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 .
1. Claims 1 – 20 are pending.
Election/Restrictions
2. Applicant’s election of Group II (claims 7 – 15) in the reply filed on 01/28/2026 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)).
3. Claims 1 – 6 and 16 – 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 in the reply filed on 01/28/2026.
Priority
4. This application claims benefit to US Provisional Application No. 63/377,951, filed 09/30/2022 and US Provisional Application No. 63/496,831, filed 04/18/2023.
Information Disclosure Statement
5. The information disclosure statement (IDS) submitted on 04/15/2024 and 09/28/2023 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
6. The specification filed on 09/28/2023 is acknowledged.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
7. Claims 7 – 15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of reducing a volume of a solid tumor present in a target region of a living subject comprising the steps of (1) isolating cancer cells from the target region of the subject containing the solid tumor, wherein the cancer cells are selected from the group consisting of hepatocellular carcinoma cells, glioblastoma cells, pleural mesothelioma cells, differentiated thyroid cancer cells, advanced renal cell carcinoma cells, breast cancers, cervical cancers, ovarian cancers, pancreatic cancers, lung cancers, and combinations thereof; (2) applying an alternating electric field to the isolated cancer cells; (3) irradiating the isolated cancer cells to which the alternating electric field has been applied for a period of time sufficient to ensure that the cells are non-viable; (4) administering the isolated, irradiated cancer cell to the subject intradermally, subcutaneously, intravenously, or intranodally in a concentration that induces an inflammatory response to the irradiated cancer cells; and (5) applying an alternating electric field to the target region of the subject, does not reasonably provide enablement for the claimed breadth of treating any cancer, any target region, any time of irradiation or any dose of radiation, and any route and dose of administration or for the claimed preventing an increase of volume of the tumor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (a) the breadth of the claims, (b) the nature of the invention, (c) the state of the prior art, (d) the level or ordinary skill in the art, (e) the level of predictability in the art, (f) the amount of direction provided by the inventor, (g) the existence of working examples, and (h) the quantity of experimentation needed to make use of the invention based on the content of the disclosure. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
(a) The breadth of the claims: The claims broadly recite “treating”, “cancer”, “target region”, “irradiating”, and “administering” and therefore the claims read on any cancer, any target region, any time of irradiating and strength of radiation, any route of administering, administering any dose of irradiated cancer cells, and preventing any increase of volume of any tumor. Consequently, the breadth of the claims is expansive. It is noted that Applicant defines “treating” as administering an agent/element/method to a patient for therapeutic and/or prophylactic/preventative purposes at page 6, para. 0020. It is noted that Applicant defines “administering” to include all routes of administration known in the art at page 7, para. 0025.
It is noted that the instant rejection is based on four separate issues:
(i) absence of an enabling disclosure of treating any cancer by targeting any region of the subject;
(ii) absence of an enabling disclosure for treating any cancer by irradiating the isolated cancer cells for any time and at any strength of radiation
(iii) absence of an enabling disclosure for treating any cancer by administering the isolated, irradiated cancer cells by any route and any dose
(iv) absence of an enabling disclosure for preventing an increase of any volume of any tumor.
(b) The nature of the invention: The nature of the invention is a combinatorial therapy for cancer combining alternating electric field treatment (such as tumor treating field, TTFields) with apoptotic cancer cell vaccination to provide a synergistic result in the treatment of cancer (page 7, para. 0026).
