a period of time (e.g., 24 hours) prior to and during administration of a suitable antibiotic…similar approaches may be used to enhance drug uptake to combat meningitis, pneumonia, infective endocarditis, etc… the alternating electric fields may be applied it to a target region that contains a tumor (e.g., a brain that includes a glioblastoma); and Claim 38: “ the step of administering the substance begins at a given time, and wherein the step of applying the first alternating electric field ends at least 12 hours after the given time” and claim 39: “ the step of applying the first alternating electric field begins at least one hour before the given time.”).
Claims 1-2, 6, 8-10, and 15-17 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US-20220203088-A1 (herein VS).
Regarding claim 1-2 and 8-9, VS teaches a method of inducing apoptosis, the method comprising the steps of: (1) applying an alternating electric field to the at least one cell (or a subject as in claim 8-9) for a period of time, wherein application of the alternating electric field downregulates at least one DNA damage repair pathway in the at least one cell; and (2) exposing the at least one cell to a clustered regularly interspaced short palindromic repeats (CRISPR) associated protein (CRISPR-Cas) system comprising: a single guide RNA (sgRNA) that comprises a guide sequence that hybridizes to a target DNA sequence in the at least one cell; and a CRISPR-associated endonuclease or gene encoding same; and wherein the CRISPR-associated endonuclease is…Cas9 (claim 33: “A method for reducing the viability of a cell, the method comprising: applying a first alternating electric field at a first frequency to the cell for a first period of time, wherein application of the first alternating electric field at the first frequency to the cell for the first period of time increases permeability of the cell membranes of the cell; introducing a vector to the cell, wherein the increased permeability of the cell membranes enables the vector to cross the cell membrane; and applying a second alternating electric field at a second frequency to the cell for a second period of time, wherein the second frequency is different from the first frequency, and wherein the second alternating electric field at the second frequency reduces viability of the cell;” claim 35: “ the cell is a cancer;” claim 38: “wherein the first frequency is between 50 kHz and 350 kHz, and the second frequency is between 75 kHz and 300 kHz;” [0064]: “A “sequence of interest” means a peptide or polypeptide sequence (e.g., a therapeutic protein), that is expressed from a nucleic acid sequence;” [0065]: “the sequence of interest is a selectable marker, detectable marker, or a therapeutic agent;” [0136]: “the therapeutic agent can be a pro-apoptotic factor… a cytokine, p53, a suicide gene, and/or an activator of known apoptosis genes;” [0068]: “a therapeutic agent can be, but is not limited to cDNA, DNA, mRNA, micro RNA, shRNA, siRNA, ribozyme, a guide RNA molecule (gRNA), an RNA-guided endonuclease protein or a Cas9 protein or a Cpf1 protein CRISPR-Cas;” [0085]: “the methods comprise introducing a vector to a subject… a subject comprises a cell that is the target site for the disclosed vectors;” and [0028]: the term “treat” “is meant to administer or apply a therapeutic, such as alternating electric fields and a vector, to a subject, such as a human or other mammal (for example, an animal model), that has an infection (e.g. viral) or disease (e.g. cancer) or has an increased susceptibility for developing an infection or disease, in order to prevent or delay a worsening of the effects of the disease or infection, or to partially or fully reverse the effects of the infection or disease.”).
Regarding claim 6 and 17, VS teaches at least one of: the alternating electric field is applied at a frequency in a range of from about 100 kHz to about 10 MHz; and the alternating electric field has a field strength of at least 1 V/cm; and the period of time that the alternating electric field is applied is in a range of from about 24 hours to about 72 hours, and steps (1) and (2) are repeated one or more times ([0089-0090]: “In some aspects, the alternating electric fields can be applied for a variety of different intervals ranging from 0.5 hours to 72 hours. In some aspects, a different duration can be used (e.g., between 0.5 hours and 14 days). In some aspects, application of the alternating electric fields can be repeated periodically. For example, the alternating electric fields can be applied every day for a two-hour duration. In some aspects, the exposure may last for at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, or at least 72 hours or more;” [0088]: “In some aspects, the field strength of the alternating electric fields can be between 1 and 4 V/cm RMS. In some aspects, different field strengths can be used (e.g., between 0.1 and 10 V/cm). In some embodiments the field strength is at least 1 V/cm RMS.”).
