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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/14/2025 has been entered.
Claim Status
Applicants' response and amendments to the claims, filed 10/14/2025, are acknowledged and entered. Claims 2 and 10 have been cancelled by Applicant. Claims 1, 3-9, and 11-16 are pending and under examination.
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 for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1, 3-9, and 11-16 remain rejected under 35 U.S.C. 103(a) as being unpatentable over KIRSON ET AL. (BMC Medical Physics, 2009, vol. 9, no. 1, pages 1-13), MUN ET AL. (Clin. Cancer Res., 2017, vol. 24, no. 2, pages 266-275), and BENSON (Seminars in Oncology Nursing, May 2018, vol. 34, no. 2, pages 137-150) in view of BANG ET AL. (Lancet, 2012, vol. 379, pages 315-321) and SATAKE ET AL. (Molecular and Clinical Oncology, 2017, vol. 7, pages 347-350).
The claimed “applying an alternating electric field to a target region of the subject, the alternating electric field having a frequency between 100 and 400 kHz” is also known in the art as “Tumor Treating Fields (TTFields)” which Applicants describe as “an effective anti-neoplastic treatment modality delivered via application of low intensity, intermediate frequency, alternating electric fields”. See Specification at [0004]. XELOX is a chemotherapy regimen comprising oxaliplatin and capecitabine. See Specification at [0003].
KIRSON ET AL. teach chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields) (Title). They teach combining TTFields with chemotherapeutic treatment in vitro, in vivo, and in a pilot clinical trial (Abstract). Specifically, they teach exposing human breast carcinoma (MDA-MB-231) and human glioma (U-118) cell lines to TTFields, paclitaxel, doxorubicin, cyclophosphamide, and dacarbazine separately and in combinations. The efficacy of TTFields-chemotherapy combination in vitro was additive with a tendency to synergism for all drugs and cell lines tested (Abstract; Figs. 1 and 2). Regarding claims 9 and 11-16, cancer cells were contacted with a chemotherapeutic agent and alternating electric field was applied at frequencies of 150 kHz (breast cancer cells) or 200 kHz (glioma cells) for 72 hours at an intensity of 1.75 V/cm (page 2, right column, “Cell cultures” and “TTFields treatment of cultures”). Regarding claims 1 and 3-8, for in vivo experiments TTFields were applied at an “optimal frequency” of 150 kHz and intensity of 1-2 V/cm. The animals were treated for 21 days continuously, which meets the limitation “the applying has a duration of at least 72 hours” (page 3, left and right columns, “In-vivo experiments”; Fig. 5). Further regarding claims 1 and 3-8, in a pilot clinical trial 10 newly diagnosed patients having GBM received TTFields combined with maintenance Temozolomide. They received “multiple 4-week courses of continuous NovoTTF-100A treatment” which delivered 200 kHz, 0.7 V/cm fields (paragraph bridging pages 3-4; Fig. 6). The authors conclude “…TTFields may be used clinically not only as an anti-proliferation agent…but also as effective sensitizers of currently used chemotherapeutic agents”. Chemo/TTFields combinations “are expected to provide the same or even greater therapeutic efficacy with much lower drug concentrations” (page 11, right column, “Conclusion”).
MUN ET AL. teach the safety and feasibility of TTFields in combination with chemotherapy in advanced pancreatic cancer is currently being studied in an ongoing phase II clinical trial. Specifically, they teach a prospective, nonrandomized study designed to test the safety and efficacy of TTFields (150 kHz) concomitant with gemcitabine alone or nab-paclitaxel plus gemcitabine in patients with advanced pancreatic adenocarcinoma (paragraph bridging pages 270-271). They teach the safety and preliminary efficacy of TTFields in combination with paclitaxel in patients with recurrent ovarian cancer were studied in a phase II clinical trial (See paragraph bridging pages 271-272). They teach a pilot clinical trial was conducted in Europe (NCT00749346) for inoperable stage IIIB and IV squamous and nonsquamous NSCLC patients (N=41) who received pemetrexed (500mg/m2 i.v. q3w) concurrently with TTFields daily, until disease progression (page 272, right column, first full paragraph). They teach the efficacy of TTFields in NSCLC is currently being investigated in a phase III trial (LUNAR, NCT02973789). Patients (N = 512) with squamous or nonsquamous NSCLC are enrolled and stratified by second-line therapy (either PD-1 inhibitor or docetaxel) and histology (squamous vs. nonsquamous) (Id. at second full paragraph). They teach the efficacy of TTFields in combination with chemotherapy in malignant pleural mesothelioma is currently being studied in an ongoing phase II clinical trial, STELLAR (NCT02397928). This is a prospective, nonrandomized, open-label study designed to test the safety and efficacy of TTFields (150 kHz) concomitant with pemetrexed and cisplatin or carboplatin in malignant mesothelioma (page 273, left column, first full paragraph). They teach in the future, TTFields will continue to broaden its scope of use to include new and previously unstudied solid tumors. Currently, preclinical studies investigating the utility of TTFields are underway in the following cancer types: breast, cervical, colorectal, gastric, hepatocellular, melanoma, renal, urinary transitional cell, and small-cell lung cancer (page 273, left column, second full paragraph).