(c) The state of the prior art:
Regarding issue (i) of absence of an enabling disclosure of treating any cancer by targeting any region of the subject and issue (iv) of absence of an enabling disclosure for preventing an increase of any volume of any tumor, Mun (Mun, Elijah J., et al. Clinical Cancer Research 24.2 (2018): 266-275.) teaches TTFields have proven safe and efficacious in patients with glioblastoma multiforme (GBM) and are FDA approved for use in newly diagnosed and recurrent GBM (Abstract; page 270, right col. para. 3). Mun teaches TTFields significantly reduced tumor volume in a hamster pancreatic cancer model (page 270, right col. para. 5). Mun teaches TTFields led to significantly reduced tumors in mice orthotopically implanted with ovarian cancer cells (page 271, right col. para. 3). Mun teaches TTFields are efficacious in vivo in a preclinical setting with non-small cell lung cancer (NSCLC) and in clinical trials (page 272, left col. last para. and right col. para. 1 – 3). Mun teaches TTFields reduced the number of mesothelioma cells in vitro and is being evaluated in a clinical trial in patients with malignant pleural mesothelioma (page 272, right col. last para; page 273, left col. para. 1 – 2). Mun teaches preclinical studies investigating the utility of TTFields are underway in breast, cervical, colorectal, gastric hepatocellular, melanoma, renal, urinary transitional cell, and small-cell lung cancer (page 273, left col. para. 3). Mun teaches TTFields facilitate an antitumor immune response and TTFields may act in an additive/synergistic manner with certain cytotoxic agents and potentiate immunogenic cell death when combined with immune checkpoint inhibitors but requires further evaluation (Abstract; page 273, right col. para. 2). Mun teaches preclinical studies have demonstrated possible potentiation of the immune system response against the tumor following the application of TTFields (page 273, right col. para. 2). Therefore, the prior art does not teach that any cancer can be treated with TTFields as the prior art only teaches reducing tumor volume/killing cancer cells of solid tumors.
Regarding issue (ii) of absence of an enabling disclosure for treating any cancer by irradiating the isolated cancer cells for any time and with any strength of radiation and issue (iii) of absence of an enabling disclosure for treating any cancer by administering the isolated, irradiated cancer cells by any route and any dose, Dillman (Dillman, Robert O., et al. Cancer Biotherapy and Radiopharmaceuticals 16.1 (2001): 47-54.) teaches irradiation of cancer cells for use as a vaccine where the cells were treated with 100 Gy so that they could no longer divide and such cells retain most of the metabolic activity and antigen expression for at least 7 days as they begin the process of apoptosis (page 49, left col. para. 1; Abstract). Dillman teaches patients received subcutaneous injections of 10 million irradiated tumor cells once a week for three weeks then once a month for 5 months (Abstract; page 49, right col. last para.). Luo (Luo, Lumeng, et al. OncoTargets and therapy (2019): 3805-3815.) teaches a cancer vaccine prepared from lung cancer cells that were irradiated with 8 Gy, then passaged, then irradiated with 8 Gy five more times (Abstract; page 3806, right col. para. 2; page 3807, right col. last para.). Curry (Curry Jr, William T., et al. Clinical Cancer Research 22.12 (2016): 2885-2896.) teaches irradiation of autologous glioma cells at 100 Gy for preparation of a cancer vaccine at doses ranging from 5 x 106 cells to 1 x 107 cells (page 2886, right col. last para. and right col. para. 3 – 4). Curry teaches the irradiated cells were administered via mixed subcutaneous and intradermal injection (page 2887, left col. para. 1). Graf (Graf, Martin R., et al. " Cancer Immunology, Immunotherapy 51.4 (2002): 179-189.) teaches preparation of a cancer vaccine by irradiating glioma cells with 50 Gy that prevented cellular proliferation and did not alter the level of expression of major histocompatibility complex I and intercellular adhesion molecule-1 surface antigens (page 180, right col. last para.). Graf teaches administering 5 x 106 cells subcutaneously (page 180, right col. last para.). Carlsson (Carlsson J, et. al. Eur J Nucl Med Mol Imaging. 2006 Oct;33(10):1185-95) teaches irradiating tumor cells with various dose rates and times and that continuous irradiation with dose rates of 0.2 – 0.3 and 0.4 – 0.6 Gy/hour for 7 and 3 days, respectively could kill all cells in each tumor sample (Abstract). Carlsson teaches that exposure for just 24 hours with about 0.8 Gy/hour only killed the breast cancer cells and the other cancer cells recovered (Abstract). Therefore, the prior art teaches cancer cells can be irradiated for use as a cancer vaccine but does not teach a standard irradiation procedure to induce apoptosis and maintain immunogenicity or a standard dose and route of administration for all cancer types.
(d) The level skill in the art:
The level of skill in the art of reducing tumor volume in a subject is high, as an artisan in this art needs specialized knowledge such as a postgraduate degree (Ph.D. and/or M.D.) given the complex nature of cancer, cancer therapy in general and cancer therapy by electric fields and vaccines.
