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 .
Information Disclosure Statement
The information disclosure statements (IDS) were submitted on 10/23/2025, 01/15/2026, 02/26/2026, 05/12/2026, and 06/18/2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Amendments
This Office Action is responsive to the amendment filed on 27 March 2026. As directed by the amendment: Claims 1, 5, 9-11, 18-19, and 21-22 have been amended, claims 6-7 and 13-14 are cancelled, and no claims have been added. Thus claims 1-5, 8-12, and 15-25 are presently pending for examination.
Response to Arguments
Response to Arguments Regarding 35 USC § 102/103
Applicant’s arguments, see Remarks pg. 9-19, filed 27 March 2026, with respect to the rejection(s) of independent claim(s) 1, 19, and 21 under 35 USC 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Stewart et al. (US 2022/0338925 A1), hereinafter Stewart.
Applicant has amended independent claims 1, 19, and 21 to recite the limitation of “increasing a temperature of the target tissue to a phase transition temperature of about 41 degrees C before applying current in the form of a pulsed sawtooth-shaped waveform to the target tissue, wherein the phase transition temperature initiates a change in lipid cell membranes within the target tissue from an ordered gel phase to a liquid crystalline phase”, and Applicant further argues that none of the cited references in the rejection teach or suggest these limitations. Examiner agrees and has instead used Stewart to teach the amended limitation and additionally uses Sano to teach using pulsed sawtooth-shaped waveform for electroporation (as described in detail below).
Thus, claims 1-4, 8-9, and 19 and 21 are rejected under 35 USC 103 (as described in detail below).
No additional specific arguments were presented with previous 35 U.S.C. 103 rejections of dependent claims 5, 10-12, 15-18, 20, and 22-25 nor specifically with respect to the previously cited Moss’395, Vrba, Thompson, Adler, Haidry, and Rajagopalan.
Therefore, claims 5, 10-12, 15-18, 20, and 22-25 remain rejected under 35 USC 103 (As described in detail below).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-4, 8-9, and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moss et al. (US 2023/0414274 A1, previously cited), hereinafter Moss ‘274 in view of Caplan et al. (US 2020/0261144 A1, previously cited), hereinafter Caplan in view of Stewart et al. (US 2022/0338925 A1), hereinafter Stewart in view of Sano et al. (US 2017/0266438 A1, previously cited), hereinafter Sano in view of Neal, II et al. (US 2022/0387095 A1, previously cited), hereinafter Neal in view of Jackson et al. (US 2006/0095032 A1, previously cited), hereinafter Jackson.
Regarding claims 1, Moss ‘274 discloses a method of treating diabetes with irreversible electroporation (IRE) ([00159]-[00160] “the methods and apparatuses described herein may be used to resurface the mucosal layer of the patient's duodenum. Duodenal resurfacing may be used or treat a patient to improve diabetes.”. [0082] “elongate applicator tools adapted to be inserted into a body lumen or structure, and in particular, into a lumen of an otolaryngological structure (such as an ear, nose, or throat, including anatomical structures, such as turbinates, tonsils, tongue, soft palate, parotid glands), a gastrointestinal tract (e.g., stomach, small intestine, large intestine, duodenum, colon, etc., including the esophagus), and/or a respiratory tract (e.g., trachea, pharynx, larynx, and bronchi), to deliver high voltage (e.g., microsecond, nanosecond, picosecond, etc.) electrical energy to target tissue without damaging surrounding (non-target) tissue”), comprising:
Advancing a pulsed electrical field device (elongate applicator tool 102) into a duodenum of a patient ([0082]-[0083] “Described herein are elongate applicator tools adapted to be inserted into a body lumen or structure, and in particular, into a lumen of…a gastrointestinal tract (e.g., stomach, small intestine, large intestine, duodenum, colon, etc., including the esophagus)… to deliver high voltage (e.g., microsecond, nanosecond, picosecond, etc.) electrical energy to target tissue”, [0007] “treating within a body lumen using electric fields, including sub-microsecond (e.g., nanosecond) pulsed electrical fields”), the pulsed electric field device comprising an elongate body (elongate shaft 209), an expandable member coupled to the elongate body ([0020] “the applicator tool may include one or more contact projections (e.g., contact plates, contact posts, balloons, etc.)”),