Regarding claim 10, VS teaches the at least one condition, disease, disorder, or infection is a cancer (claim 35: “the cell is a cancer”).
Regarding claims 15-16, VS teaches the CRISP-Cas system is administered about 24 hours to about 48 hours after application of the alternating electric field has begun, and/or the CRISP-Cas system is administered after the period of time has elapsed ([0098-0099]: “In some aspects, the step of introducing the composition or vector begins at a given time, and wherein the step of applying the alternating electric field ends at least 12 hours after the given time. In some aspects, the step of applying the alternating electric field begins at least one hour before the given time. In some aspects, the step of applying the alternating electric field begins at least one to around twenty-four hours before the given time. In some aspects, applying the alternating electric field and introducing the composition or vector occur simultaneously. In some aspects, applying the alternating electric field and introducing the composition or vector occur consecutively. In some aspects, applying the alternating electric field occurs prior to introducing the composition or vector.”).
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 1-4, 6-11, 13, and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., (WO-2020010188-A1, provided in IDS) in view of Jaskula-Ranga V. et al., (US-20200069818-A1), Kim et. al., (Oncotarget, Vol. 7, No. 38, 62267-62279, published 08/19/2016), and Schon EA. (US-5866337-A).
Regarding claims 1-2, 6, 8-10, and 15-17, the teaching of Chang are incorporated herein by reference to the corresponding 102 rejection above.
Regarding claim 7, Chang teaches the at least one cell is part of a biological tissue (claim 30: “wherein the cancer cells are disposed in a body of a living subject”).
Regarding claim 11, Chang teaches a method of treating or reducing the occurrence of at least one condition, disease, disorder, or infection in a subject, wherein the at least one condition, disease, disorder, or infection is a cancer (claim 35: “ method for treating a tumor in a subject’s body and delivering a substance across cell membranes in the subject’s body;” the “alternating electric field… inhibits growth of the tumor;” and claim 36: “ the tumor comprises a glioblastoma in the subject’s brain.”).
Chang does not teach: the target DNA sequence is an oncological gain of function gene mutation in an oncogene; the target DNA sequence is directed to an oncological gain of function mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA); the step of examining a sample of the biological tissue and identifying the target DNA sequence in the sample; and ceasing the alternating electrical fields prior to administering the CRISPR/Cas9 system.
Kim teaches “Alternating electric fields at an intermediate frequency (100~300 kHz), referred to as tumor-treating fields (TTF), are believed to interrupt the process of mitosis via apoptosis and to act as an inhibitor of cell proliferation” (see abstract). Kim teaches TTF are synergistic when combined “with other treatment techniques” such as “ionizing radiation (IR)” (see abstract), which “is known to result in DNA damage, including double strand breaks (DSBs)” (see The effect of TTF on cell function: TTF vs. IR vs. TTF+IR). Kim teaches “cell apoptosis, DNA damage, and mitotic abnormalities were quantified after the application of TTF, and their percentages were markedly increased when TTF was combined with IR,” see abstract. Kim teaches that the additional DNA damaging therapy of IR was administered after the TTFields were ceased (Materials and Methods, Detection of apoptotic cells through annexing V staining: “After TTF exposure for 24 h, the cells were treated with IR and then incubated for a further 24 h, 48 h and 72 hr.”). Kim teaches that TTF downregulates a DNA repair pathway specifically through caspase-3 activation leading to cleavage of PARP-1 (see TTF-induced apoptosis paragraph 2 and Figure 1e-1f). Kim further teaches that “TTF-induced apoptosis involves the p53-dependent pathway;” thus, “apoptosis induced by TTF were through subsequent activation of caspase pathway in a p53-dependent manner” (see TTF-induced apoptosis paragraph 2). Kim teaches that TTF + IR result in other cellular processes that contribute to the induction of apoptosis, see Figure 5c as a summary copied below:
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However, Kim does not teach combining TTF specifically with CRISPR/Cas systems especially adapted to target a mutation in PIK3CA oncogene.
