Alternating electric field waveform for electrosensation reduction

Abstract

An apparatus to treat a target region of a subject's body with an alternating electric field and being capable of: applying the alternating electric field to the target region of the subject's body at a first frequency while increasing an intensity of the alternating electric field from zero to a target intensity; and changing the frequency of the alternating electric field from the first frequency to a target frequency while maintaining the alternating electric field at the target intensity, wherein the target frequency and the target intensity have a known efficacy for treating the target region of the subject's body with the alternating electric field; and wherein the first frequency is greater than the target frequency.

Description

(19) *EP004696363A2* (11) EP 4 696 363 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: 18.02.2026 Bulletin 2026 / 08 (21) Application number: 25226932.9 (22) Date of filing: 31.03.2023 (51) International Patent Classification (IPC): A61N 1 / 04 (2006.01) (52) Cooperative Patent Classification (CPC): A61N 1 / 36034; A61N 1 / 0476; A61N 1 / 0492; A61N 1 / 36002 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 31.03.2022 US 202263326098 P 27.09.2022 US 202263410481 P 30.03.2023 US 202318128937 (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 23719487.3 / 4 489 845 (71) Applicant: Novocure GmbH 6340 Baar (CH) (72) Inventors: • GILADI, Moshe 31905 Haifa (IL) • AVIGDOR, Lilach 31905 Haifa (IL) (74) Representative: Carpmaels & Ransford LLP One Southampton Row London WC1B 5HA (GB) Remarks: This application was filed on 23.12.2025 as a divisional application to the application mentioned under INID code 62. (54) ALTERNATING ELECTRIC FIELD WAVEFORM FOR ELECTROSENSATION REDUCTION (57) An apparatus to treat a target region of a sub- ject’s body with an alternating electric field and being capable of: applying the alternating electric field to the target region of the subject’s body at a first frequency while increasing an intensity of the alternating electric field from zero to a target intensity; and changing the frequency of the alternating electric field from the first frequency to a target frequency while maintaining the alternatingelectric field at the target intensity,wherein the target frequency and the target intensity have a known efficacy for treating the target region of the subject’s body with the alternating electric field; and wherein the first frequency is greater than the target frequency. EP 4 69 6 36 3 A 2 Processed by Luminess, 75001 PARIS (FR) 2 1 EP 4 696 363 A2 2 Description CROSS-REFERENCE

[0001] This application claims priority to U.S. Patent Application No. 18 / 128,937 filed March 30, 2023, U.S. Provisional Application No. 63 / 326,098, filed March 31, 2022, and U.S. Provisional Application No. 63 / 410,481, filed September 27, 2022, the entire contents of each of which are incorporated herein by reference. BACKGROUND

[0002] Tumor treating fields (TTFields) are low inten- sity alternating electric fields within the intermediate fre- quency range, which may be used to treat tumors as described in U.S. Patent No. 7,565,205. TTFields are induced non-invasively into a region of interest by trans- ducers placed directly on a patient’s body and applying AC voltages between the transducers. AC voltage is applied between a first pair of transducers for a first interval of time to generate an electric field with field lines generally running in the front-back direction. Then, AC voltage is applied at the same frequency between a second pair of transducers for a second interval of time to generate an electric field with field lines generally running in the right-left direction. The system then re- peats this two-step sequence throughout the treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0003] FIG. 1A depicts an example method of treating a target region of a subject’s body. FIG. 1B depicts an example method of treating a target region of a subject’s body. FIG. 2 depicts an example system having four trans- ducers. FIG. 3 depicts an example apparatus to control an alternating electric field. FIGS. 4‑6 depict example waveforms of an alternat- ing electric field. FIG. 7 depicts another example method of treating a target region of a subject’s body. FIG. 8 depicts an example method of delivering an alternating electric field to a subject’s body. FIG. 9 depicts an example method of delivering an alternating electric field to a subject’s body as tem- perature rises. FIG. 10 depicts an example cytotoxicity analysis showing the effects of the field intensity. FIGS. 11A‑11Cdepict an experimental stimulation of a sciatic rat nerve bundle with alternating electric fields. DESCRIPTION OF EMBODIMENTS

[0004] This application describes exemplary systems and methods for delivering alternating electric fields to a subject’s body for treatment of the subject’s body. In particular, the present disclosure relates to systems and methods for applying an alternating electric field according to a waveform that reduces electrosensation in a subject.

[0005] When treating a subject using alternating elec- tric fields, higher intensities (e.g., amplitudes) may be strongly associated with higher efficacy of treatment. However, at higher intensity (e.g., amplitude) of the alter- nating electric field, and / or lower frequency of the alter- nating electric field (e.g., in the vicinity of 100 kHz), some subjects experience an electrosensation effect, particu- larly at the onset of the alternating electric field.

[0006] The electrosensation may originate from inter- actions between the alternating electric fields and nerve cells that are positioned near or adjacent to the transdu- cer arrays inducing the alternating electric fields. For example, an AC current at a given frequency may be coupled into a subject’s body through a pair of identical electrodes that are positioned on the subject’s skin for applying the alternating electric field. When the current density (e.g., the current through any given electrode divided by the area of that electrode) is below a threshold value (which may vary from person to person), electro- sensation may not occur. When the current density rises above that threshold, however, electrosensation can start to occur and can become more noticeable when the current density is increased further. This electrosen- sation could be, for example, a vibratory sensation, par- esthesia, and / or a twitching or contraction sensation of muscle fibers. These sensations may discourage some subjects fromcontinuing their treatment using alternating electric fields.

[0007] The inventors realized these problems and dis- coveredmethodsandsystems for reducingoreliminating electrosensation while a subject is treated with alternat- ing electric fields. In particular, the inventors realized that electrosensation occurs in response to current densities that are present during onset of a duty cycle of the alternating electric field. The present disclosure is direc- ted to systems and methods for avoiding electrosensa- tion at the onset of the duty cycle altogether by applying the alternating electric field at a higher frequency during the dimming up period. The alternating electric field is applied to the subject’s body using a voltage generated according to an AC voltage waveform. In a given duty cycle, the AC voltage waveform has a higher frequency during thedimmingupperiod, thenswitches toanoptimal frequency for treating the subject’s body at or near the time when the electric field reaches peak intensity. This hybrid frequency AC voltage waveform helps avoid elec- trosensation that might otherwise occur if the optimal frequency for treating the subject’s body were used dur- ing the entire duty cycle. 5 10 15 20 25 30 35 40 45 50 55 3 3 EP 4 696 363 A2 4

[0008] The inventors discovered systems and meth- ods for minimizing electrosensation at the onset of the duty cycle by applying the alternating electric field at a lower intensity and a higher frequency during the dim- ming up period. The alternating electric field may be applied to the subject’s body using a voltage generated according to an AC voltage waveform. During the dim- ming up period of the duty cycle, the AC voltage wave- form initially has a lower intensity than a target intensity and a higher frequency than a target frequency. As the dimming up period proceeds, the intensity is increased to the target intensity, and the frequency is decreased to the target frequency. This AC voltage waveform may help to avoid electrosensation that might otherwise occur if the target intensity and the target target frequency for treat- ing the subject’s body were used during the entire duty cycle.

[0009] FIG. 1Adepicts an examplemethod 100 to treat a target region of a subject’s body with an alternating electric field. Themethod 100may include, at step S102, determining a target frequency and a target intensity for application of an alternating electric field. In an example, the target region may include at least one of cancer, a tumor, an endothelial or epithelial tight junction (e.g., such as a blood-brain barrier (BBB) or intestinal wall tight junction), or any tissues or cells of the subject. In an example, the target region may be determined by the treating of viral infections, bacterial infections, neurode- generative diseases, and / or autoimmune diseases. In certain embodiments, the subject can experience elec- trosensation when an alternating electric field with the target intensity and the target frequency is applied.

[0010] The term "target frequency" used herein may refer to a clinically approved frequency that can provide a known efficacy for the desired treatment of a subject using an alternating electric field applied to the subject at the target frequency.Forexample, the target frequency can be a clinically approved frequency that provides a proven efficacy against tumor cell proliferation or for opening an endothelial or epithelial tight junction. For example, the target frequency may be determined from in vitro assay. The term "target frequency" may also refer to a frequency that is more effective for the intended treatment than a first frequency. In general, the target frequency is lower than the first frequency. The target frequency may be in a target frequency range corre- sponding to a particular target cell, tissue, and / or treat- ment.

[0011] In non-limiting embodiments, the target fre- quency may be approximately 50 kHz to approximately 10 MHz, approximately 50 kHz to approximately 1 MHz, approximately 50 kHz to approximately 500 kHz, or ap- proximately 100 kHz to approximately 400 kHz. As an example, if the target region is a glioblastoma (GBM), the target frequency may be approximately 100 kHz to ap- proximately 300 kHz for treating the GBM (e.g., 50 kHz - 350 kHz, or 150 kHz - 250 kHz, or 200 kHz). For example, if the treatment goal is to reduce tumor cell proliferation, the target frequency may be approximately 100 kHz to approximately 400 kHz (e.g., 150 kHz - 200 kHz, or 140 kHz - 220 kHz). As another example, if the target region is an epithelial or endothelial tight junction, the target fre- quency may be approximately 50 kHz to approximately 190 kHz for opening the epithelial or endothelial tight junction (e.g., 75 kHz - 190 kHz, or 100 kHz, or 150 kHz). As another example, if the treatment goal is to change cancer cell membrane permeability (e.g., increase can- cer cell membrane permeability), the target frequency may beapproximately 100 kHz to approximately 500 kHz (e.g., 50 kHz - 550 kHz, or 150 kHz - 350 kHz, or 250 kHz - 400 kHz). For example, if the treatment goal is to treat non-small cell lungcancer (NSCLC), the target frequency may beapproximately 100 kHz to approximately 200 kHz (e.g., 150 kHz). For example, if the target region / tissue is pancreatic tissue / cancer, the target frequency may be approximately 100 kHz to approximately 200 kHz (e.g., 150 kHz). For example, if the target region / tissue is ovarian tissue / cancer, the target frequency may be ap- proximately 150 kHz to approximately 250 kHz (e.g., 200 kHz). For example, if the target region / tissue is gastric tissue / cancer, the target frequency may be approxi- mately 100 kHz to approximately 200 kHz (e.g., 150 kHz). Although this disclosure describes and illustrates particular frequency ranges, this disclosure contem- plates any target frequency range configured to produce a proven efficacy for treating a subject.

