DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
In the amendment dated 02/07/2025, the following has occurred:
Claims 1, 9, 17 are amended,
Claims 8, 10-16, 18-20 and 23 are cancelled, and
Claims 1-7, 9, 17, 21-22 and 24-27 are pending.
Response to Arguments
Objection – Drawings
In light of the amendments to claim 23, the drawing objection is withdrawn.
Rejections under Post-AIA 35 U.S.C. § 112-First Paragraph
In light of the amendments, the rejection of claim 23 under 35 USC 112(a) is withdrawn.
Rejections under Post-AIA 35 U.S.C. § 101
In light of the amendments, the rejection of claim 23 under 35 USC 101 is withdrawn.
Rejections under Post-AIA 35 U.S.C. § 103
Applicant’s arguments, filed 02/07/2025, that the prior art does not disclose the amended limitation of “the measured impedance comprises a measured low frequency impedance, wherein the low frequency comprises a frequency from 1 Hz to 10 Hz” is moot since claims now stand rejected to Kroll (US 2005/0222646) in view of Kramer (US 2016/0082258), Ganz (US 2004/0215296), and Davies (Pat. No. US 8,262,575). Particularly Davies disclose that the measured impedance comprises a measured low frequency impedance, wherein the low frequency comprises a frequency from 1 Hz to 10 Hz (col. 25, ln. 62 - col. 26, ln. 35: electrodes are used to measure …impedance at one or more locations and at several defined frequencies, particularly very low frequencies… impedance at from about 5 to about 50 different frequencies in the range of about 0.1 Hz to about 10 Hz) for the purpose of determining a condition of a region of tissue to facilitate the location of surgical resection margins (col. 25, lns. 44-52).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor by administering an electric field based on impedance measurements of Kroll, Kramer, Ganz and Davies to include measured impedance in the low frequency range of 0.1 to 10 Hz, as taught by Davies in order to determine a condition of a region of tissue to facilitate the location of surgical resection margins.
There are no other arguments to claims other than their dependence on independent claims for which the Kroll rejection remains.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 1-2, 6 and 23-26 are rejected under 35 U.S.C. 103 as being unpatentable over Kroll et al. (Publication No. US 2005/0222646, hereinafter Kroll) in view of Kramer et al. (Publication No. US 2016/0082258 A1, hereinafter “Kramer”), Ganz et al. (US 2004/0215296 A1, hereinafter “Ganz”, cited by Applicant), and Davies et al. (Pat. No. US 8,262,575, hereinafter “Davies”). Kroll in view of Kramer, Ganz and Davies hereinafter referred to as “modified Kroll”.
Regarding claim 1, Kroll teaches a method for treating a cancerous tumor comprising:
implanting two or more leads (Figs. 2D (15)-(17) and 2G (25)-(27)) within a patient’s head, each of the two or more leads comprising one or more electric field generating electrodes (Figs. 2D, 2G, 22 (18)-(23) (86) and pars. [0070]: The devices and methods…are contemplated for use in numerous types of malignant tumors (i.e. cancer) and benign tumors…the devices and methods described herein are contemplated for use in…brain and central nervous system cancer (e.g. meningioma, astocytoma, oligodendrogliomas, ependymoma, gliomas, medulloblastoma, ganglioglioma, Schwannoma, germinoma, craniopharyngioma)…, [0106]: generator 1 with one or more electrodes…the electrodes 11 and 12 are implanted adjacent to the tumor 6 or …may be implanted into the tumor 6, [0159]: …driver 85, which provides electrical therapy to the lead electrodes 86) and one or more impedance monitoring electrodes (Figs. 22-23 (86) (91) and pars. [0159]: The driver circuit 85 delivers regulated voltage or constant current to the electrodes 86 to compensate for changes in impedance seen at the electrodes 86, [0160]: …sensor information from a tumor 6, such as tumor size, density, or chemistry data (e.g. pH) …can be detected by the electrodes 91 and specialized sensors such as…impedance…sensors, [0163], [0241]: … impedance and pH are related to the progression or regression of malignancies, and the impedance spectrum (i.e. the Z(f)) which is the impedance across the tumor at various frequencies, will allows estimation of tumor size);
measuring an impedance of tissue within the patient along a vector passing through a cancerous tumor (par. [0163]: …and the impedance spectrum (i.e. the Z(f)) which is the impedance across the tumor at various frequencies…);
administering an electric field to the cancerous tumor of the patient based on the measured impedance (pars. [0239], [0241]: In the case of sensed impedance, electrical therapy may be modified based on the impedance measured across or within the tumor…) and changes in an at least one property (pars. [0033]: …present invention can include modifying the applied electric power or current at least partially based on a detected characteristic or a change in a detected characteristic… modification of the applied electric power or current can occur in response to a measured …impedance, and the like, [0060]: A feedback unit 230 measures electric field delivery parameters and/or characteristics of the tissue of the target tissue region, measured parameters/characteristics including without limitation current, voltage, impedance, temperature modification of the applied electric power or current can occur in response to a measured temperature, impedance, and the like); and
adjusting the electric field, including changing one or more of an amplitude, pulse width, and/or duty cycle (par. [0184]: Many parameters can be programmed such as duration of therapy, duty cycle, pulse width…), in response to a sensed impedance (par. [0241]: …sensed impedance, electrical therapy may be modified based on the impedance measured across or within the tumor as a function of frequency) where impedance is measured as a function of oxygen and the oxygen is an indication of growing tumor (par. [0241]: …increased oxygen may be indicative of growing tumors as they tend to have a large oxygen supply. Sensing oxygen for this purpose will allow electrical therapy to be adjusted accordingly).