Jaskula-Ranga teaches a CRISPR/Cas system that targets PIK3CA oncogene. Specifically, Jaskula-Ranga teaches “a method for preventing, inhibiting, or treating cancer in a subject in need thereof, the method comprising: (a) providing a non-naturally occurring nuclease system comprising one or more vectors comprising: i) a promoter operably linked to at least one nucleotide sequence encoding a nuclease system guide RNA (gRNA), wherein the gRNA hybridizes with a target sequence of a DNA molecule in a cell of the subject, and wherein the DNA molecule encodes one or more oncogene products expressed in the cell; and ii) a regulatory element operable in a cell operably linked to a nucleotide sequence encoding a genome-targeted nuclease, wherein components (i) and (ii) are located on the same or different vectors of the system, wherein the gRNA targets and hybridizes with the target sequence and the nuclease cleaves one or both strands of the DNA molecule to alter expression of the one or more gene products; and (b) administering to the subject a therapeutically effective amount of the system” (see Claim 1). Jaskula-Ranga further teaches “wherein the target sequence is an oncogene comprising at least one mutation,” (see claim 20), and more specifically, “wherein the target sequence is an oncogene selected from KRAS, PIK3CA, or IDH1” (see claim 22) and “wherein the target sequence is an oncogene, said oncogene is PIK3CA” (see claim 26 and FIG. 5 A&B). Furthermore, Jaskula-Ranga teaches that “apoptosis is enhanced or increased in the cell” (see [0095]). Jaskula-Ranga teaches CRISPR/Cas systems are advantage over other strategies such as small molecules that aim to cause synthetic lethality to DNA damage in that the gRNAs of the CRISPR/Cas system “are highly specific for mutant alleles and would therefore have little effect on cells that harbor wild type alleles,” see [0109]. Jaskula-Ranga provides comprehensive lists of targetable oncogenes and cancer driver genes, see [0111, 0120, 0121, and 0157]. Jaskula-Ranga teaches “the CRISPR complex … has a wide variety of utility including modifying (e.g., deleting, inserting, translocating, inactivating, activating) a target polynucleotide in a multiplicity of cell types,” see [1082].
However, Jaskula-Ranga does not teach the step of examining a sample of the biological tissue and identifying the target DNA sequence in the sample.
Schon teaches “a method for detecting a mutation in a nucleic acid molecule,” see abstract. Specifically, “a method for detecting the presence or absence of a predefined mutation characterized by the presence of a predefined nucleotide at a predefined position in a nucleic acid molecule associated with a genetic disorder in a subject…,” see claim 25. Schon teaches the methods “have utility in the detection of a specific DNA or RNA target in, for example, Southern analysis, Northern analysis, in situ hybridization to tissue sections,” see DETAILED DESCRIPTION OF THE INVENTION paragraph 14.