[0012] In some embodiments, the term "target inten- sity" may refer to a clinically approved intensity that can provide a known efficacy for the desired treatment of a subject using an alternating electric field applied to the subject at the target intensity. For example, the target intensity can be a clinically approved intensity that pro- vides a proven efficacy against tumor cell proliferation or for opening an epithelial or endothelial tight junction. For example, the target intensity may be determined from in vitro assay.

[0013] In some embodiments, the term "target inten- sity" may refer to an intensity that ismore effective for the intended treatment than a first intensity applied to a subject. In general, the target intensity is higher than the first intensity. In certain embodiments, the target intensitymaybe in a target intensity range corresponding to a particular target cell, tissue, and / or treatment.

[0014] In some embodiments, the term "target inten- sity" may refer to an intensity based on a temperature related to the alternating electric field applied to the subject’s body. For example, the target intensity may be based on a temperature of the subject’s body mea- sured at a location on the subject’s body that receives the alternating electric field. For example, the target intensity may be based on a temperature of an electrode that is providing the alternating electric field to the subject’s body. For example, the target intensity may be the max- imum intensity that can be achievedwithout the subject’s body and / or an electrode applying the alternating electric fieldexceedinga temperature thresholdbetweena range 5 10 15 20 25 30 35 40 45 50 55 4 5 EP 4 696 363 A2 6 (e.g., between approximately 37° C and approximately 43° C).

[0015] In some embodiments, the term "target inten- sity" may refer to a combination of two or more of the above exemplary target intensities, in the aggregate and / or in the alternative.

[0016] In non-limiting embodiments, the target inten- sity may be approximately 0.5 V / cm to approximately 10 V / cm, or approximately 0.1 V / cm to approximately 20 V / cm. For example, if the target region is a GBM, the target intensity may be approximately 1 V / cm to approxi- mately 5 V / cm for treating the GBM (e.g., 1 V / cm - 3 V / cm). For example, if the treatment goal is to reduce tumor cell proliferation, the target intensity may be ap- proximately 1V / cm to approximately 5V / cm (e.g., 1V / cm - 3 V / cm). For example, if the target region is a BBB, the target intensity may be approximately 1 V / cm to approxi- mately 5 V / cm (e.g., 1 V / cm - 3 V / cm) for opening the BBB. For example, if the treatment goal is to change cell membrane permeability (e.g., increase cell membrane permeability), the target intensitymaybeapproximately1 V / cm to approximately 5 V / cm (e.g., 1 V / cm - 3 V / cm).

[0017] Although this disclosure describes and illus- trates particular frequency ranges and intensity ranges, this disclosure contemplates any target frequency range andany target intensity rangehavinga knownefficacy for treating a subject. In non-limiting embodiments, the tar- get frequency and / or the target intensity can vary de- pending on the target region.

[0018] At step S104, the method 100 may include selecting a first frequency to reduce electrosensation in the subject’s body. An alternating electric field that begins at the first frequency is able to reduce electro- sensation of the subject compared to an alternating electric field that is applied at the target frequency while the intensity is ramped up to the target intensity. In one example, the first frequencymaybe selected bydecreas- ing a frequency level of the alternating electric field stepwise from an initial frequency until the subject ex- periences the electrosensation, as indicated by the re- sponse of the subject. In one example, the first frequency may be selected by decreasing a frequency level of the alternatingelectric field stepwise froman initial frequency until the subject experiences the electrosensation, as indicated by an objective measure, such as detection of nerve stimulation.

[0019] The first frequency is greater than the target frequency. For example, the first frequency may be at least approximately10%higher than the target frequency (e.g., at least approximately 20% higher, 30% higher, 50% higher, 75% higher, 100% higher, 150% higher, 200% higher, or 300% higher). As another example, the first frequency may be at least approximately 10 kHz higher than the target frequency (e.g., at least ap- proximately 20 kHz higher, 30 kHz higher, 50 kHz higher, 75 kHz higher, 100 kHz higher, 150 kHz higher, 200 kHz higher, or 300 kHz higher). In an example, the first fre- quency may be between approximately 100 kHz and approximately 400 kHz, between approximately 200 kHz and approximately 600 kHz, between approximately 300kHzandapproximately 800kHz, orbetweenapproxi- mately 50 kHz and approximately 350 kHz. In an exam- ple, the first frequencymaybeashighas900kHz, 1MHz, 10MHz, or higher. The first frequencymaydependon the current being applied to the transducer pairs. In general, a subject feels a greater degree of electrosensation at higher intensities. Accordingly, in some embodiments, a higher first frequency may be used when higher inten- sities (e.g.. higher currents) are applied to compensate for the greater degree of electrosensation at higher in- tensities. For example, in an embodiment where a 2Amp current is applied, the first frequency may be between approximately 300 kHz and 400 kHz. As another exam- ple, in an embodiment where a 4 Amp current is applied, the first frequency may be between approximately 500 kHz and 600 kHz. In certain embodiments, the first fre- quencymay be pre-determined based on certain criteria, such as the type of treatment, body part to which the transducers will be applied on the subject, and / or other information on the subject.

[0020] At stepS106, themethod 100 includes applying an alternating electric field to the target region of the subject’s body at the first frequency while increasing an intensity of the alternating electric field from zero to the target intensity. This represents the beginning of a duty cycle of the alternating electric field. The duty cycle of thealternatingelectric fieldmaybeginwithapplying the alternating electric field at the first frequency while ramp- ing up (or "dimming up") the intensity of the alternating electric field.

[0021] At step S108, the method 100 includes chan- ging the frequency of the alternating electric field from the first frequency to the target frequency while maintaining the alternating electric field at the target intensity. In particular, the frequency of the alternating electric field decreases from thefirst frequency to the target frequency that is optimal for treatment of the subject’s body. In an example, the frequency change may be immediate or may take less than approximately 200 ms, less than approximately 100 ms, less than approximately 50 ms, less than approximately 25 ms, less than approximately 10 ms, less than approximately 5 ms, less than approxi- mately 1 ms, or less than approximately 0.1 ms to occur. In another example, the frequency change may be gra- dual (e.g., taking at least approximately 0.1 ms, at least approximately 1ms, at least approximately 5ms, at least approximately 10 ms, at least approximately 25 ms, at least approximately 50 ms, at least approximately 100 ms, or at least approximately 200 ms to occur and / or taking place in a stepwise manner). The change in fre- quencymay take place immediately when or shortly after the alternating electric field reaches the target intensity.

[0022] Thealternating electric fieldmay continueat the target frequency until, at step S110, a first period of time has passed. The first period of time may be less than approximately 3 seconds (e.g., less thanapproximately 2 5 10 15 20 25 30 35 40 45 50 55 5 7 EP 4 696 363 A2 8 seconds, or less than approximately 1 second).

[0023] After the first period of time (S110), the method 100 may include, at step S112, halting application of the alternating electric field to complete a first duty cycle of the alternating electric field. The alternating electric field may be configured to reduce electrosensation of the subject compared to when an alternating electric field is applied at the target frequency for its entire duty cycle.

[0024] At step S114, the method 100 may include determiningwhether a secondperiodof timehaspassed. The second period of timemay be fromapproximately 12 hours to approximately 4 weeks (e.g., between approxi- mately 48 hours and 3 weeks, or between approximately 1week and 2weeks). If the second period of time has not passed, themethod 100may repeat steps S106 to S114. That is, the method 100 may include applying one or more subsequent duty cycles of the alternating electric field of steps S106 to S 112. In certain embodiments, the method 100may include alternately applying duty cycles of the alternating electric field via a first pair of transducer arrays and via a second pair of transducer arrays.

[0025] Once the second period of time (S114) has passed, the method 100 may include, at step S116, switching from applying the alternating electric field to the target region of the subject’s body to applying a second alternating electric field to the target region of the subject’s body with a second frequency that is lower than the first frequency and closer to or at the target frequency throughout each duty cycle. After the second period of time (S114), the subject’s body may be desen- sitized to the current density at the electrode / skin inter- face such that the subject will no longer experience electrosensation during the dimming up period. As such, the second alternating electric field having the lower (or target) frequency throughout the entire duty cyclemaybe well tolerated by the subject and used to deliver higher efficacy of treatment.

[0026] In some embodiments, the alternating electric field can be cyclically applied to the target region. Cycling treatment involves the application of the alternating elec- tric field for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling treatment may reduce or avoid electrosensation and / or may improve the efficacy of the treatment. In non- limiting embodiments, the number of cycles can be from approximately 1 to approximately 50, or from approxi- mately 1 to approximately 24. In one example, the rest time can be from approximately ten seconds to approxi- mately a week. In certain embodiments, the treatment stops when the subject experiences electrosensation and / or is intolerable to the adverse effects associated with the alternating electric field.

[0027] The subject’s bodymay not experience electro- sensation when the second alternating electric field is applied. In one example, the second alternating electric field can have a second frequency closer to or at the target frequency than the first frequency. In one example, the second alternating electric field can have a second intensity closer to or at the target intensity than the first intensity. In one example, the second alternating electric field canhaveasecond frequencyandasecond intensity, which are the target frequency and the target intensity. In non-limiting embodiments, the first alternating electric field may be continuously switched to the second alter- nating electric field without turning off the system / trans- ducer for a wait time. In an example, an alternating electric field may be applied, with or without pausing, while the parameters of the alternating electric field are changed between a first set and a second set. In an example, the alternating electric field with the first fre- quency and the first intensity can be ceased, and a second alternating electric field can be applied to the target region of the subject’s body. "Ceased"may refer to the stoppage of the alternating electric field so that no alternating electric field is applied or a change in the parameters of the alternating electric fields so that, in effect, a different alternating electric field may then be applied.

[0028] It should be noted that the target frequency, target intensity, first frequency, first period of time, and second period of time may be specifically tailored to the individual subject receiving treatment, based on the tar- get region and / or the presence or amount of electrosen- sation felt by the subject.

[0029] In one example, the alternating electric field can be applied to the target region in a single dose or divided doses. For example, the alternating electric field can be applied to the target regiononceaday, twiceaday, oncea week, twice a week, three times a week, four times a week, five timesaweek, six timesaweek, onceevery two weeks, once a month, twice a month, once every other month or once every third month.

[0030] During the treatment dose, the patientmay take breaks within the treatment and still be considered dose. For example, a patient may receive the alternating elec- tric field treatment approximately 80% of the time and takebreaks. In oneexample, for openingaBBB,apatient may wear or equip the disclosed systems / devices for approximately three days (e.g., approximately 72 hours) to open the BBB but can have breaks during the treat- ment time. For tumors, the device may be used for ex- tendedperiods of time (indefinitely), againwith breaks for showering, swimming, changing the arrays, etc., with the goal being80%of the treatment time thearraysareon.As an example, once a month may be useful for a BBB application, if the "once a month" is at least 72 hours, but for tumors, longer stretches of using the device may be required.