The embodiments of Figs. 2D and 2G of Kroll are silent about impedance and impedance monitoring electrodes , however, in an envisioned embodiment of Kroll teaches controlling therapy based on sensed parameters including impedance across or within a tumor (par. [0239]) and that electrical therapy may be modified based on the impedance measured across or within the tumor (par. [0241]) to provide the benefit of numerous closed-loop approaches for use in electrical therapy (par. [0239]).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to include in the two or more leads and electrodes of Figs. 2D and 2G, the embodiment of impedance sensing across or within a tumor, that includes both electric field generating electrodes and impedance monitoring electrodes on the leads , in order to provide the benefit closed-loop approaches for use in electrical therapy.
While Kroll discloses administering an electric field to the cancerous tumor of the patient based on the measured impedance and changes in a property (pars. [0184], [0241]), Kroll fails to disclose measuring at least one property selected from the group consisting of temperature, blood flow, blood pressure, metabolite concentrations, and systemic cancerous marker concentrations;
monitoring for changes in the at least one property; and
a measured decrease in impedance reflecting a lack of a decrease in the size of the tumor;
wherein the measured impedance comprises a measured low frequency impedance, wherein the low frequency comprises a frequency from 1 Hz to 10 Hz.
However Kramer, in the same field of endeavor: selective stimulation to target a medical condition, discloses measuring at least one property selected from the group consisting of blood flow, blood pressure; and
monitoring for changes in the at least one property (Fig. 1 and par. [0067]: …pulse generator (IPG) 102 comprises circuitry which initiates or modifies the electrical stimulation in response to one or more sensors. Example sensors include, among others…blood pressure sensors, blood flow sensors…) for the purpose of improving the status of the treatment in real time (par. [0068]).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor using two or more leads by administering an electric field based on impedance measurements indicative of tumor growth, as taught by Kroll, to incorporate monitoring of blood flow or blood pressure changes, as taught by Kramer, in order to improve the status of the treatment in real time.
While the combination of Kroll and Kramer discloses the impedance is related to the progression or regression of tumor malignancies and size (Kroll, par. [0163]), the combination does not disclose that the decreased impedance across the treatment area is indicative of tumor progression.
However, Ganz in the same field of endeavor: treating abnormal tissue, discloses a measured decrease in impedance reflecting a lack of a decrease in the size of the tumor (par. [0058]: During the treatment the tissue impedance was monitored as an indicator of the progress of the treatment, high impedance being an indication of desiccation; a measure of high impedance is an indication that the tumor is shrinking, therefore a decrease in measured impedance would cause a lack of desiccation or shrinkage and hence a lack of decrease in size of the tumor) to provide the benefit of determining, through monitoring, tumor progression/regression using tissue impedance (par. [0058]).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor by administering an electric field based on impedance measurements indicative of tumor growth and monitoring of blood flow or blood pressure changes, of Kroll and Kramer, where measuring a decrease in impedance reflects a lack of desiccation or lack of decrease in tumor size, as taught by Ganz to provide the benefit of determining, through monitoring, tumor progression/regression using tissue impedance.
While the combination of Kroll, Kramer and Ganz discloses measuring an impedance of tissue within the patient in a treatment area along a vector passing through a cancerous tumor (Kroll, par. [0163]), the combination does not disclose that the measured impedance comprises a measured low frequency impedance, wherein the low frequency comprises a frequency from 1 Hz to 10 Hz.