Regarding claims 1-4, 6, 8-11, 13, 15, and 17, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the method of Chang to employ (either during or after applying TTFields) a CRISPR/Cas system adapted to target a mutation within an oncogene, such as PIK3CA, as taught by Jaskula-Ranga, and to further include examining a biological sample to identify the presence of the target mutation as taught by Schon. One would have had a reasonable expectation of success because Chang teaches a framework to treat cancer cells in which alternating electric fields (TTFields) are applied to increase cell membrane permeability, enhance delivery of therapeutic agents including genome editing systems such as CRISPR/Cas9, and decrease the viability of the cancer cells. While Jaskula-Ranga teaches the CRISPR/Cas systems can be specifically designed to target oncogenic mutations, including mutations in PIK3CA, and that such targeting results in selective modulation of cancer cells and induction of apoptosis. One of ordinary skill in the art would have been motivated to utilize the mutation-specific targeting capability of CRISPR/Cas systems in the Chang method in order to increase therapeutic specifically and selectively target cancer cells harboring oncogenic mutations while minimizing effects on normal cells, which is an art recognized goal in cancer therapy. Furthermore, Chang expressly teaches that TTFields enhance cellular uptake of large molecules, thereby providing a suitable delivery mechanism for CRISPR/Cas components, and Kim teaches that TTFields induce DNA damage and apoptosis and are synergistic with additional DNA-damaging modalities, Accordingly, it would have been obvious to combine TTFields with CRISPR/Cas-mediated targeting of oncogenic mutations to achieve enhanced induction of apoptosis through both increased DNA damage and disruption of oncogenic pathways.
Regarding claim 16, it would have further been obvious to modify the timing of administering the substance in the methods of Chang to administer the CRISPR/Cas system after ceasing the TTFields. One would have a reasonable expectation of success because Kim teaches administering a therapy that further induces DNA damage after administering the TTFields. A person of ordinary skill in the art would have been motivated to administer the CRISPR/Cas system to generate additional DNA damage in a step-wise fashion after the application of TTFields in order to achieve an additive if not even a synergistic effect toward causing cancer cells to enter apoptosis.
Regarding claims 7 and 18, it would have been obvious to include the step of examine a biological sample and identifying the presence of the target mutation prior to CRISPR targeting, as taught by Schon, because identification of a target nucleic acid sequence in a sample was well-known and routine prerequisite to designing sequence-specific targeting reagents, including guide RNAs. Thus, incorporating such a step into the combined method merely represents the application of a known technique to ensure proper target selection and would have been obvious to try with a reasonable expectation of success.
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.
Claim 1-4, 6-11, 13, and 15-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-20 of U.S. Patent No. US-11103698-B2 in view of Jaskula-Ranga V. et al., (US-20200069818-A1), Kim et. al., (Oncotarget, Vol. 7, No. 38, 62267-62279, published 08/19/2016), and Schon EA. (US-5866337-A).
Regarding claims 1, 2 and 9, the claims of US-11103698-B2 teach a method of inducing apoptosis, the method comprising the steps of: (1) applying an alternating electric field to the at least one cell for a period of time, wherein application of the alternating electric field downregulates at least one DNA damage repair pathway in the at least one cell (claim 16: “applying an electric field at a second frequency between 50 and 500 kHz to the tumor, wherein the second frequency is selected to reduce viability of the cells in the tumor;” wherein “reduce viability of the cell” is defined as “reducing the growth, proliferation, or survival of the cell, or increasing cytotoxicity of the cell,” see DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS, first paragraph); and (2) exposing the at least one cell to a clustered regularly interspaced short palindromic repeats (CRISPR) associated protein (CRISPR-Cas) system comprising: a single guide RNA (sgRNA) that comprises a guide sequence that hybridizes to a target DNA sequence in the at least one cell; and a CRISPR-associated endonuclease or gene encoding same is Cas9 (claim 16: “a method for treating a tumor in a subject's body and facilitating delivery of a substance across cell membranes in the subject's body… applying an electric field at the first frequency between 50 and 500 kHz to the tumor for an interval of time, wherein the first frequency is selected to increase permeability of the cell membranes…,” wherein “a substance” is disclosed to be including but not limited to “genome editing system including but not restricted to meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR/Cas9),” see DISCUSSION paragraph 44).