(e) The level of predictability in the art:
Regarding issue (i) of absence of an enabling disclosure of treating any cancer by targeting any region of the subject and issue (iv) of absence of an enabling disclosure for preventing an increase of any volume of any tumor, the prior art does not teach the predictability of treating any cancer by targeting any region of the subject because the prior art does not teach that TTFields can treat blood cancers. The predictability of treating any cancer by applying an alternating electric field to any target region of the subject encompassed by the instant claim would be low given that the prior art lacks any teachings of using TTFields for treating blood cancers.
Regarding issue (ii) of absence of an enabling disclosure for treating any cancer by irradiating the isolated cancer cells for any time and any strength of radiation and issue (iii) of absence of an enabling disclosure for treating any cancer by administering the isolated, irradiated cancer cells by any route and any dose, the prior art does not teach the predictability of irradiating any isolated cancer cells for any time and strength and administering the irradiated cells for treating any cancer because Dillman teaches significant anti-tumor responses were not seen in patients with measurable disease at the time vaccine treatment was initiated (Abstract; page 53, left col. para. 1). Dillman teaches that one possible method of improving the cancer cell vaccine would be to transduce the tumor cells with the genes to enable endogenous production of an adjuvant cytokine (page 53, left col. para. 2 – 3). Curry teaches that vaccination resulted in vigorous humoral responses to tumor-associated angiogenic cytokines and T-lymphocyte activation was seen (Abstract), but Curry does not teach the vaccination resulted in reducing tumor volume. Graf teaches that the results of vaccination indicate that treatment of an established intracranial glioma with a cellular vaccination alone may induce enhanced tumor growth; however, when the vaccination is combined with radiation therapy, the results are beneficial in terms of increased survival time or complete remission that is accompanied by the development of tumor-specific cellular immunity (Abstract; page 187, right col. para. 2). Thus, the predictability of treating any cancer by the claimed method would be low given that the prior art teaches that vaccination with isolated, irradiated cancer cells does not treat cancer.
(f) The amount of direction provided by the inventor:
The specification teaches that alternating electric fields (tumor targeting fields, TTFields) target solid tumors by disrupting mitosis and the treatment is non-invasive (page 1, para. 0002). The specification teaches that cancer cells/cancers/tumors that can be treated in accordance with the present disclosure include hepatocellular carcinomas, glioblastomas, pleural mesotheliomas, differentiated thyroid cancers, advanced renal cell carcinomas, ovarian cancers, cervical cancers, breast cancers, pancreatic cancers, lung cancers (such as, but not limited to, non-small cell lung cancers), and the like, as well as any combination thereof (page 8, para. 0029). Thus, the specification does not teach targeting a region of the subject (blood) having blood cancer cells such as leukemias, lymphomas.
The specification teaches cancer immunotherapy is to activate a preexisting, endogenous immune response in cancer patients and that although significant advances have been made, treatment efficacy still needs to be improved (page 2, para. 0004; page 21, para. 0070). The specification teaches that previous studies have shown that TTFields treatment potentiates immunogenic cell death in cancer cells, ultimately stimulating an immune response through engulfing cancer cells (page 21, para. 0070). Thus, the specification teaches the unpredictability of cancer immunotherapy to treat cancer because the specification teaches treatment efficacy still needs to be improved, which is in agreement with the prior art cited above.
The specification teaches any methods of irradiating cancer cells known in the art or otherwise contemplated may be used so long as the cancer cells are irradiated at a sufficient strength of radiation and for a sufficient amount of time to render the cancer cells non-viable/proliferation incompetent (page 11, para. 0037; page 12, para. 0041). Thus, the specification teaches that for treating cancer, it is necessary that the cancer cells be irradiated under conditions that ensure that the cells are non-viable.
The specification teaches the irradiated cells may be formulated for administration by oral, topical, transdermal, intradermal, parenteral, subcutaneous, intranasal, mucosal, intramuscular, intraperitoneal, intravitreal, intravenous and/or intranodal routes (page 13, para. 0044).