[0031] In an example, the alternating electric field can be applied to the target region for a predetermined inter- val of time. For example, the interval of time may be based on how long a typical subject may experience electrosensation at the target frequency and / or target intensity. For example, the interval of time may be based on how long the subject experiences electrosensation at the target frequency and / or target intensity. Such an 5 10 15 20 25 30 35 40 45 50 55 6 9 EP 4 696 363 A2 10 interval of time may be subjective based on the subject.

[0032] In one example, the predetermined interval of time (e.g., duration of the alternating electric field treat- ment) can be between approximately one second and approximately 1month. For example, the intervalmay be approximately 1hour toapproximately 12hours, approxi- mately 12 hours to approximately 24 hours, approxi- mately 1 day to approximately 3 days, approximately 3 days to approximately 7 days, approximately 1 week to approximately 2 weeks, or approximately 1 week to approximately 3 weeks.

[0033] FIG. 1Bdepicts an examplemethod 150 to treat a target region of a subject’s body with an alternating electric field. The target region may be a similar target region as described above with regards to FIG. 1A. The method 150 may include step 102, as in FIG. 1A.

[0034] At step S124, the method 150 may include selecting a first frequency and a first intensity to reduce electrosensation in the subject’s body. During a dimming period, the first frequency and the first intensity of the alternating electric field are adjusted to the target fre- quency and the target intensity, which may be able to reduceelectrosensationof thesubjectwhencompared to initially applying the alternating electric field with the target frequency and / or the target intensity. The first frequency is greater than the target frequency as de- scribed above in step S104 of FIG. 1A.

[0035] The first intensity is lesser that the target inten- sity. For example, the first intensity may be at least approximately 10% lower than the target intensity (e.g., at least approximately 20% lower, 30% lower, 50% lower, 75% lower, 100% lower, 150% lower, 200% lower, or 300% lower). For example, the first intensity maybe lower than the target intensity by at least 0.1V / cm lower (e.g., at least approximately0.2V / cm,0.3V / cm,0.4 V / cm,0.5V / cm,0.6V / cm,0.7V / cm,0.8V / cm,0.9V / cm,1 V / cm, 1.5 V / cm, 2 V / cm, 2.5 V / cm, 3.0 V / cm, 3.5 V / cm, or 4.5 V / cm lower). In an example, the first intensity may be between approximately 0.1 V / cm and approximately 4.5 V / cm, between approximately 0.5 V / cm and approxi- mately 3.0 V / cm, between approximately 0.1 V / cm and approximately 2.5 V / cm. In an example, the first intensity may be 0V / cm, slightly above 0V / cm, or approximately 0 V / cm.

[0036] At stepS126, themethod 150 includes applying an alternating electric field to the target region of the subject’s body while increasing the intensity of the alter- nating electric field from the first intensity to the target intensity anddecreasing the frequencyof theelectric field from the first frequency to the target frequency. This represents the beginning of a duty cycle of the alternating electric field. Theduty cycle of thealternatingelectric field maybeginwithapplying thealternatingelectric fieldat the first intensity and the first frequency while ramping up (or "dimming up") the intensity of the alternating electric field and simultaneously decreasing the frequency of the al- ternating electric field.

[0037] In an example, the frequency change may be immediate or may take less than approximately 200 ms, less than approximately 100ms, less than approximately 50ms, less than approximately 25ms, less than approxi- mately 10 ms, less than approximately 5 ms, less than approximately 1ms, or less than approximately 0.1ms to occur. In another example, the frequency changemay be gradual (e.g., taking at least approximately 0.1 ms, at least approximately 1ms, at least approximately 5ms, at least approximately 10ms, at least approximately 25ms, at least approximately 50 ms, at least approximately 100 ms, or at least approximately 200 ms to occur and / or taking place in a stepwise manner).

[0038] The change in frequencymay correspond to an equivalent change in intensity. Alternatively, the rate of increase of intensity and rate of decrease of frequency may differ. The rate of increase of intensity and the rate of decrease of frequency donot need to start and stop at the same time. In some embodiments, an overlap of increas- ing intensity and decreasing frequency may occur at the onset of treatment (e.g., the overlap may occur at least within, for example, the first 0.1 seconds of treatment).

[0039] In an example, the intensity change may be immediate or may take less than approximately 200 ms, less than approximately 100 ms, less than approxi- mately 50 ms, less than approximately 25 ms, less than approximately 10ms, less than approximately 5ms, less than approximately 1 ms, or less than approximately 0.1 ms to occur. In another example, the intensity change may be gradual (e.g., taking at least approximately 0.1 ms, at least approximately 1ms, at least approximately 5 ms, at least approximately 10 ms, at least approximately 25 ms, at least approximately 50 ms, at least approxi- mately 100ms, or at least approximately 200ms to occur and / or taking place in a stepwise manner).

[0040] After step S126, the method 150 proceeds to steps S110, S112, S114, and S116 as in FIG. 1A. How- ever, the "no" branch fromstepS114goes to stepS126 in FIG. 1B. As such, for FIG. 1B, the method 150 may include applying one or more subsequent duty cycles of the alternating electric field of steps S126, S110, and S112.

[0041] FIG. 2 depicts an example system having four transducers (or "transducerarrays") 200A-D.Thesystem may be used for treating a target region of a subject’s body with an alternating electric field. In an example, the target region may be in the subject’s brain, and an alter- natingelectric fieldmaybedelivered to the subject’sbody via a pair of transducer arrays positioned on a head of the subject’s body. In another example, the target regionmay be in the subject’s torso, and an alternating electric field may be delivered to the subject’s body via a pair of transducer arrays positioned on at least one of a thorax, an abdomen, or one or both thighs of the subject’s body. Other transducer array placements on the subject’s body may be possible.

[0042] Each transducer 200A-D may include substan- tially flat electrode elements 202A-D positioned on a substrate 204A-D and electrically and physically con- 5 10 15 20 25 30 35 40 45 50 55 7 11 EP 4 696 363 A2 12 nected (e.g., through conductive wiring 206A-D). The substrates 204A-D may include, for example, cloth, foam, flexible plastic, and / or conductive medical gel. Two transducers (e.g., 200A and 200D) may be a first pair of transducers configured to apply an alternating electric field to a target region of the subject’s body. The other two transducers (e.g., 200B and 200C) may be a second pair of transducers configured to similarly apply an alternating electric field to the target region.

[0043] The transducers 200A-D may be coupled to a voltage generator 208 (i.e., AC voltage generator), and the system further includes a controller 210 communica- tively coupled to the AC voltage generator 208. The controller 210 may include a computer having one or more processors 212 andmemory 214 accessible by the one or more processors. The memory 214 may store instructions that when executed by the one or more processors control the voltage generator 208 to induce alternating electric fields between pairs of the transdu- cers 200A-D according to one or more voltage wave- forms and / or cause the computer to perform one ormore methods disclosed herein. The controller 210 maymoni- tor operations performed by the AC voltage generator 208 (e.g., via the processor(s) 212). One or more sen- sor(s) 216 may be coupled to the controller 210 for providing measurement values or other information to the controller 210.

[0044] The voltage generator 208 may provide one or more voltages to the different pairs of transducers (e.g., 200A / D, 200B / C) for applying alternating electric fields to the subject’s body. The controller 210 may instruct the voltage generator 208 to generate the one or more vol- tages according to oneormorewaveforms. For example, themethod described belowwith reference to FIG. 7may be implemented using the voltage generator 208 and controller 210.

[0045] In an example, the controller 210 may provide signals to the first pair of transducers (200A, 200D) for controlling a first alternating electric field according to a first waveform such that: the first alternating electric field begins at a first frequency; the first alternating electric field increases from zero intensity to a target intensity while remaining at the first frequency; and the first alter- nating electric field changes from the first frequency to a target frequency after reaching the target intensity, the target frequency being lower than the first frequency. Similarly, the controller 210 may provide signals to the second pair of transducers (200B, 200C) for controlling a second alternating electric field according to the same or similar waveform.

[0046] FIG. 3 depicts an example apparatus for use with the embodiments herein. As an example, the appa- ratus 300 may be a computer to implement certain tech- niques disclosed herein. As an example, the apparatus 300 may be a controller apparatus to apply alternating electric fields for the embodiments herein. For example, the apparatus 300 may be used as the controller 210 of FIG. 2. The apparatus 300 may include one or more processors 302, a memory 304, and one or more output devices 306. Thememory 304 is accessible by the one or more processors 302 so that the one ormore processors 302 can read information from and write information to thememory 304. Thememory 304may store instructions that when executed by the one or more processors 302 implement one or more embodiments of the present disclosure. For example, the apparatus 300 may include one or more processors and memory accessible by the one or more processors, where the memory stores in- structions that when executed by the one or more pro- cessors, cause the apparatus 300 to perform operations to implement one or more embodiments of the present disclosure.

[0047] In one example, based on input 308, the one or more processors 302 may generate control signals to control the voltage generator to implement an embodi- ment of the invention. The input 308 may be user input, sensor input, or input from another computer in commu- nication with the apparatus 300. The output devices 306 may provide the status of the operation of the invention, such as transducer selection, voltages being generated, and other operational information. The output devices 306 may provide visualization data.

[0048] FIGS.4‑6depict examplewaveforms (400,500, 600) that may be used to control an alternating electric field and / or are representative of an alternating electric field in accordance with the present disclosure. The waveforms (400, 500, 600) show patterns of alternating electric fields during oneormoreduty cycles according to themethodof FIG. 1. In anexample, thewaveforms (400, 500, 600) may represent an amplitude (402, 502, 602) of the intensity of the alternating electric fieldwith respect to time (404, 504, 604), or an amplitude (402, 502, 602) of the voltageapplied to apair of transducerswith respect to time (404, 504, 604).

[0049] As shown in FIGS. 4 and 5, the waveform (400, 500) may include an initial ramp up period (406, 506) during which the amplitude (402, 502) of the waveform (400, 500) increases from zero (408, 508) to a target amplitude (410, 510) while a frequency of the waveform (400, 500) is at a first frequency.Thewaveform (400, 500) also includes a sustained intensity period (412, 512) during which the frequency of the waveform (400, 500) changes to a target frequency that is lower than the first frequencywhile theamplitude (402, 502)of thewaveform (400, 500) remains at the target amplitude (410, 510).

