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 .
Status of Application, Amendments and/or Claims
The amendment, filed 13 December 2023, has been entered in full. Claims 1-19, 21, 26-31, 33, 35, 37-41, 43 and 44 are canceled. Claims 22-25, 32, 34, 36 and 42 are amended. New claims 45-55 are added.
The amendment, filed 20 July 2026, corrects the misnumbering of the instant claims, which lists two “claim 51”. Therefore, the new claims, which were added in the amendment filed 13 December 2023, are “new claims 45-56” not “new claims 45-55”.
Applicant’s election of Group I (claims 20, 22-25, 32, 34, 36, 42, 48-56) in the reply filed on 20 July 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Claims 45-47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 20 July 2026.
The amendment, filed 20 July 2026, has been entered in full. Claims 45-47 are canceled.
Claims 20, 22-25, 32, 34, 36, 42, 48-56 are pending and under examination.
Information Disclosure Statement
The information disclosure statement(s)(IDS) (filed 9/28/2023 and 5/22/2024) were received. They have been placed in the application file and the information referred to therein has been considered as to the merits.
It is noted that some of the references fail to comply with the provisions of 37 CFR §§1.97, 1.98 and MPEP § 609. MPEP 609.05 [R-3] states that information disclosure statements will be reviewed for compliance with the requirements of 37 CFR 1.97 and 37 CFR 1.98 as discussed in MPEP 609.04(a) and MPEP 609.04(b). The references will be lined through and not considered by the Examiner.
The following references not considered by the Examiner for the following reasons:
1. MPEP 609.04(a) Contents Requirements for an Information Disclosure Statement teaches the following: 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly.
U.S. patents must be identified by the inventor, patent number, and issue date.
U.S. patent application publications must be identified by the applicant, patent application publication number, and publication date. The Office will also accept a citation in an IDS where a U.S. patent application publication is identified using the inventor instead of the applicant.
In the instant case, the cited U.S. patents are not identified by the inventor (i.e. first author).
Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Claim Objections
Claims 20 and 48 are objected to because of the following informalities:
In claim 20, subparts (1)-(4) should be renumbered utilizing “(i)-(iv)” or “(a)-(d)” so as to prevent confusion with claim numbering. Claims 22, 24, and 25 should also be renumbered to reflect the amendments to claim 20.
In claim 48, subparts (1)-(5) should be renumbered utilizing “(i)-(v)” or “(a)-(e)” so as to prevent confusion with claim numbering. Claims 49, 52, and 53 should also be renumbered to reflect the amendments to claim 48.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 20, 22-25, 32, 34, 36, 42, and 55 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 20 is indefinite because it lacks antecedent basis for the limitation “the subject” in step (1). Amending step (1) to recite, “applying an alternating electric field to a target region of a subject”, would be remedial.
Claims 22-25, 32, 34 are included in this rejection insofar as they depend from claim 20 and do not resolve the issue discussed above.
Claims 22 and 49 are indefinite because they recite the limitation "or precursors thereof". Claim 22 depends from claim 20 (claim 49 depends from claim 48). Claims 20 and 48 step (3) do not recite “or precursors thereof”. There is insufficient antecedent basis for this limitation in the claims.
Claim 23 is indefinite because it recites the acronym "HLA", which has not been defined in the claims. Acronyms should be defined upon their first use in a claim. The presence of an undefined acronym renders a claim indefinite.
Claim 25 is indefinite because of the recitation, “the method of claim 20, further comprising the step of: (6) applying the alternating electric field to the target region of the subject. Claim 25 depends from claim 20. However, claim 20 does not have a step (5). Thus, it is unclear how claim 25 can have a step (6).
Claim 34 is indefinite because it depends from canceled claim 21. The metes and bounds of claim 34 cannot be determined because the dependency is unclear.
Claim 36 is indefinite because it depends from canceled claim 1. The metes and bounds of claim 36 cannot be determined because the dependency is unclear.
Claim 42 is indefinite because it depends from canceled claim 1. The metes and bounds of claim 42 cannot be determined because the dependency is unclear.
Claims 34 and 55 are indefinite because of the phrase "such as". It is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 34 and 55 are indefinite because they contain the trademark/tradenames OPDUALAG and Relatimad. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an anti-LAG3 agent and, accordingly, the identification/description is indefinite.
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.