However, Davies in the same field of endeavor: detecting electrophysiological changes in pre-cancerous and cancerous tissue discloses that the measured impedance comprises a measured low frequency impedance, wherein the low frequency comprises a frequency from 1 Hz to 10 Hz (col. 25, ln. 62 - col. 26, ln. 35: electrodes are used to measure …impedance at one or more locations and at several defined frequencies, particularly very low frequencies… impedance at from about 5 to about 50 different frequencies in the range of about 0.1 Hz to about 10 Hz) for the purpose of determining a condition of a region of tissue to facilitate the location of surgical resection margins (col. 25, lns. 44-52).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor by administering an electric field based on impedance measurements of Kroll, Kramer and Ganz, to include measured impedance in the low frequency range of 0.1 to 10 Hz, as taught by Davies in order to determine a condition of a region of tissue to facilitate the location of surgical resection margins.
Regarding claim 2, modified Kroll teaches the method of claim 1, comprising administering electric field to the cancerous tumor of the patient based on changes in the measured impedance (Kroll, pars. [0159]: The driver circuit 85 delivers regulated voltage or constant current to the electrodes 86 to compensate for changes in impedance seen at the electrodes 86, [0160]: …embodiments include …an index of tumor regression or proliferation… This type of information can be detected by the electrodes 91 and specialized sensors such as physical, impedance…sensors).
Regarding claim 6, modified Kroll teaches the method of claim 1, further comprising monitoring for changes in the heart rate of the patient in response to the administered electric field; and
adjusting the electric field if changes in a heart rate of the patient are detected (Kroll, par. [0224]: Fig. 28b… … in response to an input from a microprocessor…changes may be in response to a sensor input, to …changes in measured heart rate variability).
Regarding claim 23, method of claim 1, further comprising implanting a third lead within the patient's head (Kroll, Figs. 2D and 2G (16)(25)), wherein the third lead comprises one or more impedance monitoring electrodes (Kroll, Figs. 2D and 2G (20)(21)) and par. [0241]: …sensed impedance, electrical therapy may be modified based on the impedance measured across or within the tumor…).
Regarding claim 24, while modified Kroll teaches the method of claim 1, further comprising administering one or more electric fields to the cancerous tumor of the patient (Kroll, par. [0103]) based on the measured impedance (Kroll, pars. [0239], [0241]: In the case of sensed impedance, electrical therapy may be modified based on the impedance measured across or within the tumor…) and changes in the at least one property (pars. [0033], [0060]), and that the multiple electrodes may function in any combination of anodes and cathodes (Figs 2D-G 18, 19, 20, 21, 22, and 23 and par. [0107]). Therefore, electric fields are produced along multiple vectors as electrodes function in any combination. However, the examiner notes that Kroll does not explicitly disclose the vectors at least separated by 10 degrees.
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to contrive any number of desirable ranges for the degrees of vector separation disclosed by Applicant, since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 105 USPQ 233. Further, it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980). Refer to MPEP §2144.05.
Regarding claim 25, modified Kroll teaches wherein the electric field is delivered using currents ranging from 1 mAmp to 1000 mAmp (Kroll, par. [0223]: …a therapeutic current level 143 of between 50 mA and 25 mA will be attained…).
Regarding claim 26, modified Kroll teaches the electric field is delivered using voltages ranging from 1 Vrms to 50 Vrms (Kroll, par. [0223]: …a therapeutic current level 143 of between…50 mV to 25 V will be attained… ).
Claims 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Kroll et al. (Pub. No. US 2005/0222646, hereinafter Kroll) in view of Kramer et al. (Pub. No. US 2016/0082258 A1, hereinafter “Kramer”), Ganz et al. (Pub No. US 2004/0215296 A1, hereinafter “Ganz”, cited by Applicant), and Davies et al. (Pat. No. US 8,262,575, hereinafter “Davies”) or “modified Kroll,” as applied to claims 1-2, 6 and 23-26 above, and further in view of Guo et al. (Pub. No. US 2018/0154142, hereinafter “Guo”).
Regarding claim 3, modified Kroll teaches the method of claim 1, except the electrodes comprising electric field generating electrodes and passive electric field sensing electrodes.
However, Guo in the same field of endeavor: methods and devices for treatment of tumors with nano-pulse stimulation, discloses the method of claim 1, the electrodes comprising electric field generating electrodes and passive electric field sensing electrodes (Fig. 3 and par. [0134] …an applicator tip with electrodes, which may be used in various embodiments of the present disclosure. In particular, an applicator tip 302 is shown that has one delivery electrode 304 and four ground electrodes 306 surrounding the delivery electrode 304; ground electrodes are considered sensing electrodes as the receive current and sense electrical activity) for the benefit of applying electrical pulses having certain parameters at a local tumor site in order to induce antitumor immunity and prevent distant metastases (par. [0125]).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method of testing and treating a cancerous tumor, as taught by modified Kroll to include field generating as field sensing electrodes as taught by Guo, in order to provide the benefit of applying electrical pulses having certain parameters at a local tumor site in order to induce antitumor immunity and prevent distant metastases.