[0050] As shown in FIG. 4, the change in the frequency of the waveform 400 (e.g., alternating electric field) from the first frequency to the target frequency may be per- formed instantly (or nearly instantly) at one time during application of the alternating electric field. In an example, the change in the frequencyof thewaveform400 from the first frequency to the target frequency may be performed in less than a period of 200 ms. As such, the waveform 400maystart at a higher frequency during the initial ramp up period 406 and then switch instantly (or near instantly) to a lower, optimal treatment frequency once a high 5 10 15 20 25 30 35 40 45 50 55 8 13 EP 4 696 363 A2 14 enough amplitude 402 is reached.

[0051] As shown in FIG. 5, the change in the frequency of the waveform 500 (e.g., alternating electric field) from the first frequency to the target frequency may be per- formed gradually over a period of time during application of the alternating electric field (e.g., during the sustained intensity period 512). As such, the waveform 500 may start at a higher frequency during the initial ramp up period 506 and then switch gradually to a lower, optimal treatment frequency once a high enough amplitude 502 is reached. As shown in FIG. 5, the frequency gradually changes from the first frequency to the target frequency during the sustained intensity period 512. In some em- bodiments, the frequencygraduallymay change from the first frequency to the target frequency during the initial ramp up period 506 or during both the initial ramp up period 506 and the sustained intensity period 512.

[0052] An alternating electric field according to the present disclosure may be applied using a voltage gen- erated according to an AC voltage waveform (e.g., 400, 500). As shown in FIGS. 4 and5, the change in frequency from the first frequency to the target frequency may be performed at one or more times each corresponding to a zero crossing of the AC voltage waveform (e.g., 400, 500). A "zero crossing" may be any point in time (404, 504)where the amplitude (402, 502) is zero (408, 508). In one example, as shown in FIG. 4, the change in fre- quencymay be performed at a single time corresponding to a zero crossing of the waveform 400. In another ex- ample, as shown in FIG. 5, the change in frequency may be performed in a stepwise manner with each shift hap- pening at a different zero crossing of the waveform 500. Changing the frequency at one or more zero crossings provides a smooth transition of the electric field applied to the subject’s body such that no shockor electrosensation occurs in the subject’s body.

[0053] FIGS.4and5each represent asingleduty cycle of an alternating electric field applied according to a waveform (e.g., "first waveform" as described abovewith reference to FIG. 2). FIG. 6 represents two duty cycles 620A and 620B of an alternating electric field. The duty cycles 620Aand620Bmaybe for the same transducer or different transducers. As shown, the second duty cycle 620B follows a similar pattern of intensities (e.g., ampli- tudes 602) and frequencies as the first duty cycle 620A. The term"similarpattern"may refer toageneral pattern in which the frequency changes to a lower frequency after the initial ramp up period (i.e., once the amplitude 602 reaches the target level). As such, the frequencies and amplitudes need not be exactly the same between the first duty cycle 620A and the second duty cycle 620B as long as they follow the same general pattern. In some embodiments, as shown in FIG. 6, the duty cycles 620A, 620Bmay be applied according to an identical waveform 600 (i.e., the first frequency, target frequency, and time(s) when the frequency is changed are the same in both duty cycles).

[0054] FIG. 7 depicts an example method 700 of treat- ing a target region of a subject’s body with an alternating electric field. Themethod700maybe implementedusing the voltage generator 208 and controller 210 of FIG. 2. The method 700 may include, at step S702, generating and providing a first voltage to a first pair of transducers, the first voltage being generated according to a first waveform (e.g., AC voltage waveform). The first wave- form may be similar to waveforms shown in FIGS. 4‑6. That is, the first waveform may include an initial ramp up period during which the amplitude increases from zero to a target amplitude while the frequency is at a first fre- quency, after which the frequency changes to a target frequency lower than the first frequency while the ampli- tude remains at the target amplitude.

[0055] At step S704, the method 700 may include generating and providing a second voltage to a second pair of transducers, the second voltage being generated according to the first waveform (e.g., AC voltage wave- form). At step S706, the method 700 may include alter- nately switching betweenproviding the first voltage to the first pair of transducers and providing the second voltage to the second pair of transducers. Step S706 may be repeated until a second time period has passed at step S708. After the second time period has passed, the method 700 proceeds to step S710. The second time period (S708) of FIG. 7 may be the same as the second time period (S114) of FIG. 1.

[0056] At step S710, the method 700 may include generating and providing a third voltage to the first pair of transducers, the third voltage being generated accord- ing to a second waveform (e.g., AC voltage waveform). The second waveform may include an initial ramp up period during which the amplitude of the second wave- form increases from zero to a target amplitude while a frequencyof thesecondwaveform isat a frequency lower than the first frequency. The frequency lower than the first frequency may be equal to the target frequency. The second waveformmay include a sustained intensity per- iod duringwhich the frequency of the secondwaveform is at the target frequencywhile the amplitude remains at the target amplitude.

[0057] FIG. 8 depicts an example method 800 of de- livering an alternating electric field to a subject’s body. Themethod 800 includes, at step S802, applying a target alternating electric field to the subject’s body to treat the subject’s body. The target alternating electric field has a target frequency and a target intensity, the target fre- quency and the target intensity having a known efficacy for treating the subject’s body. At step S804, the method 800 includes receiving a response from the subject re- garding electrosensation. The response from the subject may include feedback 806 from the subject, a measure- ment 808 (e.g., sensor measurement) of the subject, or both. At stepS810, themethod 800 includes determining if the response indicates that the subject’s body experi- ences electrosensation from the target alternating elec- tric field. If at step S810 the response indicates that the subject’s body does not experienceelectrosensation, the 5 10 15 20 25 30 35 40 45 50 55 9 15 EP 4 696 363 A2 16 method 800 proceeds to step S812: continuing to apply the target alternating electric field to the subject’s body to treat the subject’s body.

[0058] If at step S810 the response indicates that the subject’s body experiences electrosensation, the meth- od 800 proceeds to step S814: selecting a first frequency for an alternating electric field to reduce the electrosen- sation experienced by the subject’s body. The first fre- quency is higher than the target frequency. At step S816, the method 800 includes applying an alternating electric field to the subject’s body, the alternating electric field having the first frequency while ramping up in intensity from zero to the target intensity and then changing to the target frequency upon reaching the target intensity. The method 800 of FIG. 8 allows for tuning the process of reducing or eliminating electrosensation to the individual subject, as not all subjects will experience electrosensa- tion from a target alternating electric field.

[0059] FIG. 9 depicts an example method 900 of de- livering an alternating electric field to a subject’s body as temperature rises. In method 900, the intensity and / or frequency of the alternating electric fieldmay bemodified as temperature changes. At stepS902, after applying the alternating electric field with the first frequency while increasing an intensity of the alternating electric field from zero to the target intensity in step S106, the tem- peraturewhere the alternating electric field is applied can bemonitored. For example, the temperature of the trans- ducer that applies the alternating electric field, the tem- perature of the target region, and / or the temperature of the skin of the subject at or near where the alternating electric field is applied can be monitored. A sensor to monitor the temperature may be part of or separate from the transducer.

[0060] At step S904, if the measured temperature is equal to or lower than a predetermined threshold, flow proceeds to step S902, and the loop is repeated. The alternating electric field with the first frequency and the first intensity may continue to be applied to the subject’s body. In one example, the predetermined threshold tem- perature of the transducermay be approximately 37°C to approximately 39°C, or approximately 38.5°C to approxi- mately 39°C, or approximately 37°C to approximately 41.5°C On the other hand, if the measured temperature is greater than a predetermined threshold, the flow pro- ceeds to step S906.

[0061] At step S906, a second intensity can be se- lected. In non-limiting embodiments, the second intensity can be lower than the first intensity. For example, the second intensitymay be lower than the target intensity by at least 10% than the first intensity (e.g., at least approxi- mately 20% lower, 30% lower, 40% lower, 50% lower, or 60% lower). For example, the second intensity may be lower than the target intensity by at least 0.1 V / cm lower than the first intensity (e.g., at least approximately 0.2 V / cm, 0.3 V / cm, 0.4 V / cm, 0.5 V / cm, 0.6 V / cm, 0.7 V / cm, 0.8 V / cm, 0.9 V / cm, 1 V / cm, or 2 V / cm lower). For ex- ample, the second intensity can range from approxi- mately 0.1 V / cm to approximately 20 V / cm, e.g., approxi- mately 0.5 V / cm to approximately 10 V / cm.

[0062] At step S908, a second frequency can be se- lected after selecting the second intensity. In one exam- ple, the second frequency can be lower than the first frequency and closer to or at the target frequency in order to compensate for the decreased efficacy caused by lowering the intensity. For example, the second fre- quency can be lower than the first frequency by at least 10% (e.g., at least approximately 20%, 30%, 40%, 50%, or 60%) without going below the target frequency. In one example, the second frequency can be lower than the target frequencybyat least approximately10kHz (e.g., at least approximately 20 kHz, 30 kHz, 50 kHz, 75 kHz, 100 kHz, 150 kHz, 200 kHz, or 300 kHz) without going below the target frequency. In one example, the second fre- quency can be based on the range of the first frequency.

[0063] At step S910, applying the alternating electric field with the first frequency and the first intensity to the subject’s body may be switched to applying a second alternating electric field with the second frequency and the second intensity to the subject’s body. In one exam- ple, the second alternating electric field can provide similar efficacy to the alternating electric field with the first frequency and the first intensity. In another example, the second alternating electric field can provide better efficacy than the alternating electric field with the first frequency and the first intensity. In non-limiting embodi- ments, the alternating electric fields can be generated from the same transducer or different transducers. In non-limiting embodiments, the first alternating electric field may be continuously switched to the second alter- nating electric field without turning off the system / trans- ducer or a wait time. EXPERIMENTAL RESULTS

[0064] FIG. 10 depicts an example cytotoxicity analy- sis showing theeffects of the field intensity on the survival of various types of cancer. The cytotoxicity analysis was performed by counting cell numbers (percent of control) following 72 hours of application of the disclosed fre- quency TTFields to cell lines from various types of can- cers: glioblastoma (U373, U87-MG, and A172; 200 kHz), lung (NCI-H520 and A549; 150 kHz), mesothelioma (MSTO‑211 and H2052; 150 kHz), gastric (KATO III and AGS; 150 kHz), ovarian (OVCAR‑3, Caov‑3, and A2780; 200 kHz), and cervical (HeLa and Ca-Ski; 150 kHz).

[0065] FIGS. 11A‑11C depict experimental stimulation of a sciatic rat nervebundlewithalternatingelectric fields. FIG. 11Adepicts five graphs showing the nerve response after treatment with an increasing voltage (4,000 mV, 6,000 mV, 8,000 mV, 10,000 mV, and 12,500 mV). As voltage was increased, the nerve response increased. FIG. 11B depicts a graph plotting the stimulation ampli- tude in mV p-p vs. the response amplitude in mV (blue circles, "A") and the response width in msec (red circles, 5 10 15 20 25 30 35 40 45 50 55 10 17 EP 4 696 363 A2 18 "B"). The response width is a measurement proxy for velocity along the nerve bundle. As the response ampli- tude increased more nerves in the nerve bundle were activated.