Claims 48-56 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification teaches that the methods involve application of an alternating electric field (TTFields) to immature dendritic cells or precursors thereof to mature/activate the dendritic cells. The methods may further include a step of loading the dendritic cells with antigens from a particular source (such as, but not limited to, cancer antigens, viral antigens, bacterial antigens, fungal antigens, etc.). Then the activated, antigen-loaded dendritic cells can be administered to a subject for treatment of a condition, infection, or disease. The inventive concepts also include a combinatorial therapy for cancer that combines (i) production of alternating electric field- (TTField-) treated cancer cells via application of alternating electric fields (TTFields) to either a subject or ex vivo to cells isolated from the subject; (ii) use of these alternating electric field- treated cancer cells to activate dendritic cells (i.e., load the dendritic cells ex vivo with antigens from the alternating electric field-treated cancer cells); and (iii) administration to the subject. The combination of alternating electric fields with composition(s) containing dendritic cells activated by co-culture with alternating electric field-treated cancer cells provides a synergistic result in the treatment of cancer.
The Examples teach that data from 8 experiments indicates physiological dendritic cells (DCs) cDC1, cDC2, and pDC are activated by the 150 kHz TTFields treatment. For all DC subtypes, the major part of the maturation achievable by exposure to a strong activator such as LPS could also be achieved solely by the exposure of PBMC to TTFields at 150kHz. The Examples teach that these results indicate that TTFields may act as a "physical adjuvant" that enhances the maturation status of DC in an antigen-non-specific manner. The Examples teach that the primary goal of cancer immunotherapy is to activate a preexisting, endogenous immune response in cancer patients.
The Examples state that to support the rationale for using TTFields as an immune modulator, mice are treated with TTFields for 72 h using the INOVITRO™ system. Cancer cells are then isolated from the mice. PBMCs are also isolated from the mice, either before or after TTFields exposure, or from an HLA-matched donor. The PBMCs are co-cultured with the cancer cells to activate and load neoantigens into the dendritic cells. The activated, antigen- loaded dendritic cells are isolated away from the co-culture and the cancer cells and then administered to mice as a vaccine to trigger an immune response to cancer development.
The Examples state that in this manner, methods of increasing immunity to cancer cells are combined with TTFields treatment. The combination of TTFields treatment with administration of personalized activated dendritic cell-containing composition(s) provides a synergistic effect over either treatment alone and initiates an immune response in the patient that will allow the immune system to eliminate the cancer cells. The Examples state dendritic cells are activated by exposure to TTFields as in Example 1. The TTFields- exposed dendritic cells are then antigen-loaded by pulsing with antigens of interest or co-culture with a source of antigen (e.g., cancer cells, bacterial cells, viral-infected cells, fungal-infected cells, etc.). The activated, antigen-loaded dendritic cells are isolated away from the culture and then administered to the same subject or an allogenic subject as an immunomodulator or vaccine to trigger an immune response.
The instant claims are not enabled for the following reasons:
1. The instant claims are drawn to a method of treating cancer in a subject. Cancer encompasses diverse cancers such as brain cancer, cervical cancer, breast cancer, colon cancer, leukemia, etc.
See wherein Hassanpour et al. teach that cancer in the broader sense refers to more than 277 different types of cancer disease. Hassanpour et al. teach that cancer is a variety disease at the tissue level. Hassanpour et al. teach that this variety is a major challenge for its specific diagnosis, followed by efficacy of treatment. Hassanpour et al. teach scientists have stated several gene mutations are involved in cancer pathogenesis; also included are chemical compounds, environmental chemical substances with carcinogenic properties, viruses, bacteria and radiation rays (Hassanpou et al. Review of cancer from perspective of molecular. Journal of Cancer Research and Practice. Volume 4:127-129; available July 2017).
Upadhyay teaches that intratumor heterogeneity (i.e., extreme genetic diversity among cell populations residing in the same tumor mass), leads to Darwinian principles and natural selection forces to work on it and establish a more robust variety of cancer cells. Upadhyay teaches that this heterogeneity increases drug resistance and thus poses a great therapeutic challenge before clinicians in developing cancer treatment(page 657)(Upadhyay, A. Cancer: An unknown territory; rethinking before going ahead. Genes & Diseases Volume 8:655-661, 2021; available online 18 Sept 2020).
2. The Examples teach that dendritic cells (DCs) are activated by the 150 kHz TTFields treatment in vitro.
The specification then teaches “prophetic Examples”. A working Example is based on work actually performed. A prophetic Example describes an embodiment of the invention based on predicted results rather than work actually conducted or results actually achieved.