Regarding claim 6 and 17, the claims of US-11103698-B2 teach at least one of: the alternating electric field is applied at a frequency in a range of from about 100 kHz to about 10 MHz; and the alternating electric field has a field strength of at least 1 V/cm ( claim 16: “applying an electric field at the first frequency between 50 and 500 kHz to the tumor for an interval of time ,” and claim 17: “the first frequency is between 250 kHz and 350 kHz, and the second frequency is between 150 kHz and 250 kHz”); and the period of time that the alternating electric field is applied is in a range of from about 24 hours to about 72 hours (claim 16: “the interval of time is at least 12 hours,” and claim 20: “ the interval of time is between 12 and 72 hours), steps (1) and (2) are repeated one or more times (claim 16: “accepting a request to switch to a first frequency… automatically reverting to applying the electric field at the second frequency to the tumor when the interval of time has elapsed”).
Regarding claim 8, the claims of US-11103698-B2 teach a method of treating or reducing the occurrence of at least one condition, disease, disorder, or infection in a subject, the method comprising the steps of:(1) applying an alternating electric field to at least a portion of the subject for a period of time, wherein application of the alternating electric field downregulates at least one DNA damage repair pathway in at least a portion of the subject (claim 16: “applying an electric field at a second frequency between 50 and 500 kHz to the tumor, wherein the second frequency is selected to reduce viability of the cells in the tumor;” wherein “reduce viability of the cell” is defined as “reducing the growth, proliferation, or survival of the cell, or increasing cytotoxicity of the cell,” see DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS, first paragraph); and (2) administering to the subject a clustered regularly interspaced short palindromic repeats (CRISPR) associated protein (CRISPR-Cas) system comprising: a single guide RNA (sgRNA) that comprises a guide sequence that hybridizes to a target DNA sequence associated with the at least one condition, disease, disorder, or infection; and a CRISPR-associated endonuclease or gene encoding same (claim 16: “a method for treating a tumor in a subject's body and facilitating delivery of a substance across cell membranes in the subject's body… applying an electric field at the first frequency between 50 and 500 kHz to the tumor for an interval of time, wherein the first frequency is selected to increase permeability of the cell membranes…,” wherein “a substance” is disclosed to be including but not limited to “genome editing system including but not restricted to meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR/Cas9),” see DISCUSSION paragraph 44).
Regarding claim 10, the claims of US-11103698-B2 teach the at least one condition, disease, disorder, or infection is a cancer (claim 16: “the second frequency is selected to reduce viability of the cells in the tumor”).
The claims of US-11103698-B2 further teach:
wherein the first frequency is between 250 kHz and 350 kHz, and the second frequency is between 150 kHz and 250 kHz;
wherein the first frequency is between 125 kHz and 175 kHz, and the second frequency is between 75 kHz and 125 kHz;
wherein the first frequency is between 75 kHz and 175 kHz, and the second frequency is between 100 kHz and 300 kHz; and
wherein the interval of time is between 12 and 72 hours.
To the extent that there are limitations of the instant claims that are not taught by the claims of US-11103698-B2, the teachings of Jaskula-Ranga, Kim, and Schon are discussed above.
Given the substantially similar subject matter between the claims of US-11103698-B2 and the
teachings of Jaskula-Ranga, Kim, and Schon endure, it would have been obvious to have
modified the subject matter of the claims in US-11103698-B2 in the manner discussed above to arrive at the instant claims for substantially the same reasons as discussed above.
Claim 1-4, 6-11, 13, and 15-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. US-11529511-B2 in view of Jaskula-Ranga V. et al., (US-20200069818-A1), Kim et. al., (Oncotarget, Vol. 7, No. 38, 62267-62279, published 08/19/2016), and Schon EA. (US-5866337-A).