[0066] FIG. 11C depicts graphs representing an ex- periment where amplitude, frequency, and both ampli- tude and frequency were dimmed for 100 milliseconds. Human testingwasconductedwith a 100msdimming-up cycle on an OPTUNE ® electric field generator, in which frequency was decreased from 300 Hz to 100 Hz. The threshold for electro-sensation was 0.8 A when ampli- tude was increased in 1 milli steps. The threshold for electro-sensation was about 1.4‑1.5 A when both ampli- tude and frequency were dimmed.

[0067] The AM graph shows a nerve response to a stimulus in which amplitude increased from 500 mV to 12.5 volts in 100 microseconds. The FM graph shows a similar response to a stimulus inwhich the frequencywas reduced from400Hz to 200Hz in 100microseconds. The AM + FM graph shows that there was no response to a stimulus in which the amplitude increased and the fre- quencywasdecreasedsimultaneously.Thebottom three graphs depict a repetition of the experiment depicted in the top three graphs, which produced appreciably similar results. The right graph depicts the measured response for each treatment; increasing both amplitude and fre- quency produced no action potential.

[0068] The invention includes other illustrative embo- diments ("Embodiments") as follows.

[0069] Embodiment 1:Amethod to treat a target region of a subject’s body with an alternating electric field, the method comprising: applying the alternating electric field to the target region of the subject’s body at a first fre- quency while increasing an intensity of the alternating electric field from zero to a target intensity; and changing the frequency of the alternating electric field from the first frequency to a target frequency while maintaining the alternatingelectric fieldat the target intensity,wherein the target frequency and the target intensity have a known efficacy for treating the target region of the subject’s body with the alternating electric field; and wherein the first frequency is greater than the target frequency.

[0070] Embodiment 2: The method of Embodiment 1, wherein changing the frequencyof thealternatingelectric field is performed instantly at one time during application of the alternating electric field.

[0071] Embodiment 3: The method of Embodiment 2, wherein: the alternating electric field is applied using a voltage generated according to anACvoltagewaveform, and changing the frequency of the alternating electric field is performed at a time corresponding to a zero crossing of the AC voltage waveform.

[0072] Embodiment 4: The method of Embodiment 1, wherein changing the frequencyof thealternatingelectric field is performed in less than a period of 200 ms.

[0073] Embodiment 5: The method of Embodiment 4, wherein: the alternating electric field is applied using a voltage generated according to anACvoltagewaveform, and changing the frequency of the alternating electric field is performed at a time corresponding to a zero crossing of the AC voltage waveform.

[0074] Embodiment 6: The method of Embodiment 1, wherein changing the frequencyof thealternatingelectric field is performed gradually over a period of time during application of the alternating electric field.

[0075] Embodiment 7: The method of Embodiment 6, wherein: the alternating electric field is applied using a voltage generated according to anACvoltagewaveform, and changing the frequency of the alternating electric field is performed in a stepwise manner with each shift happening at a different zero crossing of the AC voltage waveform.

[0076] Embodiment 8: The method of claim 1, further comprising: after a first period of time, halting application of the alternating electric field to complete a first duty cycle of the alternatingelectric field; applyingoneormore subsequent duty cycles of the alternating electric field, each subsequent duty cycle following the samepattern of intensities and frequencies as the first duty cycle.

[0077] Embodiment 9: The method of Embodiment 8, wherein the alternating electric field is applied using a voltage generated according to anACvoltagewaveform, with each duty cycle of the alternating electric field being applied according to the same AC voltage waveform.

[0078] Embodiment 10: Themethod of Embodiment 8, further comprising: after a second period of time, switch- ing fromapplying the alternating electric field to the target region of the subject’s body to applying a second alter- nating electric field to the target region of the subject’s body with a second frequency that is lower than the first frequency and closer to or at the target frequency throughout each duty cycle.

[0079] Embodiment 11: The method of Embodiment 10,wherein thesecondperiodof time is approximately12 hours to approximately 4 weeks.

[0080] Embodiment 12: Themethod of Embodiment 8, wherein the first period of time is less than three seconds.

[0081] Embodiment 13: Themethod of Embodiment 1, wherein the target frequency is approximately 50 kHz to approximately 1 MHz.

[0082] Embodiment 14: Themethod of Embodiment 1, wherein the target frequency is approximately 50 kHz to approximately 500 kHz.

[0083] Embodiment 15: Themethod of Embodiment 1, wherein the first frequency is at least approximately 10% higher than the target frequency.

[0084] Embodiment 16: Themethod of Embodiment 1, wherein the first frequency is at least approximately 10 kHz higher than the target frequency.

[0085] Embodiment 17: Themethod of Embodiment 1, wherein the target intensity is approximately 0.1 V / cm to approximately 10.0 V / cm.

[0086] Embodiment 18: Themethod of Embodiment 1, wherein the alternating electric field is configured to re- duce electrosensation of the subject compared to when an alternating electric field is applied at the target fre- 5 10 15 20 25 30 35 40 45 50 55 11 19 EP 4 696 363 A2 20 quency for its entire duty cycle.

[0087] Embodiment 19: Themethod of Embodiment 1, wherein the target region is glioblastoma (GBM),wherein the target frequency is approximately 100 kHz toapproxi- mately 300 kHz.

[0088] Embodiment 20: Themethod of Embodiment 1, wherein the target region is an endothelial or epithelial tight junction, wherein the target frequency is approxi- mately 50 kHz to approximately 190 kHz.

[0089] Embodiment 21: Themethod of Embodiment 1, wherein the alternating electric field is delivered to the subject’s body to change cancer cell membrane perme- ability, wherein the target frequency is approximately 100 kHz to approximately 500 kHz.

[0090] Embodiment 22: Themethod of Embodiment 1, wherein the alternating electric field is delivered to the subject’s body via a pair of transducer arrays positioned on a head of the subject’s body, wherein the target region is in the subject’s brain.

[0091] Embodiment 23: Themethod of Embodiment 1, wherein the alternating electric field is delivered to the subject’s body via a pair of transducer arrays positioned on at least one of a thorax, an abdomen, or one or both thighsof the subject’s body,wherein the target region is in the subject’s torso.

[0092] Embodiment 24: An apparatus for treating a target region of a subject’s body with an alternating electric field, the apparatus comprising: a first pair of transducers configured to apply a first alternating electric field to a target region of the subject’s body; a voltage generator coupled to the first pair of transducers and capable of providing a first voltage to the first pair of transducers for applying the first alternating electric field; and a controller coupled to the voltage generator, the controller comprising one or more processors and mem- ory accessible by the one or more processors, the mem- ory storing instructions that when executed by the one or more processors, cause the controller to instruct the voltage generator to generate the first voltage according to a first waveform having: an initial ramp-up period duringwhichanamplitudeof thefirstwaveform increases from zero to a target amplitude while a frequency of the first waveform is at a first frequency; and a sustained intensity period during which the frequency of the first waveform changes to a target frequency lower than the first frequency while the amplitude of the first waveform remains at the target amplitude.

[0093] Embodiment 25: Theapparatus of Embodiment 24, wherein the frequency of the first waveform changes instantly from the first frequency to the target frequency.

[0094] Embodiment 26: Theapparatus of Embodiment 25, wherein the frequency of the first waveform changes at a zero crossing of the first waveform

[0095] Embodiment 27: Theapparatus of Embodiment 24, wherein the frequency of the first waveform changes from the first frequency to the target frequency in less than 200 ms.

[0096] Embodiment 28: Theapparatus of Embodiment 27, wherein the frequency of the first waveform changes at a zero crossing of the first waveform.

[0097] Embodiment 29: Theapparatus of Embodiment 24, wherein the frequency of the first waveform changes gradually from the first frequency to the target frequency.

[0098] Embodiment 30: Theapparatus of Embodiment 29, wherein the frequency of the first waveform changes in a stepwise manner with each shift happening at a different zero crossing of the first waveform.

[0099] Embodiment 31: Theapparatus of Embodiment 24, wherein the voltage generator is coupled to the first pair of transducers and capable of providing a third voltage to the first pair of transducers for applying a third alternating electric field to a target region of the subject’s body, and the instructions, when executed by the one or more processors, cause the controller to instruct the voltage generator to generate the third voltage according to a second waveform having: an initial ramp-up period during which an amplitude of the second waveform in- creases from zero to the target amplitude while a fre- quency of the second waveform is at a frequency lower than the first frequency; and a sustained intensity period during which the frequency of the second waveform is at the target frequency while the amplitude of the second waveform remains at the target amplitude.

[0100] Embodiment 32: Theapparatus of Embodiment 31, wherein the second waveform is at the target fre- quency during the initial ramp-up period.

[0101] Embodiment 33: Theapparatus of Embodiment 24, further comprising: a second pair of transducers configured to apply a second alternating electric field to a target region of the subject’s body, wherein the voltage generator is coupled to the second pair of trans- ducers and capable of providing a second voltage to the second pair of transducers for applying the second alter- nating electric field, and the instructions, when executed by the one or more processors, cause the controller to instruct the voltage generator to generate the second voltage according to the first waveform.

[0102] Embodiment 34: Theapparatus of Embodiment 33,wherein the instructions,whenexecutedby theoneor more processors, cause the controller to instruct the voltage generator to alternately switch between provid- ing the first voltage to the first pair of transducers and providing the second voltage to the second pair of trans- ducers at regular intervals.

[0103] Embodiment 35: A method to deliver an alter- nating electric field to a subject’s body, the method com- prising: applying a target alternating electric field to the subject’s body to treat the subject’s body, the target alternating electric field having a target frequency and a target intensity, the target frequency and the target intensity havingaknownefficacy for treating the subject’s body; receiving a response from the subject regarding electrosensation, wherein the response from the subject comprises at least one of feedback from the subject or a measurement of the subject; if the response indicates that the subject’s body experiences electrosensation 5 10 15 20 25 30 35 40 45 50 55 12 21 EP 4 696 363 A2 22 from the target alternating electric field, selecting a first frequency for an alternating electric field to reduce the electrosensation experienced by the subject’s body from the target alternating electric field, the first frequency being higher than the target frequency; and applying an alternating electric field to the subject’s body, the alternating electric field having the first frequency while ramping up in intensity from zero to the target intensity and then changing to the target frequency upon reaching the target intensity.