BENSON teaches TTFields therapy is non-invasive, and the therapeutic effect is achieved through the regional delivery of low-intensity, intermediate frequency specific (100 to 300 kHz), alternating electric fields to the site of a tumor in the body (page 138, left column, first paragraph). Regarding claims 1, 4-5, 9, and 12-13, Benson teaches for all cancer types the frequency of the alternating electric field of TTFields is 120 kHz, 150 kHz, or 200 kHz (Figure 2). Also see page 146, paragraph bridging left and right columns (“Clinical development is currently underway for brain metastases from lung cancers (150 kHz), non–small cell lung cancer (150 kHz), ovarian cancer (200 kHz), pancreatic cancer (150 kHz), and mesothelioma (150 kHz)”). Regarding claims 6-8, and 14-16, Benson teaches TTFields treatment effect is dose-dependent, where “dose” is equated with the peak-to-peak alternating electric field intensity, which has a minimal threshold value of 1 V/cm. Below this value there is little effect on cancer cell proliferation (page 146, left column, first paragraph). Benson, like Mun et al. supra, also teaches preclinical studies are ongoing in the following cancer types; breast, cervical, colorectal, gastric, hepatocellular, melanoma, renal, urinary transitional cell and small cell lung cancer (page 146, paragraph bridging left and right columns). Benson teaches ongoing research suggests that there are potential complementary or synergistic effects when TTFields are added to chemotherapies or immunotherapies. Localized, regional therapy with TTFields may provide tumor control in combination with therapies having synergistic mechanisms of action without dose-limiting toxicity or compounding any potential adverse effects associated with the systemic treatment (paragraph bridging pages 146-147).
The instant claims differ from the combined teachings of Kirson et al., Mun et al., and Benson only in so far as the references do not disclose administering the chemotherapeutic regimen of oxaliplatin and capecitabine to subjects with gastric cancer in combination with TTFields. However, as evidenced by BANG ET AL. and SATAKE ET AL., combination chemotherapy with oxaliplatin and capecitabine was a known, effective treatment for patients with gastric cancer.
BANG ET AL. teach administering therapeutically effective doses of oxaliplatin and capecitabine to patients having gastric cancer in a Phase 3, open-label randomized controlled trial. 3 year disease-free survival was 74% (95% CI 69–79) in the chemotherapy and surgery group and 59% (53–64) in the surgery only group. They teach adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer (Summary). They teach several phase 2 trials have shown the activity of capecitabine and oxaliplatin in advanced gastric cancer (page 316, left column, first full paragraph). They teach patients assigned to the chemotherapy group received eight 3-week cycles of oral capecitabine (1000 mg/m² twice daily on days 1–14 of each cycle) plus intravenous oxaliplatin (130 mg/m² on day 1 of each cycle) (page 316, right column, “Procedures”).
SATAKE ET AL. teach combination chemotherapy with capecitabine and oxaliplatin for gastric cancer (G‑XELOX) is considered as a potentially promising regimen. Enrolled metastatic gastric cancer patients received systemic chemotherapy with oxaliplatin 130 mg/m2 on day 1 and capecitabine 2,000 mg/m2/day, b.i.d. for 14 days, repeated every 3 weeks and the response rate and disease control rate were both 67% (Abstract).
A claimed invention is unpatentable if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious to one of ordinary skill in the relevant art. 35 U.S.C. § 103. Whether a claimed invention would have been obvious is a question of law, based on factual determinations regarding the scope and content of the prior art, differences between the prior art and the claims at issue, the level of ordinary skill in the pertinent art, and any objective indicia of non-obviousness. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007); Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17-18 (1966).