The specification teaches that the irradiated cancer cells may be administered to the subject at any concentration that is capable of inducing an inflammatory response to the tumor or cancer cells. Thus, the specification teaches that for treating cancer, it is necessary to administer a dose of irradiated cancer cells that induces an inflammatory response.
(g) The existence of working examples:
The specification provides a prophetic example in which mice are treated with TTFields for 72 hours using the INOVITRO system; cancer cells are then isolated from the mice and irradiated; the irradiated, apoptotic cancer cells are isolated away from the culture, and the apoptotic cancer cells are administered to mice as a vaccine to trigger an immune response to cancer development (page 22, para. 0071) but does not show treatment of cancer or reduction in tumor volume. This prophetic example does not teach a time of irradiation or dose of radiation, nor does it teach how to isolate apoptotic cancer cells away from the culture, or the dose or route of administration to trigger an immune response. The specification does not provide any additional examples or guidance on how to treat any cancer or reduce any tumor volume as claimed. Thus, the specification enables triggering an immune response in a subject with a solid tumor selected from hepatocellular carcinomas, glioblastomas, pleural mesotheliomas, differentiated thyroid cancers, advanced renal cell carcinomas, ovarian cancers, cervical cancers, breast cancers, pancreatic cancers, lung cancers. The prior art provides no compensatory guidance for applying electric fields to the blood of a subject with a blood cancer.
With regards to prevention of claim 15, the Examiner notes that the instant specification does not provide any working examples of a method of preventing- nor does it provide adequate guidance on how to overcome the art-recognized difficult nature of this goal. One skilled in the art could not practice the method to achieve the results of prevention of an increase of volume of the tumor as claimed because the specification does not provide any guidance on how to prevent tumor volume increase and the state of the prior art teaches that administering isolated irradiated tumor cells can increase tumor growth (see Graf above).
(h) The quantity of experimentation needed to make use of the invention based on the content of the disclosure:
The amount of experimentation would be undue because it would require determining how to treat cancers that do not form solid tumors with the claimed method, including determining the parameters for irradiating the cancer cells such that they induce an immunogenic reaction and how to apply an alternating electric field to a target region that contains cancer cells but not a solid tumor to treat the cancer. Since, as discussed above, it is not routine to apply an alternating electric filed to any target region to treat any cancer, knowing only that TTFields can reduce tumor volume at target regions containing solid tumors would mean that significant experimentation would be required. This is because one cannot extrapolate between the prophetic example in the specification that does not even teach a specific cancer, irradiation protocol, dose and route of administration, or even that any cancer is treated and the treatment of other cancer types claimed and since there is little guidance provided. Further, significant experimentation would be required because the prior art teaches that cancer vaccines are not efficacious in treating cancer and can instead increase tumor growth. Thus, the full scope of claim 7 is not enabled by the disclosure.
Claim Interpretation
8. Claim 10 broadly recites “a period of time sufficient to ensure that the cells are non-viable”. For the purpose of applying prior art, “a period of time sufficient” is interpreted as at least about 30 minutes based on Applicant’s specification at page 11, para. 0037.
9. Claims 9, 11, and 14 recite “about”. For the purpose of applying prior art, “about” is interpreted to include the recited value and values that vary by plus or minus 1 – 12%, 15%, or 20% based on Applicant’s specification at page 4, para. 0014.
10. For the purpose of applying prior art, “at least one immunogenic composition” of claim 13 is interpreted as the isolated, irradiated cancer cells of step (4) of claim 7.
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.
11. Claim(s) 7 – 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kim (Kim, Eun Ho, et al. Oncotarget 7.38 (2016): 62267.), hereinafter Kim which is cited on the IDS filed 04/15/2024 in view of Porat (Porat, Yaara, et al. Journal of visualized experiments: JoVE 123 (2017): 55820.), hereinafter Porat in view of Lumniczky (Lumniczky, Katalin, et al." Cancer gene therapy 9.1 (2002): 44-52.), hereinafter Lumniczky in view of Chen (WO-2021050093-A1; Filed 11/04/2019; Published 03/18/2021), hereinafter Chen.