[0104] Embodiment 36: An apparatus for treating a target region of a subject’s body with an alternating electric field, the apparatus comprising: a pair of trans- ducers configured to apply a first alternating electric field to a target region of the subject’s body; and a controller implemented with at least one processor to provide sig- nals to the pair of transducers for controlling the first alternating electric field such that: the first alternating electric field begins at a first frequency; the first alternat- ing electric field increases from zero intensity to a target intensity while remaining at the first frequency; and the first alternating electric field changes from the first fre- quency to a target frequency after reaching the target intensity, the target frequency being lower than the first frequency.

[0105] Embodiment 37: A method to treat a target region of a subject’s body with an alternating electric field, the method comprising: applying the alternating electric field to the target region of the subject’s body at a first frequency while increasing a current of the alternating electric field from zero to a target current; and changing the frequency of the alternating electric field from the first frequency to a target frequency while maintaining the alternating electric field at the target current, wherein the target frequency and the target current have a known efficacy for treating the target region of the subject’s body with the alternating electric field; and wherein the first frequency is greater than the target frequency.

[0106] Illustrative Embodiment 38. Amethod to deliver an alternating electric field to a subject’s body, the meth- od comprising: applying a target alternating electric field to the subject’s body to treat the subject’s body, the target alternating electric field having a target frequency and a target intensity, the target frequency and the target in- tensity having a known efficacy for treating the subject’s body; receiving feedback regarding electrosensation ex- perienced by the subject’s body from applying the target alternating electric field; if the subject’s body experiences electrosensation from the target alternating electric field at the target frequency and the target intensity, select at least one of a first frequency or a first intensity for an alternating electric field to reduce the electrosensation experienced by the subject’s body from the target alter- nating electric field, the first frequency being higher than the target frequency, the first intensity being lower than the target intensity; and applying a first alternating elec- tric field to the subject’s body to treat the subject’s body, the first alternating electric field having at least one of the first frequency or the first intensity.

[0107] Illustrative Embodiment 39. The method of Il- lustrative Embodiment 38, wherein the first frequency is at least approximately 10% higher than the target fre- quency and wherein the first intensity is at least approxi- mately 10% lower than the target intensity.

[0108] Illustrative Embodiment 40. The method of Il- lustrative Embodiment 39, further comprising: after an interval of time, ceasing to apply the first alternating electric field to the subject’s body; applying a second alternating electric field to the subject’s body with at least one of a second frequency closer to or at the target frequency or a second intensity closer to or at the target intensity.

[0109] Illustrative Embodiment 41. Amethod to deliver an alternating electric field to a subject’s body, the meth- od comprising: applying the alternating electric field to a target region of the subject’s body, wherein the alternat- ing electric field has a first frequency and a first intensity, wherein for a target frequencyanda target intensity of the alternating electric field, the subject experiences electro- sensation,wherein thefirst intensity is the target intensity, and wherein the first frequency is greater than the target frequency.

[0110] Illustrative Embodiment 42. The method of Il- lustrative Embodiment 41, wherein the alternating elec- tric field is configured to reduce electrosensation of the subject compared to when an alternating electric field is applied at the target frequency and the target intensity.

[0111] Illustrative Embodiment 43. Themethod of Illus- trative Embodiment 41, the method further comprises prior to applying the alternating electric field, determining the first intensity of the alternating electric field; and after the first intensity is determined, identifying the first fre- quency of the alternating electric field based on a re- sponse from the subject regarding electrosensation ex- perienced by the subject, wherein the first frequency is a frequency of the alternating electric field that reduces the subject’s electrosensation with the first intensity.

[0112] Illustrative Embodiment 44. The method of Il- lustrative Embodiment 43, wherein identifying the first frequency of the alternating electric field comprises: de- creasing a frequency level of the alternating electric field stepwise froman initial frequency until the response from the subject indicates that the subject experiences the electrosensation.

[0113] Illustrative Embodiment 45. The method of Il- lustrativeEmbodiment43,wherein the response from the subject comprises at least one of feedback from the subject or a measurement of the subject.

[0114] Illustrative Embodiment 46. The method of Il- lustrative Embodiment 41, wherein the target frequency is approximately 100 kHz to approximately 400 kHz, and the target intensity is approximately 0.5 V / cm to approxi- mately 10.0 V / cm.

[0115] Illustrative Embodiment 47. The method of Il- lustrative Embodiment 41, the method further comprises 5 10 15 20 25 30 35 40 45 50 55 13 23 EP 4 696 363 A2 24 when a temperature where the alternating electric field is applied reaches a threshold temperature, determining a second intensity for the alternating electric field, wherein the second intensity is lower than the first intensity; identifying a second frequency of the alternating electric field, wherein the second frequency is lower than the first frequency; switching from applying the alternating elec- tric field to applying another alternating electric field with the second intensity and the second frequency.

[0116] Illustrative Embodiment 48. The method of Il- lustrative Embodiment 41, the method further comprises after an interval of time, switching from applying the alternating electric field to the target region of the sub- ject’s body to applying a second alternating electric field to the target region of the subject’s body with a lower frequency closer to or at the target frequency.

[0117] Illustrative Embodiment 49. The method of Il- lustrative Embodiment 48, wherein the interval between applying the alternating electric field with the first fre- quency and the second alternating electric field with the lower frequency is approximately 12 hours to approxi- mately 4 weeks (e.g., approximately 12 hours to approxi- mately 2 weeks).

[0118] Illustrative Embodiment 50. The method of Il- lustrative Embodiment 41, wherein the first frequency is at least approximately 10% higher than the target fre- quency.

[0119] Illustrative Embodiment 51. The method of Il- lustrative Embodiment 41, wherein the first frequency is at least approximately 10 kHz higher than the target frequency.

[0120] Illustrative Embodiment 52. The method of Il- lustrative Embodiment 41, wherein the target region is glioblastoma (GBM), wherein the target frequency is approximately 50 kHZ to approximately 350 kHz, and the target intensity is approximately 1 V / cm to approxi- mately 5 V / cm.

[0121] Illustrative Embodiment 53. The method of Il- lustrative Embodiment 41, wherein the target region is a blood-brainbarrier (BBB),wherein the target frequency is approximately 50 kHz to approximately 190 kHz, and the target intensity is approximately 1 V / cm to approximately 5 V / cm.

[0122] Illustrative Embodiment 54. The method of Il- lustrative Embodiment 41, wherein the alternating elec- tric field is delivered to the subject’s body to change cell membrane permeability, wherein the target frequency is approximately 50 kHz to approximately 550 kHz, and the target intensity is approximately 0.5 V / cm to approxi- mately 20 V / cm.

[0123] Illustrative Embodiment 55. An apparatus for treating a target region of a subject’s body with an alter- nating electric field, the apparatus comprising: a trans- ducer configured to apply the alternating electric field to a target region of the subject’s body; and a controller im- plemented with at least one processor to provide signals to the transducer for the alternating electric field, wherein the alternating electric field has a first frequency and a target intensity, wherein for a frequency and an intensity having a known efficacy for treating the target region of the subject’s body with the alternating electric field, the subject experiences electrosensation, wherein the first intensity is the intensity having the known efficacy, and wherein the first frequency is greater than the frequency having the known efficacy.

[0124] Illustrative Embodiment 56. The apparatus of Illustrative Embodiment 55, wherein the controller com- prises one or more processors; and memory storing processor-executable instructions that, when executed by the one or more processors, cause the controller to determine the first intensity of the alternating electric field prior to applying thealternating electric field; andafter the first intensity is determined, identify the first frequency of the alternating electric field based ona response from the subject regarding electrosensation experienced by the subject, wherein the first frequency is a frequency of the alternating electric field that reduces the subject’s elec- trosensation with the first intensity.

[0125] Illustrative Embodiment 57. The apparatus of Illustrative Embodiment 56, wherein the response from the subject comprises at least one of feedback from the subject or a measurement of the subject.

[0126] Illustrative Embodiment 58. The apparatus of Illustrative Embodiment 56, wherein the memory storing processor-executable instructions that, when executed by the one or more processors, further cause the appa- ratus to decrease a frequency level of the alternating electric field stepwise from an initial frequency until feed- back from the subject indicates that subject experiences electrosensation.

[0127] Illustrative Embodiment 59. The apparatus of Illustrative Embodiment 56, wherein the memory storing processor-executable instructions that, when executed by the one or more processors, further cause the appa- ratus to decrease a frequency level of the alternating electric field stepwise from an initial frequency until a measurement of nerve stimulation of the subject indi- cates that subject experiences electrosensation.

[0128] Illustrative Embodiment 60. The apparatus of Illustrative Embodiment 55, wherein the controller com- prises one or more processors; and memory storing processor-executable instructions that, when executed by the one or more processors, cause the controller to when a temperature where the alternating electric field is applied reaches a threshold temperature, determine a second intensity of the alternating electric field, the sec- ond intensity being lower than the first intensity; identify- ing a second frequency of the alternating electric field, wherein the second frequency is lower than the first frequency; and apply the alternating electric field with the second intensity and the second frequency.

[0129] Illustrative Embodiment 61. The apparatus of Illustrative Embodiment 55, wherein the alternating elec- tric field is capable of applying a tumor treating field, opening a blood-brain barrier of the subject, disrupting a cell membrane of the subject, or changing permeability 5 10 15 20 25 30 35 40 45 50 55 14 25 EP 4 696 363 A2 26 of a cell membrane of the subject.

[0130] Illustrative Embodiment 62. An apparatus to calibrate delivery of an alternating electric field to a sub- ject’s body, comprising: one or more processors; and memory storing processor-executable instructions that, whenexecuted by the oneormoreprocessors, cause the apparatus to determine a target frequency and a target intensity for application of the alternating electric field to treat a target region of the subject’s body, the target frequency and the target intensity having known efficacy to treat the subject’s body; and select a first frequency for application of an alternating electric field to treat the target region of the subject’s body, the first frequency selected to reduce electrosensation in the subject’s body experienced at the target intensity, wherein the first fre- quency is higher than the target frequency.

[0131] Illustrative Embodiment 63. The apparatus of Illustrative Embodiment 62, wherein the target frequency and the target intensity have known efficacy for treating a tumor, opening a blood-brain barrier of the subject, dis- rupting a cell membrane of the subject, or changing permeability of a cell membrane of the subject.

[0132] Illustrative Embodiment 64. Amethod to deliver an alternating electric field to a subject’s body, the meth- od comprising: applying a target alternating electric field to the subject’s body to treat the subject’s body, the target alternating electric field having a target frequency and a target intensity, the target frequency and the target in- tensity having a known efficacy for treating the subject’s body; receiving a response from the subject regarding electrosensation, wherein the response from the subject comprises at least one of feedback from the subject or a measurement of the subject; if the response indicates that subject’s body experiences electrosensation from the target alternating electric field at the target frequency and the target intensity, selecting a first frequency for an alternating electric field to reduce the electrosensation experienced by the subject’s body from the target alter- nating electric field, the first frequency being higher than the target frequency; and applying a first alternating electric field to the subject’s body to treat the subject’s body, the first alternating electric field having the first frequency and the target intensity.