Regarding claim 4, while modified Kroll discloses the method of claim 3, further comprising implanting sensing electrodes within the cancerous tumor (Kroll, Fig. 2B and par. [0016]: The electrodes are implanted in or near the tumor…), the combination does not explicitly disclose the passive electric field sensing electrodes within the cancerous tumor.
However, Guo disclose implanting the passive electric field sensing electrodes within the cancerous tumor (Fig. 3 and par. [0139]: …one or more of the needle electrodes…penetrates the tumor…the needle electrodes 402 are configured to pierce the tumor) for the benefit of precisely applying the electrode to the tumor to conduct the electric pulses produced (par. [0139]).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor with implantable sensing electrodes of modified Kroll, to include implanted electric field sensing electrodes as taught by Guo in order to precisely applying the electrode to the tumor to conduct the electric pulses produced.
Regarding claim 5, modified Kroll teaches the method of claim 3, further comprising implanting the electrical field generating electrodes adjacent to the cancerous tumor (Kroll, Fig. 2C and par. [0106]: …the electrodes 11 and 12 are implanted adjacent to the tumor 6).
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Kroll et al. (Pub. No. US 2005/0222646, hereinafter Kroll) in view of Kramer et al. (Pub. No. US 2016/0082258 A1, hereinafter “Kramer”), Ganz et al. (Pub No. US 2004/0215296 A1, hereinafter “Ganz”, cited by Applicant), and Davies et al. (Pat. No. US 8,262,575) or “modified Kroll,” as applied to claims 1-2, 6 and 23-26 above, and further in view of Palti (Publication No. US 2004/0176804).
Regarding claim 7, modified Kroll discloses the method of claims 6, wherein adjusting the electric field comprises reducing a strength of the delivered electric field (Kroll, par. [0241]: If in the case that a high level of "free" or gaseous oxygen is measured, the system may be programmed to decrease the amount of current applied), but does not disclose reducing the strength to a predetermined threshold.
Palti discloses applying a maximum optimal field strength that is less than the highest electric field strength focused at the targeted area, and therefore, optimizes the correlation between a calculated electric field and the desired electric field (par. [0138]) for the benefit of protecting the tissue area surrounding the tumor (par. [0138]).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to combine the method for treating a cancerous tumor that decreases field strength in accordance with heart rate sensor input, as taught by Kroll, Kramer and Ganz, with an optimal threshold strength as taught by Palti, in order protect the tissue area surrounding the tumor.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Kroll et al. (Pub. No. US 2005/0222646, hereinafter Kroll) in view of Kramer et al. (Pub. No. US 2016/0082258 A1, hereinafter “Kramer”), Ganz et al. (Pub No. US 2004/0215296 A1, hereinafter “Ganz”, cited by Applicant), and Davies et al. (Pat. No. US 8,262,575) or “modified Kroll,” and further in view of Azure (Publication No. US 2009/0076500).
Regarding claim 9, Kroll teaches a method for treating a cancerous tumor comprising:
implanting two or more leads (Figs. 2D (15)-(17) and 2G (25)-(27)) within a patient, each of the two or more leads comprising one or more electric field generating electrodes (Figs. 2D, 2G (18)-(23) and par., [0106]: generator 1 with one or more electrodes…the electrodes 11 and 12 are implanted adjacent to the tumor 6 or …may be implanted into the tumor 6);
measuring an impedance of tissue within the patient along a vector passing through a cancerous tumor (par. [0163]: …and the impedance spectrum (i.e. the Z(f)) which is the impedance across the tumor at various frequencies…);
assessing tumor progression based on the measured impedance (par. [0163]: …impedance and pH are related to the progression or regression of malignancies…and the impedance spectrum (i.e. the Z(f)) which is the impedance across the tumor at various frequencies, will allows estimation of tumor size).