Regarding step (2) and step (3) of claim 7, Kim teaches a method of applying an alternating electric field (TTF) to glioblastoma multiforme (GBM) cells (step (2)) followed by irradiating (IR) the GBM cells (step (3)) (Abstract; page 62268, left col. para. 2; page 62277, left col. para. 1). Kim does not teach “isolating cancer cells from a target region of the subject” (step (1)) or “administering the isolated, irradiated cancer cells to the subject” (step (4)) or “applying an alternating, electric field to the target region of the subject” (step (5)).
Regarding claim 8, Kim teaches the cancer cells are glioblastoma cells (Abstract).
Regarding claim 9, Kim teaches treating the GBM cells with an applied electric field intensity and frequency of 0.9 V/cm (“at least about 1 V/cm”) and 150 kHz (“at a frequency in a range of from about 50 kHz to about 1 MHz”) for 24 hours (“at least about 24 hours”) (page 62277, left col. para. 1).
Regarding claim 10 and 11, Kim teaches irradiating the cancer cells were irradiated for 24 hours (“a period of time sufficient to ensure that the cells are non-viable” of claim 10; “from about 24 hours” of claim 11) where cell death was 23.9% with a significant decrease in the survival fraction (page 62268, left col. para. 2; Figure 1; page62275, left col.; Figure 5; page 62277, left col. para. 1).
Kim does not teach “isolating cancer cells from a target region of the subject” (step (1)) or “administering the isolated, irradiated cancer cells to the subject” (step (4)) or “applying an alternating, electric field to the target region of the subject” (step (5)) of claim 7 or “subcutaneously” of claim 12 or “an immunogenic composition”, “a cytokine”, and “GM-CSF” of claim 13 or “the period of time that the alternating electric field is applied is at least about 24 hours” of claim 14, or “reducing tumor volume” of claim 15. However, Kim teaches GBM is one of the most dangerous cancers, with poor prognosis (page 62267, left col.). Kim teaches alternating electric field with very low-intensity, intermediate-frequence (TTF) can effectively inhibit the growth of a variety of human and rodent tumor cell lines (page 62267, left col.). Kim teaches TTF+IR synergistically induces apoptosis in the GBM cells, synergistically induces DNA damage in GBM cells, synergistically induces cell death and impairs the DNA damage response in GBM cells, and synergistically suppressed the invasive and migratory capacities of GBM cells (page 62268, left col. para. 2; page 62270, left col. para. 1 and right col. para. 1; page 62272, left col. para. 1 and right col. para. 2). Kim teaches radiotherapy with TTF pretreatment may be considered as a strong candidate for significantly improving clinical outcomes (page 62275, right col.; page 62276, left col. para. 1). Kim teaches radiation therapy is considered only as an adjuvant therapy for patients with newly diagnosed GBM and should be carried out as a standard of care following surgery (page 62272, right col. last para.). Kim teaches because the radiosensitizing effects of TTF are intended to enhance tumor cell death, while having a much less of an effect on normal tissues, experiments with in vivo mouse models and normal tissue should also be conducted in future studies to minimize the possible complications in clinical applications (page 62276, left col. para. 1).
Regarding “isolating cancer cells from a target region of the subject” of step (1) of claim 7, Porat teaches studying the effects of TTFields on cancerous cells in vitro currently provides the only way to determine the optimal frequency to apply to a specific tumor type (page 1, para. 2; page 2, para. 2). Porat teaches frequency scans for the determination of optimal TTFields for GBM cells at 1.7 V/cm for 72 hours (Figure 2B and 3B). Porat teaches maximizing anti-tumor efficacy is a desirable outcome for all treatment modalities and fighting for every additional percent of cancerous cell growth inhibition may have a significant effect on the long-term clinical outcome for patients (page 7, para. 1). Porat teaches finding the right combination with other therapies and determining the optimal frequency relies heavily on in vitro results, as no validated markers for TTFields treatment outcomes are currently available (page 7, para. 1). Porat teaches the method can potentially be used to screen the combination of other cancer treatment modalities (e.g., chemotherapy agents or irradiation) with TTFields and to determine the optimal frequency for TTFields administration for each specific combined treatment (page 7, para. 1).