[0133] Illustrative Embodiment 65. The method of Il- lustrative Embodiment 64, wherein the first frequency is at least approximately 10% higher than the target fre- quency.

[0134] Illustrative Embodiment 66. The method of Il- lustrative Embodiment 64, the method further comprises after an interval of time, switching from applying the first alternatingelectric field to the subject’s body to applyinga second alternating electric field to the subject’s body with a second frequency closer to or at the target frequency.

[0135] Illustrative Embodiment 67: A method to treat a target region of a subject’s body with an alternating electric field, the method comprising: applying the alter- nating electric field to the target region of the subject’s body at a frequency and an intensity, wherein the fre- quency is a first frequency, wherein the intensity is a first intensity; and increasing the intensity from the first in- tensity to a target intensity while decreasing the fre- quency from the first frequency to a target frequency, wherein the target frequency and the target intensity have a known efficacy for treating the target region of the subject’s body with the alternating electric field; wherein the first frequency is greater than the target frequency; and wherein the first intensity is lesser than the target intensity.

[0136] Illustrative Embodiment 68: Themethod of Em- bodiment 67, wherein the frequency is decreased from the first frequency to the target frequency instantly at one time during application of the alternating electric field.

[0137] Illustrative Embodiment 69: Themethod of Em- bodiment 67, wherein increasing the intensity while de- creasing the first frequency of the alternating electric field is performed in less than a period of 200 ms.

[0138] Illustrative Embodiment 70: Themethod of Em- bodiment 67, wherein increasing the intensity while de- creasing the first frequency of the alternating electric field is performed gradually over a period of time during ap- plication of the alternating electric field.

[0139] Illustrative Embodiment 71: The method of claim 67, further comprising: after a first period of time, halting application of the alternating electric field to com- plete a first duty cycle of the alternating electric field; applying one or more subsequent duty cycles of the alternating electric field, each subsequent duty cycle following the same pattern of intensities and frequencies as the first duty cycle.

[0140] Illustrative Embodiment 72: Themethod of Em- bodiment 71, wherein the alternating electric field is applied using a voltage generated according to an AC voltage waveform, with each duty cycle of the alternating electric field being applied according to the same AC voltage waveform.

[0141] Illustrative Embodiment 73: Themethod of Em- bodiment 71, further comprising: after a second period of time, switching from applying the alternating electric field to the target region of the subject’s body to applying a second alternating electric field to the target region of the subject’s body with a second frequency that is lower than the first frequency and closer to or at the target frequency throughout each duty cycle.

[0142] Illustrative Embodiment 74: Themethod of Em- bodiment 73, wherein the second period of time is ap- proximately 12 hours to approximately 4 weeks.

[0143] Illustrative Embodiment 75: Themethod of Em- bodiment 71, wherein the first period of time is less than three seconds.

[0144] Illustrative Embodiment 76: Themethod of Em- bodiment 67, wherein the target frequency is approxi- mately 50 kHz to approximately 1 MHz.

[0145] Illustrative Embodiment 77: Themethod of Em- bodiment 67, wherein the target frequency is approxi- mately 50 kHz to approximately 500 kHz.

[0146] Illustrative Embodiment 78: Themethod of Em- 5 10 15 20 25 30 35 40 45 50 55 15 27 EP 4 696 363 A2 28 bodiment 67, wherein the first frequency is at least ap- proximately 10% higher than the target frequency.

[0147] Illustrative Embodiment 79: Themethod of Em- bodiment 67, wherein the first frequency is at least ap- proximately 10 kHz higher than the target frequency.

[0148] Illustrative Embodiment 80: Themethod of Em- bodiment 67, wherein the target intensity is approxi- mately 0.1 V / cm to approximately 10.0 V / cm.

[0149] Illustrative Embodiment 81: Themethod of Em- bodiment 67, wherein the alternating electric field is configured to reduce electrosensation of the subject compared to when an alternating electric field is applied at the target frequency for its entire duty cycle.

[0150] Illustrative Embodiment 82: Themethod of Em- bodiment 67, wherein the target region is glioblastoma (GBM), wherein the target frequency is approximately 100 kHz to approximately 300 kHz.

[0151] Illustrative Embodiment 83: Themethod of Em- bodiment 67, wherein the target region is an endothelial or epithelial tight junction, wherein the target frequency is approximately 50 kHz to approximately 190 kHz.

[0152] Illustrative Embodiment 84: Themethod of Em- bodiment 67, wherein the alternating electric field is delivered to the subject’s body to change cancer cell membrane permeability, wherein the target frequency is approximately 100 kHz to approximately 500 kHz.

[0153] Illustrative Embodiment 85: Themethod of Em- bodiment 67, wherein the alternating electric field is delivered to the subject’s body via a pair of transducer arrays positioned on a head of the subject’s body, where- in the target region is in the subject’s brain.

[0154] Illustrative Embodiment 86: Themethod of Em- bodiment 67, wherein the alternating electric field is delivered to the subject’s body via a pair of transducer arrays positioned on at least one of a thorax, an abdo- men, or one or both thighs of the subject’s body, wherein the target region is in the subject’s torso.

[0155] Illustrative Embodiment 87: An apparatus for treating a target region of a subject’s body with an alter- nating electric field, the apparatus comprising: a first pair of transducers configured to apply a first alternating electric field to a target region of the subject’s body; a voltage generator coupled to the first pair of transducers and capable of providing a first voltage to the first pair of transducers for applying the first alternating electric field; and a controller coupled to the voltage generator, the controller comprising one or more processors and mem- ory accessible by the one or more processors, the mem- ory storing instructions that when executed by the one or more processors, cause the controller to perform opera- tions comprising: applying the alternating electric field to the target region of the subject’s body at a first frequency while increasing an intensity of the alternating electric field from zero to a target intensity; and changing the frequency of the alternating electric field from the first frequency to a target frequency while maintaining the alternatingelectric fieldat the target intensity,wherein the target frequency and the target intensity have a known efficacy for treating the target region of the subject’s body with the alternating electric field; and wherein the first frequency is greater than the target frequency.

[0156] Illustrative Embodiment 88: An apparatus for treating a target region of a subject’s body with an alter- nating electric field, the apparatus comprising: a first pair of transducers configured to apply a first alternating electric field to a target region of the subject’s body; a voltage generator coupled to the first pair of transducers and capable of providing a first voltage to the first pair of transducers for applying the first alternating electric field; and a controller coupled to the voltage generator, the controller comprising one or more processors and mem- ory accessible by the one or more processors, the mem- ory storing instructions that when executed by the one or more processors, cause the controller to perform opera- tions comprising: applying the alternating electric field to the target region of the subject’s body at a frequency and an intensity, wherein the frequency is a first frequency, wherein the intensity is a first intensity; and increasing the intensity from the first intensity to a target intensity while decreasing the frequency from the first frequency to a target frequency, wherein the target frequency and the target intensity have a known efficacy for treating the target region of the subject’s body with the alternating electric field, wherein the first frequency is greater than the target frequency, and wherein the first intensity is lesser than the target intensity.

[0157] Embodiments illustrated under any heading or in any portion of the disclosure may be combined with embodiments illustrated under the same or any other heading or other portion of the disclosure unless other- wise indicatedherein or otherwise clearly contradictedby context.

[0158] Numerous modifications, alterations, and changes to the described embodiments are possible without departing from the scope of the present invention defined in the claims. It is intended that the present invention not be limited to the described embodiments, but that it has the full scopedefinedby the languageof the following claims, and equivalents thereof. Embodiments:

[0159] 1. An apparatus for treating a target region of a subject’s body with an alternating electric field, the apparatus comprising: a first pair of transducers configured to apply a first alternating electric field to a target region of the subject’s body; a voltage generator coupled to the first pair of transducers and capable of providing a first voltage to the first pair of transducers for apply- ing the first alternating electric field; and a controller coupled to the voltagegenerator, the 5 10 15 20 25 30 35 40 45 50 55 16 29 EP 4 696 363 A2 30 controller comprising one or more processors and memory accessible by the one or more processors, thememorystoring instructions that when executed by the one or more processors, cause the controller to perform operations com- prising: applying the alternating electric field to the target region of the subject’s body at a first frequency while increasing an intensity of the alternating electric field from zero to a target intensity; and changing the frequency of the alternating electric field from the first frequency to a target frequencywhilemaintaining thealter- nating electric field at the target intensity, wherein the target frequency and the target intensity have a known efficacy for treating the target region of the subject’s body with the alternating electric field; and wherein the first frequency is greater than the target frequency. 2. The apparatus of embodiment 1, wherein: the alternating electric field is applied using a voltage generated according to an AC voltage waveform, and changing the frequency of the alternating elec- tric field is performed at a time corresponding to a zero crossing of the AC voltage waveform. 3. The apparatus of embodiment 1, wherein chan- ging the frequency of the alternating electric field is performed gradually over a period of time during application of the alternating electric field. 4. The apparatus of embodiment 3, wherein: the alternating electric field is applied using a voltage generated according to an AC voltage waveform, and changing the frequency of the alternating elec- tric field is performed in a stepwise manner with each shift happening at a different zero crossing of the AC voltage waveform. 5. The apparatus of embodiment 1, further compris- ing: after a first period of time, halting application of the alternating electric field to complete a first duty cycle of the alternating electric field; applying one or more subsequent duty cycles of the alternating electric field, each subsequent duty cycle following a similar pattern of intensi- ties and frequencies as the first duty cycle. 6. An apparatus for treating a target region of a subject’s body with an alternating electric field, the apparatus comprising: a first pair of transducers configured to apply a first alternating electric field to a target region of the subject’s body; a voltage generator coupled to the first pair of transducers and capable of providing a first voltage to the first pair of transducers for apply- ing the first alternating electric field; and a controller coupled to the voltagegenerator, the controller comprising one or more processors and memory accessible by the one or more processors, thememorystoring instructions that when executed by the one or more processors, cause the controller to instruct the voltage gen- erator to generate the first voltageaccording to a first waveform having: an initial ramp-up period during which an amplitude of the first waveform increases from zero to a target amplitude while a frequency of the first waveform is at a first frequency; and a sustained intensity period during which the frequency of the first waveform changes to a target frequency lower than the first frequency while the amplitude of the first waveform remains at the target amplitude. 7. The apparatus of embodiment 6, wherein the frequency of the first waveform changes instantly from the first frequency to the target frequency. 8. The apparatus of embodiment 7, wherein the frequency of the first waveform changes at a zero crossing of the first waveform. 9. The apparatus of embodiment 6, wherein the frequency of the first waveform changes from the first frequency to the target frequency in less than 200 ms. 10. The apparatus of embodiment 9, wherein the frequency of the first waveform changes at a zero crossing of the first waveform. 11. The apparatus of embodiment 6, wherein the frequency of the first waveform changes gradually from the first frequency to the target frequency. 12. The apparatus of embodiment 11, wherein the frequency of the first waveform changes in a step- wise manner with each shift happening at a different zero crossing of the first waveform. 13. The apparatus of embodiment 6, wherein the 5 10 15 20 25 30 35 40 45 50 55 17 31 EP 4 696 363 A2 32 target frequency is approximately 50 kHz to approxi- mately 500 kHz, and wherein the target intensity is approximately 0.1 V / cm to approximately 10.0 V / cm. 14. Theapparatus of embodiment 6,wherein the first frequency is at least approximately 10 kHz higher than the target frequency. 15. An apparatus for treating a target region of a subject’s body with an alternating electric field, the apparatus comprising: a first pair of transducers configured to apply a first alternating electric field to a target region of the subject’s body; a voltage generator coupled to the first pair of transducers and capable of providing a first voltage to the first pair of transducers for apply- ing the first alternating electric field; and a controller coupled to the voltagegenerator, the controller comprising one or more processors and memory accessible by the one or more processors, thememorystoring instructions that when executed by the one or more processors, cause the controller to perform operations com- prising: applying the alternating electric field to the target region of the subject’s body at a fre- quency and an intensity, wherein the fre- quency is a first frequency, wherein the in- tensity is a first intensity; and increasing the intensity from the first inten- sity to a target intensitywhile decreasing the frequency from thefirst frequency toa target frequency, wherein the target frequency and the target intensity have a known efficacy for treating the target region of the subject’s body with the alternating electric field, wherein the first frequency is greater than the target frequency, and wherein the first intensity is lesser than the target intensity. Claims 1. An apparatus for treating a target region of a sub- ject’s body with an alternating electric field, the ap- paratus comprising: a first pair of transducers configured to apply a first alternating electric field to a target region of the subject’s body; a voltage generator coupled to the first pair of transducers and capable of providing a first voltage to the first pair of transducers for apply- ing the first alternating electric field; and a controller coupled to the voltagegenerator, the controller comprising one or more processors and memory accessible by the one or more processors, thememorystoring instructions that when executed by the one or more processors, cause the controller to perform operations com- prising: applying the alternating electric field to the target region of the subject’s body at a fre- quency and an intensity, wherein the fre- quency is a first frequency, wherein the in- tensity is a first intensity; and increasing the intensity from the first inten- sity to a target intensitywhile decreasing the frequency from thefirst frequency toa target frequency, wherein the target frequency and the target intensity have a known efficacy for treating the target region of the subject’s body with the alternating electric field, wherein the first frequency is greater than the target frequency, and wherein the first intensity is lesser than the target intensity. 2. Theapparatus of claim1,wherein the first intensity is at least 10% lower than the target intensity, optionally wherein the first intensity is at least 50% lower than the target intensity, further optionally wherein the first intensity is at least 75% lower than the target intensity. 3. The apparatus of claim 1 or claim 2, wherein the change in frequency is gradual. 4. The apparatus of claim 3, wherein the change in frequency takes at least 0.1 ms, optionally, wherein the change in frequency takes at least 5 ms, further optionally, wherein the change in fre- quency takes at least 100 ms. 5. The apparatus of any preceding claim, wherein the change in intensity is gradual. 6. The apparatus of claim 5, wherein the change in intensity takes at least 0.1 ms, optionally, wherein the change in intensity takes at least 5 ms, further optionally, wherein the change in inten- sity takes at least 100 ms. 7. The apparatus of any preceding claim, wherein the 5 10 15 20 25 30 35 40 45 50 55 18 33 EP 4 696 363 A2 34 increase in intensity and decrease in frequency do not start and stop at the same time. 8. The apparatus of any preceding claim, wherein the target frequency is between 50 kHz and 500 kHz. 9. The apparatus of any preceding claim, wherein the first frequency is at least 10% higher than the target frequency. 10. The apparatus of claim 9, wherein the first frequency is at least 50% higher than the frequency intensity. 11. The apparatus of claim 10, wherein the first fre- quency is at least 100% higher than the target in- tensity. 12. The apparatus of any preceding claim, wherein the first frequency is at least 10 kHz higher than the target frequency. 13. The apparatus of claim 12, wherein the first fre- quency is at least 50 kHz higher than the target frequency. 14. The apparatus of claim 13, wherein the first fre- quency is at least 100 kHz higher than the target frequency. 15. The apparatus of any preceding claim, wherein the first frequency is between 200 kHz and 600kHz. 5 10 15 20 25 30 35 40 45 50 55 19 EP 4 696 363 A2 20 EP 4 696 363 A2 21 EP 4 696 363 A2 22 EP 4 696 363 A2 23 EP 4 696 363 A2 24 EP 4 696 363 A2 25 EP 4 696 363 A2 26 EP 4 696 363 A2 27 EP 4 696 363 A2 28 EP 4 696 363 A2 29 EP 4 696 363 A2 30 EP 4 696 363 A2 REFERENCES CITED IN THE DESCRIPTION This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard. Patent documents cited in the description • US 12893723

[0001] • US 63326098

[0001] • US 63410481

[0001] • US 7565205 B

[0002] (19) *EP004696363A3* (11) EP 4 696 363 A3 (12) EUROPEAN PATENT APPLICATION (88) Date of publication A3: 25.03.2026 Bulletin 2026 / 13 (43) Date of publication A2: 18.02.2026 Bulletin 2026 / 08 (21) Application number: 25226932.9 (22) Date of filing: 31.03.2023 (51) International Patent Classification (IPC): A61N 1 / 36 (2006.01) A61N 1 / 04 (2006.01) (52) Cooperative Patent Classification (CPC): A61N 1 / 36034; A61N 1 / 0476; A61N 1 / 0492; A61N 1 / 36002 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 31.03.2022 US 202263326098 P 27.09.2022 US 202263410481 P 30.03.2023 US 202318128937 (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 23719487.3 / 4 489 845 (71) Applicant: Novocure GmbH 6340 Baar (CH) (72) Inventors: • GILADI, Moshe 31905 Haifa (IL) • AVIGDOR, Lilach 31905 Haifa (IL) (74) Representative: Carpmaels & Ransford LLP One Southampton Row London WC1B 5HA (GB) (54) ALTERNATING ELECTRIC FIELD WAVEFORM FOR ELECTROSENSATION REDUCTION (57) An apparatus to treat a target region of a sub- ject’s body with an alternating electric field and being capable of: applying the alternating electric field to the target region of the subject’s body at a first frequency while increasing an intensity of the alternating electric field from zero to a target intensity; and changing the frequency of the alternating electric field from the first frequency to a target frequency while maintaining the alternatingelectric field at the target intensity,wherein the target frequency and the target intensity have a known efficacy for treating the target region of the subject’s body with the alternating electric field; and wherein the first frequency is greater than the target frequency. EP 4 69 6 36 3 A 3 Processed by Luminess, 75001 PARIS (FR) 2 EP 4 696 363 A3 5 10 15 20 25 30 35 40 45 50 55 3 EP 4 696 363 A3 5 10 15 20 25 30 35 40 45 50 55 摘要 一种用交变电场治疗受试者的身体的目标区域的设备，该设备能够：以第一 频率向受试者的身体的目标区域施加交变电场，同时将交变电场的强度从零增加 到目标强度；以及将交变电场的频率从第一频率改变到目标频率，同时将交变电 场维持在目标强度，其中目标频率和目标强度对于用交变电场治疗受试者的身体 的目标区域具有已知功效；并且其中第一频率大于目标频率。

Claims

1. An apparatus for treating a target region of a subject's body with an alternating electric field, the apparatus comprising: a first pair of transducers configured to apply a first alternating electric field to a target region of the subject's body; a voltage generator coupled to the first pair of transducers and capable of providing a first voltage to the first pair of transducers for applying the first alternating electric field; and a controller coupled to the voltage generator, the controller comprising one or more processors and memory accessible by the one or more processors, the memory storing instructions that when executed by the one or more processors, cause the controller to perform operations comprising: applying the alternating electric field to the target region of the subject's body at a frequency and an intensity, wherein the frequency is a first frequency, wherein the intensity is a first intensity; and increasing the intensity from the first intensity to a target intensity while decreasing the frequency from the first frequency to a target frequency, wherein the target frequency and the target intensity have a known efficacy for treating the target region of the subject's body with the alternating electric field, wherein the first frequency is greater than the target frequency, and wherein the first intensity is lesser than the target intensity.

2. The apparatus of claim 1, wherein the first intensity is at least 10% lower than the target intensity, optionally wherein the first intensity is at least 50% lower than the target intensity, further optionally wherein the first intensity is at least 75% lower than the target intensity.

3. The apparatus of claim 1 or claim 2, wherein the change in frequency is gradual.

4. The apparatus of claim 3, wherein the change in frequency takes at least 0.1 ms, optionally, wherein the change in frequency takes at least 5 ms, further optionally, wherein the change in frequency takes at least 100 ms.

5. The apparatus of any preceding claim, wherein the change in intensity is gradual.

6. The apparatus of claim 5, wherein the change in intensity takes at least 0.1 ms, optionally, wherein the change in intensity takes at least 5 ms, further optionally, wherein the change in intensity takes at least 100 ms.

7. The apparatus of any preceding claim, wherein the increase in intensity and decrease in frequency do not start and stop at the same time.

8. The apparatus of any preceding claim, wherein the target frequency is between 50 kHz and 500 kHz.

9. The apparatus of any preceding claim, wherein the first frequency is at least 10% higher than the target frequency.

10. The apparatus of claim 9, wherein the first frequency is at least 50% higher than the frequency intensity.

11. The apparatus of claim 10, wherein the first frequency is at least 100% higher than the target intensity.

12. The apparatus of any preceding claim, wherein the first frequency is at least 10 kHz higher than the target frequency.

13. The apparatus of claim 12, wherein the first frequency is at least 50 kHz higher than the target frequency.

14. The apparatus of claim 13, wherein the first frequency is at least 100 kHz higher than the target frequency.

15. The apparatus of any preceding claim, wherein the first frequency is between 200 kHz and 600kHz.

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