Delivering a plurality of pulsed waveforms to the electrode array to generate a pulsed or modulated electric field thereby treating the target tissue of the duodenum ([0014] “One or more (e.g., a plurality) of electrodes configured for the delivery of high voltage, sub-microsecond electrical pulses (nanosecond pulsing, to deliver a nanosecond pulsed electric field to a target tissue) may be present at an end region of the elongate body.”, [0160] “the applicator may be configured as a catheter that may include one or more tissue-expanding projections that may be used to provide access to the tissue of the duodenum, and completely or partially circumferential mucosal-specific ablation may be provided by nanosecond pulsed electric field.”), wherein each one of the pulsed waveforms comprise a pulse width between about 1µs to about 4 µs ([0024] “a train of electrical pulses having a pulse width, for example, of between 0.1 nanoseconds (ns) and 1000 nanoseconds.” Examiner notes that 1000 ns – 1 µs, [0105] “In some examples, the pulse duration may be…about 1 μs, about 2 μs, about 3 μs, about 4 μs…”), wherein the plurality of pulses comprise a current between about 30 A to about 90 A ([0105] “In some examples, the current may be…about 25 A, about 40 A, about 50 A, about 60 A, about 75 A, about 100 A…”) , and is further configured to generate energy at the tissue between about 3 J and about 6 J ([0150] “In some treatments, energy delivered was between 1 J and 12 J”)
Wherein the therapeutic electric field comprises a field strength between about 200 V/cm to about 5000 V/cm ([0022] “this pulsed energy may have high peak voltages, such as 1 to 5 kilovolts per centimeter (kV/cm), 10 kV/cm, 20 kV/cm, 100 kV/cm or higher”),
Wherein the therapeutic electric field is configured to irreversibly electroporate cells within at least the outer mucosal layer of the duodenum ([0158] “the epithelial mucosal surface may be modified, e.g., resurfaced, by the application of nanosecond pulsed field”)
wherein the therapeutic electric field does not treat cells within a muscularis layer of the duodenum ([0007] “the methods and apparatuses described herein may be configured to selectively treat, for example, a portion of a wall of a body lumen, e.g., the outermost layer(s), with nanosecond pulsed electrical fields that may prevent damage to deeper, non-target regions.”)
Although Moss ‘274 does not explicitly teach these ranges, it would be obvious to one of ordinary skill in the art to use values within these ranges because Moss ‘274’s ranges are shown to be effective and they overlap heavily with the applicant’s ranges, therefore discovering the optimum or workable ranges of a result effective variable involves only routine skill in the art. In re Aller, 105 USPQ 233.
Moss ‘274 fails to teach wherein the expandable member comprises an electrode array comprising a plurality of electrodes, and a temperature sensor configured to measure temperature of a target tissue within the duodenum; increasing a temperature of the target tissue to a phase transition temperature of about 41 degrees C before applying current in the form of a pulsed sawtooth-shaped waveform to the target tissue, wherein the phase transition temperature initiates a change in lipid cell membranes within the target tissue from an ordered gel phase to a liquid crystalline phase; and wherein the plurality of pulses comprise a frequency between about 50 kHz and about 950 kHz, a drive voltage at the electrode array between about 400 V and about 950 V, and a current density through the target tissue between about 36 A and about 48A per square centimeter of the tissue; wherein the pulsed electric field comprises a therapeutic electric filed at a tissue depth of between 0.25mm to about 1.5 mm; wherein the therapeutic electric field is configured to irreversibly electroporate cells within at least the outer mucosal layer of the duodenum , while leaving tissue scaffolding within the mucosal layer intact; wherein the measured temperature is required to be within the range of about 41 degrees C to about 45 degrees C before applying the pulsed sawtooth-shaped waveform.