The Examples never actually teach a method of treating all cancers or treating a particular cancer comprising applying an alternating electric field to a target region of the subject; isolating cancer cells from the target region to which the alternating electric field has been applied; co-culturing the isolated cancer cells with dendritic cells to produce antigen-loaded dendritic cells; isolating antigen-loaded dendritic cells from the co-culture and from the cancer cells; and administering the antigen-loaded dendritic cells to the subject.
The Examples never actually teach a method of treating all cancers or treating a particular cancer comprising applying an alternating electric field to a target region of the subject; isolating cancer cells from the target region to which the alternating electric field has been applied; co-culturing the isolated cancer cells with dendritic cells from an HLA-matched donor to produce antigen-loaded dendritic cells; isolating antigen-loaded HLA-matched dendritic cells from the co-culture and from the cancer cells; and administering the antigen-loaded HLA-matched dendritic cells to the subject.
It is noted that compliance with the enablement requirement of 35 U.S.C. 112, first paragraph, does not turn on whether an Example is disclosed. In the instant case, the method is prophetic, offering no guidance regarding how to practice it.
The specification need not contain an Example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. Lack of a working Example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.
In the instant case, it could not be predicted that the data presented in the specification would be correlative with in vivo treatments for cancers using the claimed methods steps. There is no clear nexus between any specific disease state and said disease state being treated. It cannot be said that the specification provides the necessary guidance.
Due to the inherent unpredictability regarding treating any/all cancers or a particular cancer using the claimed method steps; the lack of direction/guidance presented in the specification regarding same; the absence of working examples directed to same; the complex nature of the invention; the state of the prior art which
teach that cancer in the broader sense refers to more than 277 different types of cancer disease, that cancer is a variety disease at the tissue level, which is a major challenge for its specific diagnosis, followed by efficacy of treatment and that there is extreme genetic diversity among cell populations residing in the same tumor mass; undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
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.
Claims 20 and 32 are rejected under 35 U.S.C. 102(a1) as being anticipated by Voloshin et al. (Reference submitted by Applicant; Cancer Immunology, Immunotherapy 69:1191-1204; 2020).
Voloshin et al. teach tumor-treating fields (TTFields), an anti-cancerous treatment modularity, are alternating electric fields (page 1192, left column). Voloshin et al. teach administering Lewis lung carcinoma (LLC-1) cells to mice. Voloshin et al. teach treating said mice with TTFields at 150 kHz or anti-PD1 or a combination of both TTFields and anti-PD1 (applies to claim 20 step 1). Voloshin et al. teach that said mice treated with TTFields and anti-PD-1 demonstrated decreased tumor volume as compared to control group (pages 1198-1199 and Figure 5). Voloshin et al. teach that the tumors were harvested and isolated. Voloshin et al. teach testing the isolated tumor sample. Voloshin et al. teach a significantly higher frequency of macrophages and dendritic cells (DCs) in tumors from mice that were concomitantly treated with TTFields and anti-PD-1 (pages1198-1199 and Figure 5)(applies to claim 20 steps 2-4 and claim 32). Voloshin et al. teach similar results in mice bearing CT-26 colon carcinoma tumors (pages 1200 and Figure 6)(applies to claims 20 and 32). Additionally, Voloshin et al. teach Lewis Lung carcinoma (LLC-1) cells that were treated with TTFields where phagocytosed by isolated bone marrow-derived dendritic cells in vitro while untreated LLC-1 cells did not show similar outcomes (page 1196, left column).
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.
1. Claims 20, 22, 24 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Voloshin et al. (Cancer Immunology, Immunotherapy 69:1191-1204; 2020) in view of Ladhams et al. (TREATMENT OF HEPATOCELLULAR CARCINOMA. Treatment of non-resectable hepatocellular carcinoma with autologous tumor-pulsed dendritic cells. Journal of Gastroenterology and Hepatology Volume 17:889-896; 2002).
Voloshin et al. teach tumor-treating fields (TTFields), an anti-cancerous treatment modularity, are alternating electric fields (page 1192, left column). Voloshin et al. teach administering Lewis lung carcinoma (LLC-1) cells to mice. Voloshin et al. teach treating said mice with tumor-treating fields (TTFields) at 150 kHz or anti-PD1 or a combination of both TTFields and anti-PD1 (applies to claim 20 step 1). Voloshin et al. teach that said mice treated with TTFields and anti-PD-1 demonstrated decreased tumor volume as compared to control group (pages 1198-1199 and Figure 5). Voloshin et al. teach that the tumors were harvested/isolated. Voloshin et al. teach a significantly higher frequency of macrophages and dendritic cells (DCs) in tumors from mice that were concomitantly treated with TTFields and anti-PD-1 (pages1198-1199 and Figure 5)(applies to claim 20 steps 2-4 and claim 32). Voloshin et al. teach similar results in mice bearing CT-26 colon carcinoma tumors (pages 1200 and Figure 6)(applies to claims 20 and 32). Additionally, Voloshin et al. teach Lewis Lung carcinoma (LLC-1) cells that were treated with TTFields where phagocytosed by isolated bone marrow-derived dendritic cells in vitro, while untreated LLC-1 cells did not show similar outcomes (page 1196, left column).