In the present case, it is well established in the art that applying an alternating electric field to a target region of a subject with cancer at a frequency between 100 and 400 kHz, specifically between 120 kHz and 200 kHz, and a field strength of at least 1 V/cm in combination with standard chemotherapy is clinically effective in treating numerous cancers as evidenced by Kirson et al., Mun et al., and Benson. Indeed, such combined treatment was being actively investigated in numerous clinical trials in the treatment of glioblastoma, advanced pancreatic cancer, recurrent ovarian cancer, stage IIIB and IV squamous and nonsquamous NSCLC, and malignant pleural mesothelioma. See Mun et al. Additionally, preclinical studies were already ongoing in the following cancer types; breast, cervical, colorectal, gastric, hepatocellular, melanoma, renal, urinary transitional cell and small cell lung cancer at the time the application was filed. See Mun et al. and Benson.
As administration of oxaliplatin and capecitabine was a known, clinically effective chemotherapeutic regimen for the treatment of gastric cancer (Bang et al. and Satake et al.), a person of ordinary skill in the art would have found it prima facie obvious at the time the application was filed to combine the teachings of the references so as to administer oxaliplatin and capecitabine to subject with gastric cancer in combination with applying TTFields to the subject at a frequency of 120 to 200 kHz. A person of ordinary skill in the art would have a reasonable expectation of success because each of these treatment modalities were already known to be clinically effective in treating cancer and the cited prior art expressly teaches that TTFields is used in combination with standard chemotherapy in the treatment of cancer patients. Indeed, the prior art expressly teaches “…TTFields may be used clinically not only as an anti-proliferation agent…but also as effective sensitizers of currently used chemotherapeutic agents” and chemo/TTFields combinations “are expected to provide the same or even greater therapeutic efficacy with much lower drug concentrations” (Kirson et al.). See also Benson who teaches ongoing research suggests that there are potential complementary or synergistic effects when TTFields are added to chemotherapies or immunotherapies. As such, because combined administration of oxaliplatin and capecitabine was already a “currently used” chemotherapeutic agent combination for treating gastric cancer, a person of ordinary skill in the art would reasonably expect TTFields to be an effective sensitizer of oxaliplatin and capecitabine and to provide the same or even greater therapeutic efficacy than administration of oxaliplatin and capecitabine alone as expressly suggested by the cited prior art.
Regarding the newly added limitation “wherein the oxaliplatin and capecitabine are administered at therapeutically effective doses”, such therapeutically effective doses for treating gastric taught are taught by both Bang et al. and Satake et al. It would have been obvious to administer oxaliplatin and capecitabine at doses already known to be therapeutically effective in treating gastric cancer as taught in Bang et al. and Satake et al. when treating gastric cancer in a subject.
Response to Arguments
Applicant’s arguments have been fully considered and are unpersuasive. Applicants argue that a fundamental flaw in the Office’s reasoning is that Mun and Benson do not teach the efficacy of TTFields for treatment of gastric cancer, let alone motivate a specific combination with oxaliplatin and capecitabine (Emphasis Applicant’s). More specifically, Applicants argue a careful review of Mun and Benson reveals that these references do not teach the efficacy of TTFields for the treatment of gastric cancer, nor do these references provide a basis for a reasonable expectation of success for such treatment or for combining it with oxaliplatin and capecitabine.