However, Caplan teaches a device for ablating the duodenal mucosa wherein the expandable member (expandable assemblies 130a and 130b) comprises an electrode array comprising a plurality of electrodes ([0131] “Expandable assembly 130a of FIG. 1 includes an ablation element comprising a pair of electrodes, first electrode 136a and second electrode 137a. In some embodiments, three or more electrodes can be included, such as an expandable assembly 130a which includes at least 4 electrodes. Electrodes 136a and/or 137a can be mounted on, within and/or inside of expandable assembly 130a”) and a temperature sensor configured to measure temperature of the tissue of the duodenum ([0150] “Functional elements 131a and 131b can comprise a sensor configured to provide information related to the tissue treatment performed by expandable assembly 130a and/or 130b, such as a temperature sensor configured to monitor the temperature of treatment provided by expandable assembly 130a and/or tissue proximate expandable assembly 130a”)
wherein the therapeutic electric field does not treat cells within a muscularis layer of the duodenum ([0009] “The device can be further configured to avoid damaging tissue selected from the group consisting of: a duodenal muscularis layer;”).
It would have been prima facia obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274 to incorporate the teachings of Caplan to have the expandable member comprises an electrode array comprising a plurality of electrodes and a temperature sensor configured to measure temperature of the tissue of the duodenum and wherein the therapeutic electric field does not treat cells within a muscularis layer of the duodenum, as these prior art references and the instant application are directed to delivering energy to duodenum. One would be motivated to do this to prevent damage to the target tissue while being able to make sufficient contact.
Moss ‘274 and Caplan, alone or in combination, fail to teach increasing a temperature of the target tissue to a phase transition temperature of about 41 degrees C before applying current in the form of a pulsed sawtooth-shaped waveform to the target tissue, wherein the phase transition temperature initiates a change in lipid cell membranes within the target tissue from an ordered gel phase to a liquid crystalline phase; and wherein the plurality of pulses comprise a frequency between about 50 kHz and about 950 kHz, a drive voltage at the electrode array between about 400 V and about 950 V, and a current density through the target tissue between about 36 A and about 48A per square centimeter of the tissue; wherein the pulsed electric field comprises a therapeutic electric filed at a tissue depth of between 0.25mm to about 1.5 mm; wherein the therapeutic electric field is configured to irreversibly electroporate cells within at least the outer mucosal layer of the duodenum , while leaving tissue scaffolding within the mucosal layer intact; wherein the measured temperature is required to be within the range of about 41 degrees C to about 45 degrees C before applying the pulsed sawtooth-shaped waveform.
However, Stewart et al. (US 2022/0338925 A1) teaches a device, system and method for delivering energy to a tissue wherein “heat the cells to a target temperature. Heating the tissue may reduce the threshold electric field strength of the tissue that is required to cause irreversible cell membrane damage. The temperature increase required, and thus the target temperature, to achieve increased electroporation effectiveness may be less than the minimum temperature that would be required to achieve cell death by thermal means alone (approximately 50° C.)… In one embodiment, the tissue may be optimized by heating to a temperature of at least approximately 45° C. and as high as approximately 60° C. That is, the tissue may be heated to a temperature of between approximately 45° C. and approximately 60° C.” ([0080]).
It would have been prima facia obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274 and Caplan to incorporate the teachings of Stewart to increase a temperature of the target tissue to a phase transition temperature of about 41 degrees C before applying current in the form of a pulsed sawtooth-shaped waveform to the target tissue, wherein the phase transition temperature initiates a change in lipid cell membranes within the target tissue from an ordered gel phase to a liquid crystalline phase, as these prior art references are directed to treating cells by delivering energy. One would be motivated to do this increase the depth of electroporation ablation, as recognized by Stewart ([0080]).
Although Stewart does not explicitly teach these ranges and values, it would be obvious to one of ordinary skill in the art to use values within these ranges because Stewart’s ranges are shown to be effective and they overlap heavily with the applicant’s ranges, therefore discovering the optimum or workable ranges of a result effective variable involves only routine skill in the art. In re Aller, 105 USPQ 233.
Additionally, Examiner would like to note that phase transition temperature, wherein the phase transition temperature initiates a change in lipid cell membranes within the target tissue from an ordered gel phase to a liquid crystalline phase to be a recitation of the recited heating, therefore, achieving the required heating would also achieve the phase transition result.