administering an electric field to the cancerous tumor of the patient based on the measured impedance (pars. [0239], [0241]: In the case of sensed impedance, electrical therapy may be modified based on the impedance measured across or within the tumor…) and changes in an at least one property (pars. [0033]: present invention can include modifying the applied electric power or current at least partially based on a detected characteristic or a change in a detected characteristic… modification of the applied electric power or current can occur in response to a measured …impedance, and the like, [0060]: A feedback unit 230 measures electric field delivery parameters and/or characteristics of the tissue of the target tissue region, measured parameters/characteristics including without limitation current, voltage, impedance, temperature modification of the applied electric power or current can occur in response to a measured temperature, impedance, and the like); and
adjusting the electric field, including changing one or more of an amplitude, pulse width, and/or duty cycle (par. [0184]: Many parameters can be programmed such as duration of therapy, duty cycle, pulse width…), in response to a sensed impedance (par. [0241]: …sensed impedance, electrical therapy may be modified based on the impedance measured across or within the tumor as a function of frequency) where impedance is measured as a function of oxygen and the oxygen is an indication of growing tumor (par. [0241]: …increased oxygen may be indicative of growing tumors as they tend to have a large oxygen supply. Sensing oxygen for this purpose will allow electrical therapy to be adjusted accordingly).
The embodiments of Figs. 2D and 2G of Kroll are silent about impedance and impedance monitoring electrodes , however, in an envisioned embodiment, Kroll teaches controlling therapy based on sensed parameters including impedance across or within a tumor (par. [0239]) and that electrical therapy may be modified based on the impedance measured across or within the tumor (par. [0241]) to provide the benefit of numerous closed-loop approaches for use in electrical therapy (par. [0239]).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to include in the two or more leads and electrodes of Figs. 2D and 2G, the embodiment of impedance sensing across or within a tumor, that includes both electric field generating electrodes and impedance monitoring electrodes on the leads , in order to provide the benefit closed-loop approaches for use in electrical therapy.
While Kroll discloses administering an electric field to the cancerous tumor of the patient based on the measured impedance and changes in a property (pars. [0184], [0241]), Kroll fails to disclose measuring at least one property selected from the group consisting of temperature, blood flow, blood pressure, metabolite concentrations, and systemic cancerous marker concentrations;
monitoring for changes in the at least one property; and
wherein the electric field is generated at frequencies selected from a range of between 10 kHz to 1MHz at the treatment area, wherein the electric field is effective to prevent and/or disrupt cellular mitosis in a cancerous cell; and
wherein the measured impedance comprises a measured low frequency impedance, wherein the low frequency comprises a frequency from 1 Hz to 10 Hz.
However, Kramer, discloses measuring at least one property selected from the group consisting of blood flow, blood pressure; and
monitoring for changes in the at least one property (Fig. 1 and par. [0067]: …pulse generator (IPG) 102 comprises circuitry which initiates or modifies the electrical stimulation in response to one or more sensors. Example sensors include, among others…blood pressure sensors, blood flow sensors…) for the purpose of improving the status of the treatment in real time (par. [0068]).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor using two or more leads by administering an electric field based on impedance measurements indicative of tumor growth, as taught by Kroll, to incorporate monitoring of blood flow or blood pressure changes, as taught by Kramer, in order to improve the status of the treatment in real time.
While the combination of Kroll, and Kramer discloses the impedance is related to the progression or regression of tumor malignancies and size (Kroll, par. [0163]), Kroll does not disclose that a measured decrease in impedance reflecting a lack of a decrease in the size of the tumor.
However, Ganz discloses a measured decrease in impedance reflecting a lack of a decrease in the size of the tumor (par. [0058]: During the treatment the tissue impedance was monitored as an indicator of the progress of the treatment, high impedance being an indication of desiccation; a measure of high impedance is an indication that the tumor is shrinking, therefore a decrease in measured impedance would cause a lack of desiccation or shrinkage and hence a lack of decrease in size of the tumor) to provide the benefit of determining, through monitoring, tumor progression/regression using tissue impedance.
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor by administering an electric field based on impedance measurements indicative of tumor growth and monitoring of blood flow or blood pressure changes, of Kroll and Kramer, where measuring a decrease in impedance reflects a lack of desiccation or lack of decrease in tumor size, as taught by Ganz to provide the benefit of determining, through monitoring, tumor progression/regression using tissue impedance.
While the combination of Kroll, Kramer and Ganz discloses measuring an impedance of tissue within the patient in a treatment area along a vector passing through a cancerous tumor (Kroll, par. [0163]), the combination does not disclose that the measured impedance comprises a measured low frequency impedance, wherein the low frequency comprises a frequency from 1 Hz to 10 Hz.