With regard to Applicant’s arguments pertaining to a reasonable expectation of success being required to find obviousness, the Examiner acknowledges and does not dispute Applicant’s assertion that any finding of obviousness requires that there be a reasonable expectation of success. MPEP 2143.02(1). However, the Examiner notes that absolute predictability is not required for obviousness, only that at least some degree of predictability is required for there to be a reasonable expectation of success. See MPEP 2143.02 (1). Here, with respect to Applicant’s contention that the cited references fail to provide a reasonable expectation of success, the Examiner acknowledges and does not dispute Applicant’s contention that no single individual reference demonstrates that combining oxaliplatin and capecitabine chemotherapy with TTFields in a subject with gastric cancer is therapeutically effective. In other words, it is true that the cited prior art does not provide any working examples of this specific combination in this specific cancer. However, Applicants are reminded that the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references, which make up the state of the art with regard to the claimed invention. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference and it is not that the claimed invention must be expressly suggested in any one or all of the references; but rather the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, each of the therapeutics (TTFields and the chemotherapy combination of oxaliplatin and capecitabine) had been individually taught in the prior art to be successful at treating cancer. A person of ordinary skill in the art would have a reasonable expectation of success because each of these treatment modalities were already known to be clinically effective in treating cancer and the cited prior art expressly teaches that TTFields is used in combination with standard chemotherapy in the treatment of cancer patients. Indeed, the prior art expressly teaches “…TTFields may be used clinically not only as an anti-proliferation agent…but also as effective sensitizers of currently used chemotherapeutic agents” and chemo/TTFields combinations “are expected to provide the same or even greater therapeutic efficacy with much lower drug concentrations” (Kirson et al.). See also Benson who teaches ongoing research suggests that there are potential complementary or synergistic effects when TTFields are added to chemotherapies or immunotherapies. As such, because combined administration of oxaliplatin and capecitabine was already a “currently used” chemotherapeutic agent combination for treating gastric cancer, a person of ordinary skill in the art would reasonably expect TTFields to be an effective sensitizer of oxaliplatin and capecitabine and to provide the same or even greater therapeutic efficacy than administration of oxaliplatin and capecitabine alone as expressly suggested by the cited prior art.
Regarding Applicant’s argument that the prior art only teaches that “preclinical studies are underway” and is therefore not a disclosure of established efficacy or even preliminary positive results, the prior art had already established the clinical efficacy of combining TTFields with known chemotherapeutic regimens in other cancer types. Further, the prior art had already established the clinical efficacy of the combination of oxaliplatin and capecitabine in gastric cancer. That the prior art had not yet demonstrated efficacy in gastric cancer when TTFields are combined with the known gastric cancer chemotherapeutic regimen of oxaliplatin and capecitabine, is not probative that there was no reasonable expectation of success in doing so as alleged by Applicants.
Applicants argue:
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In response, the Examiner never suggested or implied that “preclinical studies” carries an inherent disclosure or presumption of efficacy. Rather, the fact that preclinical studies were ongoing suggests that those skilled in the art reasonably expected TTFields to be broadly applicable to other cancers, including gastric cancer. Indeed, combining TTFields with known chemotherapeutic regimens was already being investigated in Phase II and Phase III clinical trials prior to Applicant’s invention.
Applicants argue:
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In response, the Examiner also never relied on “official notice” or common knowledge in the art regarding the implications of “preclinical studies” being underway. The Examiner’s citation to the prior art teaching that preclinical studies were underway for TTFields in other cancer types, including gastric cancer, is simply a statement of fact of the prior art teachings.
For the above reasons and those already of record, claims 1, 3-9, and 11-16 remain rejected as being prima facie over the combined teachings of the cited prior art.
Conclusion
Claims 1, 3-9, and 11-16 are rejected.
No claims are allowed.
Applicant is requested to specifically point out the support for any amendments made to the disclosure in response to this Office action, including the claims (M.P.E.P. §§ 714.02 and 2163.06). In doing so, applicant is requested to refer to pages and line (or paragraph) numbers (if available) in the as-filed specification, not the published application. Due to the procedure outlined in M.P.E.P. § 2163.06 for interpreting claims, other art may be applicable under 35 U.S.C. § 102 or 35 U.S.C. § 103(a) once the aforementioned issue(s) is/are addressed.
Applicant is reminded that MPEP §2001.06(b) clearly states that “[t]he individuals covered by 37 C.F.R. 1.56 have a duty to bring to the attention of the examiner, or other Office official involved with the examination of a particular application, information within their knowledge as to other copending United States applications which are "material to patentability" of the application in question." See Armour & Co. v. Swift & Co., 466 F.2d 767, 779, 175 USPQ 70, 79 (7th Cir. 1972). MPEP §2001.06(b) clearly indicates that “if a particular inventor has different applications pending in which similar subject matter but patentably indistinct claims are present that fact must be disclosed to the examiner of each of the involved applications.” See Dayco Prod. Inc. v. Total Containment, Inc., 329 F.3d 1358, 1365-69, 66 USPQ2d 1801, 1806-08 (Fed. Cir. 2003).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES D ANDERSON whose telephone number is (571)272-9038. The examiner can normally be reached on Monday-Friday, 8:30 am - 5:00 pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/James D. Anderson/Primary Examiner, Art Unit 1629
UNITED STATES PATENT AND TRADEMARK OFFICE
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Tel. No.: (571) 272-9038