Regarding claim 1, the claims of US-11529511-B2 teach a method of inducing apoptosis, the method comprising the steps of: (1) applying an alternating electric field to the at least one cell for a period of time, wherein application of the alternating electric field downregulates at least one DNA damage repair pathway in the at least one cell; and (2) exposing the at least one cell to a clustered regularly interspaced short palindromic repeats (CRISPR) associated protein (CRISPR-Cas) system comprising: a single guide RNA (sgRNA) that comprises a guide sequence that hybridizes to a target DNA sequence in the at least one cell; and a CRISPR-associated endonuclease or gene encoding same (claim 1: “A method for attacking cancer cells, the method comprising: applying a first alternating electric field at a first frequency to the cancer cells for a first period of time, wherein application of the first alternating electric field at the first frequency to the cancer cells for the first period of time increases permeability of cell membranes of the cancer cells; introducing a substance to the cancer cells, wherein the increased permeability of the cell membranes enables the substance to cross the cell membranes; and applying a second alternating electric field at a second frequency to the cancer cells for a second period of time, wherein the second frequency is different from the first frequency, and wherein the second alternating electric field at the second frequency reduces viability of the cancer cells;” wherein “a substance” is disclosed to be including but not limited to “genome editing system including but not restricted to meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR/Cas9),” see column 23 lines 30-50).
Regarding claims 2 and 9, the claims of US-11529511-B2 teach the CRISPR-associated endonuclease is…Cas9 (claim 10: “administering the substance to the subject” wherein “a substance” is disclosed to be including but not limited to “genome editing system including but not restricted to meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR/Cas9),” see column 23 lines 30-50).
Regarding claim 6 and 17, the claims of US-11529511-B2 teach at least one of: the alternating electric field is applied at a frequency in a range of from about 100 kHz to about 10 MHz; and the alternating electric field has a field strength of at least 1 V/cm (claim 2: “ the first frequency is between 250 kHz and 350 kHz, and the second frequency is between 150 kHz and 250 kHz,” and claim 6: “the first alternating electric field has a field strength of at least 1 V/cm RMS”); and the period of time that the alternating electric field is applied is in a range of from about 24 hours to about 72 hours, steps (1) and (2) are repeated one or more times.
Regarding claim 8, the claims of US-11529511-B2 teach a method of treating or reducing the occurrence of at least one condition, disease, disorder, or infection in a subject, the method comprising the steps of:(1) applying an alternating electric field to at least a portion of the subject for a period of time, wherein application of the alternating electric field downregulates at least one DNA damage repair pathway in at least a portion of the subject; and (2) administering to the subject a clustered regularly interspaced short palindromic repeats (CRISPR) associated protein (CRISPR-Cas) system comprising: a single guide RNA (sgRNA) that comprises a guide sequence that hybridizes to a target DNA sequence associated with the at least one condition, disease, disorder, or infection; and a CRISPR-associated endonuclease or gene encoding same (claim 10: “A method for treating a tumor in a subject's body and delivering a substance across cell membranes in the subject's body, the method comprising: applying a first alternating electric field at a first frequency to the subject's body for a first period of time, wherein application of the first alternating electric field at the first frequency to the subject's body for the first period of time increases permeability of the cell membranes in the subject's body; administering the substance to the subject, wherein the increased permeability of the cell membranes enables the substance to cross the cell membranes; and applying a second alternating electric field at a second frequency to the subject's body for a second period of time that is at least one week long, wherein the second frequency is different from the first frequency, and wherein the second alternating electric field at the second frequency inhibits growth of the tumor;” wherein “a substance” is disclosed to be including but not limited to “genome editing system including but not restricted to meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR/Cas9),” see column 23 lines 30-50).
Regarding claim 10, the claims of US-11529511-B2 teach the at least one condition, disease, disorder, or infection is a cancer (claim 11: “the tumor comprises a glioblastoma in the subject's brain”).
Regarding claim 15 claims of US-11529511-B2 teach the CRISP-Cas system is administered about 24 hours to about 48 hours after application of the alternating electric field has begun (claim 13: “ the step of administering the substance begins at a given time, and wherein the step of applying the first alternating electric field ends at least 12 hours after the given time;” and claim 14: “the step of applying the first alternating electric field begins at least one hour before the given time.”).
To the extent that there are limitations of the instant claims that are not taught by the claims of US-11529511-B2, the teachings of Jaskula-Ranga, Kim, and Schon are discussed above.