However, Davies discloses that the measured impedance comprises a measured low frequency impedance, wherein the low frequency comprises a frequency from 1 Hz to 10 Hz (col. 25, ln. 62 - col. 26, ln. 35: electrodes are used to measure …impedance at one or more locations and at several defined frequencies, particularly very low frequencies… impedance at from about 5 to about 50 different frequencies in the range of about 0.1 Hz to about 10 Hz) for the purpose of determining a condition of a region of tissue to facilitate the location of surgical resection margins (col. 25, lns. 44-52).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor by administering an electric field based on impedance measurements of Kroll, Kramer and Ganz, to include measured impedance in the low frequency range 0.1 to 10 Hz, as taught by Ganz to provide the benefit of determining, through monitoring, tumor progression/regression using tissue impedance.
Further Azure, in the same field of endeavor: electric field delivery and selective ablation of cancerous cells, discloses wherein the electric field is generated at frequencies selected from a range of between 10 kHz to 1MHz at the treatment area (par. [0050]: …the electrical current includes a frequency between about 50 kHz and about 300 kHz.), wherein the electric field is effective to prevent and/or disrupt cellular mitosis in a cancerous cell (par. [0048]…the electric field application as described was observed to be particularly effective in selectively disrupting and destroying the dividing cancerous cells, while having little or no effect on normal cells that were not exhibiting unregulated growth and proliferation…electric field application as described may specifically disrupt the cell division process (e.g., mitosis) or progression through the cell cycle, or a stage or process thereof…and, therefore, more particularly effects cells exhibiting unregulated growth (e.g., cancerous cells)…) for the purpose of preventing cancerous cells that progress more rapidly through the cell cycle (par. [0048]).
Examiner NOTES that “the electric field is effective to prevent and/or disrupt cellular mitosis in a cancerous cell” is intended use. Since Azure discloses the frequency range required it is capable of disrupt cellular mitosis of cancerous cells.
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor by administering an electric field based on impedance measurements indicative of tumor growth, as taught by Kroll, to incorporate monitoring of blood flow or blood pressure changes, as taught by Kramer, where measuring a decrease in impedance reflects a lack of desiccation or lack of decrease in tumor size, as taught by Ganz, and to apply an electric field in the range of 50 kHz to 30 kHz, as taught by Azure in order to improve the status of the treatment in real time; and to prevent cancerous cells that progress more rapidly through the cell cycle.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Kroll et al. (Publication No. US 2005/0222646, hereinafter Kroll), in view of Azure (Publication No. US 2009/0076500), Guo et al. (Publication No. US 2018/0154142, hereinafter “Guo”), Palti (Publication No. US 2004/0176804) and Davies et al. (Pat. No. US 8,262,575, hereinafter “Davies”).
Regarding claim 17, Kroll discloses a method for treating a cancerous tumor comprising:
implanting two or more leads (Figs. 2D (15)-(17) and 2G (25)-(27)) within a patient, each of the two or more leads comprising one or more electric field generating electrodes (Figs. 2D, 2G (18)-(23) and par., [0106]: generator 1 with one or more electrodes…the electrodes 11 and 12 are implanted adjacent to the tumor 6 or …may be implanted into the tumor 6).
measuring an impedance of tissue within the patient along a vector passing through a cancerous tumor (par. [0163]: …and the impedance spectrum (i.e. the Z(f)) which is the impedance across the tumor at various frequencies…);
monitoring for changes in the heart rate of the patient in response to the administered electric field (par. [0224]: Fig. 28b… … in response to an input from a microprocessor…changes may be in response to a sensor input, to …changes in measured heart rate variability); and
further adjusting the electric field by reducing the strength of the delivered electric field (par. [0241]: … the system may be programmed to decrease the amount of current applied) for the purpose of reducing any potential pain experienced by a patient (par. [0215]).
Kroll does not disclose implanting one or more electric field sensing electrodes within in the treatment area of the patient;
delivering an electric field from the electric field generating electrodes to apply an electric field therapy to a cancerous tumor;
measuring an electric field strength with the electric field sensing electrodes across the cancerous tumor;
adjusting the delivered electric field to a desired electric field strength based on the measured electrical field strength;
measuring at least one metabolite concentration;
monitoring for changes in the at least one property;
monitoring for changes in the heart rate of the patient in response to the administered electric field; and
further adjusting the delivered electric field by reducing a strength of the delivered electric field to a predetermined threshold based on the changes in the at least one property just prior to detecting a change in the patient's heart rate;
wherein the measured impedance comprises a measured low frequency impedance, wherein the low frequency comprises a frequency from 1 Hz to 10 Hz.