Porat does not teach “administering the isolated, irradiated cancer cells to the subject” (step (4)) or “applying an alternating, electric field to the target region of the subject” (step (5)) of claim 7 or “subcutaneously” of claim 12 or “an immunogenic composition”, “a cytokine”, and “GM-CSF” of claim 13 or “the period of time that the alternating electric field is applied is at least about 24 hours” of claim 14, or “reducing tumor volume” of claim 15. One would have been motivated to combine the teachings of Kim and Porat to isolate GBM cells from the brain of a patient with GBM (step (1) of claim 7) to optimize the frequency of TTF for sensitizing the cells to radiotherapy because Kim teaches TTF sensitizes GBM cells to radiation and Kim teaches radiotherapy with TTF pretreatment may be considered as a strong candidate for significantly improving clinical outcomes and Porat teaches finding the right combination with other therapies and determining the optimal frequency relies heavily on in vitro results, as no validated markers for TTFields treatment outcomes are currently available and Porat teaches studying the effects of TTFields on cancerous cells in vitro currently provides the only way to determine the optimal frequency to apply to a specific tumor type and Porat teaches maximizing anti-tumor efficacy is a desirable outcome for all treatment modalities and fighting for every additional percent of cancerous cell growth inhibition may have a significant effect on the long-term clinical outcome for patients.
Regarding “administering the isolated, irradiated cancer cells to the subject” of step (4) of claim 7 and “at least one immunogenic composition”, “a cytokine”, and “GM-CSF” of claim 13, Lumniczky teaches administering irradiated brain tumor cells as a cancer vaccine (step (4) of claim 7 and “at least one immunogenic composition” of claim 13) expressing GM-CSF or IL-4 (“a cytokine” and “GM-CSF” of claim 13) to mice (page 45, left col. para. 2 – 5 and right col. para. 1 – 3; page 48, left col. para. 2).
Regarding “subcutaneously” of claim 12, Lumniczky teaches injected subcutaneously with 1 x 106 cells (page 45, right col. para. 2).
Regarding “reducing a volume of a tumor” of claim 15, Lumniczky teaches vaccines producing GM-CSF or IL-4 cured a substantial portion of the mice having brain tumors (Figure 2A, B; page 48, left col. para. 3 – 4; page 49, left col. para. 1). Lumniczky teaches combining the vaccine with radiotherapy completely eliminated the tumor in about 80% of glioma-bearing mice (page 49, right col. para. 1 – 2; Figure 6).
Lumniczky does not teach “applying an alternating, electric field to the target region of the subject” (step (5)) of claim 7 or “the period of time that the alternating electric field is applied is at least about 24 hours” of claim 14. However, Lumniczky teaches high-grade gliomas belong to the most aggressive malignant diseases with very poor prognosis and the induction of the immune system against cancer cells might open new potentials in the treatment of brain tumors the induction of the immune system against cancer cells might open new potentials in the treatment of brain tumors (page 49, right col. para. 3). Lumniczky teaches that the anticancer effect strongly depended on the type and quantity of the secreted cytokine by the vaccine (page 48, left col. para. 3; page 50, left col. para. 2). Lumniczky teaches future clinical trials should focus on the determination of the optimal cytokine concentrations by measuring the activation of the immune system and it is possible that cytokine levels should be adjusted to the individual needs of the cancer patient (page 50, right col. para. 4). Lumniczky teaches vaccination therapy might open a new potential on the clinical treatment of gliomas when applied as an adjuvant treatment to existing therapeutic modalities to eradicate residual tumor cells (page 50, right col. para. 4). One would have been motivated to combine the teachings of Kim, Porat, and Lumniczky to administer isolated, irradiated cancer cells to a patient with a glioma because Kim teaches TTF sensitizes GBM cells to radiotherapy and Porat teaches finding the right combination with other therapies and determining the optimal frequency relies heavily on in vitro results, as no validated markers for TTFields treatment outcomes are currently available and Lumniczky teaches vaccination with irradiated cells combined with radiotherapy cured mice with gliomas.