Voloshin et al. do not teach wherein step (3) is performed in the presence of cytokines, interferons or GM-CSF. Voloshin et al. do not teach isolating the dendritic cells utilized in step (3) prior to step 1.
Ladhams et al. teach that the response of hepatocellular carcinoma (HCC) to therapy is often disappointing and new modalities of treatment are clearly needed. Ladhams et al. teach active immunotherapy is based on the injection of autologous dendritic cells (DC) co-cultured ex vivo with tumor antigens. Ladhams et al. teach dendritic cells are prepared using recombinant interleukin-4 (IL-4) and granulocyte–colony stimulating factor (GM-CSF) as monocyte differentiation factors. Ladhams et al. teach that isolated mononuclear cells are obtained from autologous whole blood of HCC patient. Non-adherent cells were removed and discarded. Adherent monocytes were cultured with IL-4 and GM-CSF (page 891, right column-page 892, left column)(applies to claim 24). Ladhams et al. teach the isolation of tumor cells from the HCC patient (page 892)(applies to claim 32). Ladhams et al. teach co-culture of DCs with the tumor cells (page 893).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of preparing an immunogenic composition comprising the steps taught by Voloshin et al., by adding GM-CSF to dendritic cells, as taught by Ladhams et al. One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons. Ladhams et al. teach IL-4 and GM-CSF are monocyte differentiation factors, which differentiate monocytes isolated from blood into dendritic cells. Ladhams et al. teach a method of isolating/preparing dendritic cells from cancer subjects. Isolating dendritic cells from a subject prior to applying TTFields would be a baseline comparison with isolated dendritic cells from a subject after applying TTFields.
2. Claims 20, 23 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Voloshin et al. (Cancer Immunology, Immunotherapy 69:1191-1204; 2020) in view of Tseng et al. (US 2016/0144009; published May 26, 2016).
Voloshin et al. teach tumor-treating fields (TTFields), an anti-cancerous treatment modularity, are alternating electric fields (page 1192, left column). Voloshin et al. teach administering Lewis lung carcinoma (LLC-1) cells to mice. Voloshin et al. teach treating said mice with tumor-treating fields (TTFields) at 150 kHz or anti-PD1 or a combination of both TTFields and anti-PD1 (applies to claim 20 step 1). Voloshin et al. teach that said mice treated with TTFields and anti-PD-1 demonstrated decreased tumor volume as compared to control group (pages 1198-1199 and Figure 5). Voloshin et al. teach that the tumors were harvested/isolated. Voloshin et al. teach a significantly higher frequency of macrophages and dendritic cells (DCs) in tumors from mice that were concomitantly treated with TTFields and anti-PD-1 (pages1198-1199 and Figure 5)(applies to claim 20 steps 2-4 and claim 32). Voloshin et al. teach similar results in mice bearing CT-26 colon carcinoma tumors (pages 1200 and Figure 6)(applies to claims 20 and 32). Additionally, Voloshin et al. teach Lewis Lung carcinoma (LLC-1) cells that were treated with TTFields where phagocytosed by isolated bone marrow-derived dendritic cells in vitro while untreated LLC-1 cells did not show similar outcomes (page 1196, left column).
Voloshin et al. do not teach wherein the dendritic cells are isolated from an HLA-matched donor.
Tseng et al. teach a method for enhancing immunization strategies by manipulation of phagocytic antigen presenting cells. Tseng et al. teach that in the method, phagocytic antigen presenting cells (phAPC) are incubated with a particular antigen in the presence of an anti-CD47 agent in a dose and for a period of time sufficient to allow the phAPC to phagocytose the antigen, which process generates a “loaded” phAPC (abstract). Tseng et al. teach that antigen presentation is the process by which innate immune cells like macrophages and dendritic cells (antigen presenting cells, APC) acquire antigens and present them to T cells to initiate the adaptive immune response.