However, Azure discloses implanting one or more electric field sensing electrodes within the patient (par. [0055]: … non-thermal ablation according to the present invention can include placement of a sensor, such as a thermocouple, within the target tissue region (e.g., proximate to the inner electrode)…);
delivering an electric field from the electric field generating electrodes to apply an electric field therapy to a cancerous tumor (pars. [0036]: As set forth above, the electrode is positioned within the target tissue region and the applied electric field is sufficient to provide low-power or non-thermal/mild hyperthermic ablation of target cells, [0045]: As the electrode 86 is positioned within the target tissue region 88, the applied electrical current can provide an electric field that radiates outward and in a plurality of directions);
measuring an electric field strength with the electric field sensing electrodes across the cancerous tumor (Fig. 16 and par. [0060]: A feedback unit 230 measures electric field delivery parameters and/or characteristics of the tissue of the target tissue region, measured parameters/characteristics including without limitation current, voltage, impedance, temperature); and
adjusting the delivered electric field to a desired electric field strength based on the measured electrical field strength (Fig. 16 and par. [0060]: A feedback unit 230 measures electric field delivery parameters and/or characteristics of the tissue of the target tissue region, measured parameters/characteristics including without limitation current, voltage, impedance, temperature…modification of the applied electric power or current can occur in response to a measured temperature, impedance, and the like) for the benefit of precisely and accurately controlling energy delivery such that tissue hyperthermia can be accurately controlled and maintained in a desired temperature range selected for preferential destruction of cancerous cells compared to non-cancerous cells (par. [0036]).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor by administering an electric field based on impedance measurements indicative of tumor growth using leads and electrodes, as taught by Kroll, to incorporate electric field sensing electrodes as taught by Azure, in order to precisely and accurately control energy delivery such that tissue hyperthermia can be accurately controlled and maintained in a desired temperature range selected for preferential destruction of cancerous cells compared to non-cancerous cells.
The Kroll and Azure combination does not discloses measuring at least one property selected from the group consisting of metabolite concentrations and systemic cancerous marker concentrations; and
monitoring for changes in metabolite concentrations.
Guo discloses measuring at least one property selected from the group consisting of metabolite concentrations and systemic cancerous marker concentrations; and
monitoring for changes in metabolite concentrations (Fig. 5 (502) and pars. [0160], [0161]: …a pre-treatment measurement may be taken of myeloid-derived suppressor cells (MDSC) and/or regulatory T cell (Tregs) concentration. For instance, blood can be extracted from a subject or a biopsy taken from the tumor site…In the case of a biopsy, tumor cells may be separated out. Different particles of interest can be labeled with biomarkers…in order to determine the MDSC/Treg concentration…When a tumor is present (e.g., pre-treatment), MDSCs/Tregs are biomarkers for the tumor, and there should be higher levels of MDSCs and Tregs in the blood or tumor microenvironment) for the purpose of treating metastatic diseases (par. [0159]).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor by administering an electric field based on impedance measurements indicative of tumor growth using leads and electrodes, as taught by Kroll and Azure, the measurement of metabolite concentrations, as taught by Guo, in order to treat metastatic diseases.
While the Kroll, Azure and Guo combination discloses further adjusting the electric field by reducing the strength of the delivered electric field (Kroll, par. [0241]), it does not disclose reducing the strength to a predetermined threshold.
Palti discloses applying a maximum optimal field strength that is less than the highest electric field strength focused at the targeted area, and therefore, optimizes the correlation between a calculated electric field and the desired electric field (par. [0138]) for the benefit of protecting the tissue area surrounding the tumor (par. [0138]).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor by administering an electric field based on impedance measurements indicative of tumor growth using leads and electrodes, as taught by Kroll, Azure and Guo, to include an optimal field strength input threshold as taught by Palti, in order to protect the tissue area surrounding the tumor.
While the Kroll, Azure, Guo and Palti discloses measuring an impedance of tissue within the patient along a vector passing through a cancerous tumor (par. [0163]) the combination does not disclose that the measured impedance comprises a measured low frequency impedance, wherein the low frequency comprises a frequency from 1 Hz to 10 Hz.