Given the substantially similar subject matter between the claims of copending Application No. 17/559,228 and the teachings of Jaskula-Ranga, Kim, and Schon endure, it would have been obvious to have modified the subject matter of the copending claims in the manner discussed above to arrive at the instant claims for substantially the same reasons as discussed above.
Claims 1-4, 6-11, 13, and 15-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 33, 35, 38, and 64-74 of copending Application No. 17/559,228 in view of Jaskula-Ranga V. et al., (US-20200069818-A1), Kim et. al., (Oncotarget, Vol. 7, No. 38, 62267-62279, published 08/19/2016), and Schon EA. (US-5866337-A).
Regarding claim 1, 2, and 8-9, the copending claims teach a method of inducing apoptosis, the method comprising the steps of: (1) applying an alternating electric field to the at least one cell for a period of time, wherein application of the alternating electric field downregulates at least one DNA damage repair pathway in the at least one cell; and (2) exposing the at least one cell to a clustered regularly interspaced short palindromic repeats (CRISPR) associated protein (CRISPR-Cas) system comprising: a single guide RNA (sgRNA) that comprises a guide sequence that hybridizes to a target DNA sequence in the at least one cell; and a CRISPR-associated endonuclease or gene encoding same; and wherein the CRISPR-associated endonuclease is…Cas9 (claim 33: “A method for reducing the viability of a cell, the method comprising: applying a first alternating electric field at a first frequency to the cell for a first period of time, wherein application of the first alternating electric field at the first frequency to the cell for the first period of time increases permeability of the cell membrane of the cell wherein the first frequency is between 50 kHz and 350 kHz; introducing a vector to the cell, wherein the increased permeability of the cell membranes enables the vector to cross the cell membrane; and applying a second alternating electric field at a second frequency to the cell for a second period of time, wherein the second frequency is different from the first frequency, and wherein the second alternating electric field at the second frequency reduces viability of the cell by interfering with mitosis of the cell;” claim 64: “the vector comprises one or more nucleic acid sequences capable of encoding one or more sequences of interest;” claim 65: “the sequence of interest is a selectable marker or a therapeutic agent;” claim 66: “the therapeutic agent is a pro- apoptotic factor;” and claim 67: “the pro-apoptotic factor is a cytokine, p53, a suicide gene, and/or an activator of known apoptosis genes,” wherein "sequence of interest means a peptide or polypeptide sequence (e.g., a therapeutic protein), that is expressed from a nucleic acid sequence,” which reads on CRISPR/Cas9 protein as evidenced by [0068]: “a therapeutic agent can be…a guide RNA molecule (gRNA), an RNA- guided endonuclease protein or a Cas9 protein or a Cpfl protein CRISPR-Cas.”).
Regarding claim 6 and 17, the copending claims teach at least one of: the alternating electric field is applied at a frequency in a range of from about 100 kHz to about 10 MHz; and the alternating electric field has a field strength of at least 1 V/cm ( claim 33: “the first frequency is between 50 kHz and 350 kHz;” claim 38: “the second frequency is between 75 kHz and 300 kHz;” claims 73 and 74: “alternating electric field has a field strength of at least 1 V/cm RMS;” ); and the period of time that the alternating electric field is applied is in a range of from about 24 hours to about 72 hours, and steps (1) and (2) are repeated one or more times.
Regarding claim 10, the copending claims teach the at least one condition, disease, disorder, or infection is a cancer (claim 35: “the cell is a cancer”).
To the extent that there are limitations of the instant claims that are not taught by the copending claims, the teachings of Jaskula-Ranga, Kim, and Schon are discussed above.
Given the substantially similar subject matter between the claims of copending Application No. 17/559,228 and the teachings of Jaskula-Ranga, Kim, and Schon endure, it would have been obvious to have modified the subject matter of the copending claims in the manner discussed above to arrive at the instant claims for substantially the same reasons as discussed above.
Conclusion
No claims are allowed.
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/COREY LANE BRETZ/ Patent Examiner, Art Unit 1635
/RAM R SHUKLA/ Supervisory Patent Examiner, Art Unit 1635
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