Tseng et al. teach that the antigen can be mammalian tumor cells such as a carcinoma, glioma, sarcoma, melanoma, myeloma, leukemia, lymphoma, etc., including without limitation the hematologic cancers AML, CML, ALL, NHL, multiple myeloma, etc., and solid tumors, including breast, colon, prostate, bladder cancers, gliomas, sarcomas, and the like (para 0008)(applies to claim 32).
Tseng et al. teach examples of phAPC are dendritic cells and macrophages (paras 0002 and 0010). Tseng et al. teach that in some embodiments the phAPC is autologous and that in some embodiments the phAPC is from an HLA-matched donor (para 0011)(applies to claim 23).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of preparing an immunogenic composition comprising the steps taught by Voloshin et al., wherein the dendritic cells are from an HLA-matched donor, as taught by Tseng et al. One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success because using HLA-matched donor dendritic cells avoids possible functional defects that may be found in a subject's own (autologous) cells.
3. Claims 20, 25 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Voloshin et al. (Cancer Immunology, Immunotherapy 69:1191-1204; 2020) in view of Wolfl et al. (Tumor treating fields for pediatric patients with high grade glioma: First case series in Germany. Neuro-Oncology, Vol. 19, Supp. Supplement 6, pp. vi185. ABSTRACT Number: PDCT-07; November 2017).
Voloshin et al. teach tumor-treating fields (TTFields), an anti-cancerous treatment modularity, are alternating electric fields (page 1192, left column). Voloshin et al. teach administering Lewis lung carcinoma (LLC-1) cells to mice. Voloshin et al. teach treating said mice with tumor-treating fields (TTFields) at 150 kHz or anti-PD1 or a combination of both TTFields and anti-PD1 (applies to claim 20 step 1). Voloshin et al. teach that said mice treated with TTFields and anti-PD-1 demonstrated decreased tumor volume as compared to control group (pages 1198-1199 and Figure 5). Voloshin et al. teach that the tumors were harvested/isolated. Voloshin et al. teach a significantly higher frequency of macrophages and dendritic cells (DCs) in tumors from mice that were concomitantly treated with TTFields and anti-PD-1 (pages1198-1199 and Figure 5)(applies to claim 20 steps 2-4 and claim 32). Voloshin et al. teach similar results in mice bearing CT-26 colon carcinoma tumors (pages 1200 and Figure 6)(applies to claims 20 and 32). Additionally, Voloshin et al. teach Lewis Lung carcinoma (LLC-1) cells that were treated with TTFields where phagocytosed by isolated bone marrow-derived dendritic cells in vitro while untreated LLC-1 cells did not show similar outcomes (page 1196, left column).
Voloshin et al. do not teach a step further comprising applying the alternating field to the target region of the subject.
Wolfl et al. teach that for adult patients suffering from glioblastoma multiforme (GBM) a treatment modality using alternating electrical fields called tumor treating fields (TTFields), showed efficacy in a randomized clinical trial. Wolfl et al. teach three pediatric glioma patients treated with TTFields. Wolfl et al. teach that three patients age 7, 9 and 11 years were treated for anaplastic astrocytoma WHO III (patient 1; pt.1) and GBM (patient 2 and patient 3; pt. 2 + pt. 3). Wolfl et al. teach tumors in pt. 1 and pt. 2 could only be partially resected prior to therapy with irradiation and concomitant temozolamide and that pt. 3 underwent complete resection and irradiation, but had to stop temozolamide treatment due to severe thrombocytopenia. Wolfl et al. teach treatment was initiated within 44 days (mean) after the end of irradiation. Pt. 1 and 2 received temozolamide concomitantly, whereas pt. 3 received additional vaccination with tumor-lysate-pulsed dendritic cells (applies to claim 32). Wolfl et al. teach that TTFields were implemented well into everyday life, as reported in structured interviews and quality of life assessment and that there were no severe side effects observed so far (applies to claim 25).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of preparing an immunogenic composition comprising the steps taught by Voloshin et al., by further adding a step comprising applying the alternating electric field to the target region of the subject. One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons.
Wolfl et al. teach that although cancer patients were being treated with temozolamide (patient 1 and patient 2) or tumor-lysate-pulsed dendritic cells (patient 3), all patients were receiving continual TTFields. Based on the teachings, it would be obvious to further add an additional step of applying alternating electric field to the target region of the subject for treatment.
Conclusion
No claims are allowed.
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/R.M.D/Examiner, Art Unit 1647 8/13/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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