However, Davies discloses that the measured impedance comprises a measured low frequency impedance, wherein the low frequency comprises a frequency from 1 Hz to 10 Hz (col. 25, ln. 62 - col. 26, ln. 35: electrodes are used to measure …impedance at one or more locations and at several defined frequencies, particularly very low frequencies… impedance at from about 5 to about 50 different frequencies in the range of about 0.1 Hz to about 10 Hz) for the purpose of determining a condition of a region of tissue to facilitate the location of surgical resection margins (col. 25, lns. 44-52).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor by administering an electric field based on impedance measurements of Kroll, Azure, Guo and Palti, to include measured impedance in the low frequency range of 0.1 to 10 Hz, as taught by Davies in order to determine a condition of a region of tissue to facilitate the location of surgical resection margins.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Kroll et al. (Pub. No. US 2005/0222646, hereinafter Kroll) in view of Kramer et al. (Pub. No. US 2016/0082258 A1, hereinafter “Kramer”), Ganz et al. (Pub No. US 2004/0215296 A1, hereinafter “Ganz”, cited by Applicant), and Davies et al. (Pat. No. US 8,262,575, hereinafter “Davies”) or “modified Kroll,” as applied to claims 1-2, 6 and 23-26, and further in view of Toth et al. (Publication No. US 2016/0029960, hereinafter “Toth”).
Regarding claim 21, modified Kroll discloses all of the method of claim 1, except further comprising implanting one or more evoked potential sensors within a patient, the one or more evoked potential sensors configured to detect one or more electrical potentials emitted by a nervous system.
Toth in the same field of endeavor: systems and methods for neuromodulation and controlled micro ablation procedures, discloses implanting one or more evoked potential sensors within a patient, the one or more evoked potential sensors configured to detect one or more electrical potentials emitted by a nervous system. (par. [0057] …monitoring one or more of …evoked potential, stimulation/sensing of nervous activity…) for the purpose of determining the properties of one or more neurological features in the vicinity of one or more monitoring sites (par. [0057]).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor, as taught by modified Kroll, to include evoked potential sensors of the nervous system as taught by Toth, in order to determine the properties of one or more neurological features in the vicinity of one or more monitoring sites.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Kroll et al. (Pub. No. US 2005/0222646, hereinafter Kroll) in view of Kramer et al. (Pub. No. US 2016/0082258 A1, hereinafter “Kramer”), Ganz et al. (Pub No. US 2004/0215296 A1, hereinafter “Ganz”, cited by Applicant), and Davies et al. (Pat. No. US 8,262,575, hereinafter “Davies”) or “modified Kroll,” as applied to claims 1-2, 6 and 23-26 above, and further in view of Fernandez (Publication No. US 2005/0043894 A1).
Regarding claim 22, modified Kroll discloses the method of claim 1, except further comprising measuring a quantity of an analyte present in the treatment area, the analyte selected from the group consisting of fibrin, fibrinogen, immunoglobulins, deoxyribonucleic acids, ribonucleic acids, and bicarbonate.
Fernandez, in the same field of endeavor: integrated biosensor and simulation system for diagnosis and therapy, discloses measuring a quantity of an analyte present in the treatment area, the analyte selected from the group consisting of fibrin, fibrinogen, immunoglobulins, deoxyribonucleic acids, and ribonucleic acids (Fig. 2 and pars. [0050]: Sensor components may include deoxyribonucleic acid (DNA) sensor 201, ribonucleic acid (RNA) sensor 202, [0073]: …sensing techniques for cancer detection contemplated herein include…tests for cancer markers including…fibrin/fibrinogen) for the purpose of detecting condition of target tissue (par. [0005]).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor, as taught modified Kroll to include tests and sensors for cancer markers, as taught by Fernandez, in order to detect condition of target tissue.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Kroll et al. (Pub. No. US 2005/0222646, hereinafter Kroll) in view of Kramer et al. (Pub. No. US 2016/0082258 A1, hereinafter “Kramer”), Ganz et al. (Pub No. US 2004/0215296 A1, hereinafter “Ganz”, cited by Applicant), and Davies et al. (Pat. No. US 8,262,575) Davies et al. (Pat. No. US 8,262,575, hereinafter “Davies”) or “modified Kroll,” as applied to claims 1-2, 6 and 23-26 above, and further in view of Leonhardt et al. (US 2017/0266371 A1, hereinafter "Leonhardt").
Regarding claim 27, modified Kroll discloses the method of claim 1, except wherein the electric field is delivered having a strength from 0.25 V/cm and 1000 V/cm.
However, Leonhardt in the same field of endeavor: precise bioelectrical stimulation of tissue, discloses applying an electric field to the target region of cancer cells in which the field strength is between 1 V/cm and 5 V/cm (par. [0073]) for the purpose of killing or inhibiting the growth of cancer cells in a target region.
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to modify the method for treating a cancerous tumor, as taught modified Kroll to include applying electric fields having a field strength of 1 V/cm and 5 V/cm, as taught by Leonhardt, in order to kill or inhibit the growth of cancer cells in a target region.
Conclusion
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/AAA/Examiner, Art Unit 3796
/DAVID HAMAOUI/SPE, Art Unit 3796
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