Regarding “applying an alternating, electric field to the target region of the subject” (step (5)) of claim 7 and “the period of time that the alternating electric field is applied is at least about 24 hours” of claim 14, Chen teaches applying TTFields to rats with GBM for seven days (claim 14) (page 11, para. 00076 – 00078; Figure 11). Chen teaches TTFields increased the cytokines IL1α and IL1β in Figure 11. Chen teaches exposing cancer cells (e.g., glioblastoma cells) to TTFields induces the STING pathway leading to production of pro-inflammatory cytokines, and activating the STING pathway with TTFields is analogous to vaccinating the cancer cell, making the cancer cell especially susceptible to treatment with anti-cancer drugs such as checkpoint inhibitors (page 2 – 3, para. 00011). Chen teaches implanting TTFields-treated cancer cells in mice where the TTFields treatment greatly reduced the tumor size (page 14, para. 00093 – 00094). Chen teaches TTFields stimulate the immune system to produce an anti-tumor immune reaction, analogous to an in situ vaccination where cells are primed for further cancer therapy (e.g., TTFields treatment for at least three days followed by treatment with a checkpoint inhibitor) (page 14 – 15, para. 00095). Chen teaches TTFields are an effective anti-neoplastic treatment modality delivered via non-invasive application of low intensity, intermediate frequency (e.g., 100 – 500 kHz), alternating electric fields (page 1, para. 0003). Chen teaches the clinically approved frequency for TTFields is 200 kHz (page 5, para. 00040).
Chen teaches GBM is the most common and deadliest malignant brain cancer in adults despite aggressive chemoradiotherapy (page 5, para. 00038). Chen teaches TTFields was recently approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed GBM patients and TTFields resulted in a significant improvement in overall survival (page 5, para. 00038). Chen teaches what is needed are methods for activating the immune response and enhance and stimulate the response to cancer treatments (page 2, para. 0009).
It would have been obvious prior to the effective filing date of the invention as claimed for a person of ordinary skill in the art to combine the teachings of Kim regarding applying TTFields followed by irradiation to GBM cells with the teachings of Porat regarding in vitro optimization of the TTField frequency applied to GBM cells with the teachings of Lumniczky regarding administering isolated irradiated glioma cells as a cancer vaccine with the teachings of Chen regarding applying TTFields to a subject to arrive at the claimed method comprising (1) isolating cancer cells from a target region of the subject; (2) applying an alternating electric field to the isolated cancer cells; (3) irradiating the isolated cancer cells to which the alternating electric field has been applied; (4) administering the isolated, irradiated cancer cells to the subject; and (5) applying an alternating electric field to the target region of the subject. One would have been motivated to combine the teachings of Kim, Porat, Lumniczky, and Chen in a method of reducing tumor volume in GBM patients as Kim teaches GBM is one of the most dangerous cancers, with poor prognosis and Porat teaches maximizing anti-tumor efficacy is a desirable outcome for all treatment modalities and fighting for every additional percent of cancerous cell growth inhibition may have a significant effect on the long-term clinical outcome for patients and Lumniczky teaches high-grade gliomas belong to the most aggressive malignant diseases with very poor prognosis and the induction of the immune system against cancer cells might open new potentials in the treatment of brain tumors the induction of the immune system against cancer cells might open new potentials in the treatment of brain tumors and Chen teaches what is needed are methods for activating the immune response and enhance and stimulate the response to cancer treatments. One would have a reasonable expectation of success in combining the teachings as Kim teaches TTF+IR synergistically induces apoptosis in the GBM cells, synergistically induces DNA damage in GBM cells, synergistically induces cell death and impairs the DNA damage response in GBM cells, and synergistically suppressed the invasive and migratory capacities of GBM cells and Porat teaches frequency scans for the determination of optimal TTFields for GBM cells and Lumniczky teaches cytokine-producing vaccines cured a substantial portion of the and combining the vaccine with radiotherapy completely eliminated the tumor in about 80% of glioma-bearing mice and Chen teaches TTFields stimulate the immune system to produce an anti-tumor immune reaction, analogous to an in situ vaccination where cells are primed for further cancer therapy and Chen teaches TTFields was recently approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed GBM patients and TTFields resulted in a significant improvement in overall survival.
Conclusion
No claims allowed.
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/ZANNA MARIA BEHARRY/Examiner, Art Unit 1632