Moss’274, Caplan, and Stewart, alone or in combination, fail to teach wherein the plurality of pulses comprise a frequency between about 50 kHz and about 950 kHz, a drive voltage at the electrode array between about 400 V and about 950 V, and a current density through the target tissue between about 36 A and about 48A per square centimeter of the tissue; wherein the pulsed electric field comprises a therapeutic electric filed at a tissue depth of between 0.25mm to about 1.5 mm; wherein the therapeutic electric field is configured to irreversibly electroporate cells within at least the outer mucosal layer of the duodenum , while leaving tissue scaffolding within the mucosal layer intact.
However, Sano teaches medical therapies involving administering electrical treatment energy through a train of electrical pulses for treating unwanted cells while sparing healthy tissue ([0003]) wherein the pulsed waveform comprises a pulse width between about 1 µs to about 4µs ([0162]-[0164] “the pulse length may range from about 0.25 microseconds to about 100 microseconds, including 0.5, 1, 2, 3, 4…μs, or any range in between these values”), applying current in the form of a pulsed sawtooth-shaped waveform ([0161] “a pulse shape that is…sawtooth…”), wherein the plurality of pulses comprise a frequency between about 50 kHz and about 950 kHz ([0170]), a drive voltage at the electrode array between about 400 V and about 950 V ([0167] “Electrical pulse generators that can be used include those capable of delivering from 0 to about 5,000 V, such as the NanoKnife® system of AngioDynamics®, which for example can deliver from 0-3,000 V.”), a current between about 30A to about 90A ([0171] “The resulting current in the treated tissue can range for example from about 1 A to about 80 A, or from about 20 A to about 60 A, or from about 30 A to about 50 A, such as 40 A.”), and a current density through the tissue between about 36 A and about 48 A per square centimeter of the tissue ([0158] “The electrode may have a surface area of 0.1-5 sq. cm or 1-2 sq. cm, for example.”, [0171] “The resulting current in the treated tissue can range for example from about 1 A to about 80 A, or from about 20 A to about 60 A, or from about 30 A to about 50 A, such as 40 A.”, Examiner notes that current density = current through the tissue/surface area of treated tissue, therefore if we consider the resulting current in the treated tissue to be 40 A and the surface area of the treated tissue (i.e. electrode surface area, as the electrode is in contact with tissue) to be 1 sq.cm., the current density would be 40 A per square centimeters), wherein the therapeutic electric field comprises a field strength between about 200 V/cm to about 5,000 V/cm ([0167]).
Sano makes it evident that these parameters: pulse shape, pulse width, frequency, drive voltage, current, current density, and field strength are known in the art of electroporation/pulsed electric fields, Sano also shows that these parameters are result-effective in the art of electroporation. Additionally, upon review of Applicant’s disclosure, there appears to be no criticality to the claimed range of these parameters, particularly that of current density and one of ordinary skill in the art would have had reasonable expectation of success in optimizing these parameters.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274 and Caplan to incorporate the optimized pulses having a pulsed sawtooth-shaped waveform, frequency between 50 kHz and about 950 kHz , drive voltage at the electrode array between about 400 V and about 950 V, and current density through the tissue between about 36 A and about 48 A per square centimeter of the tissue of Sano, as these prior art references are directed to applying electric stimulation to treat unwanted/untreated tissues or cells. One would be motivated to do this as these parameters can have effects on unwanted cells while sparing health tissues.
Moss ‘274, Caplan, Stewart, and Sano, alone or in combination, fail to teach wherein the pulsed electric field comprised a therapeutic electric filed at a tissue depth of between about 0.25 mm to about 1.5 mm, while leaving tissue scaffolding within the mucosal layer intact.
However, Neal teaches a method for delivering specialized pulsed electric field (PEF) energy to treat an area of diseased tissue wherein “the extracellular matrices are preserved, and the target tissue maintains its structural architecture including blood vessels and lymphatics. Thus sensitive structure, such as biological lumens are able to be preserved...” ([0265], extracellular matrices are interpreted to be the tissue scaffolding).
It would have been prima facia obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274, Caplan, Stewart and Sano to incorporate the teaching of Neal to wherein the therapeutic electric field is configured to treat cells while leaving tissue scaffolding within the mucosal layer intact. One would be motivated to do this in order to maintain the integrity and functionality of the tissue which allows for the treatment of tissues considered untreatable, tissues near sensitive structures, and for the influx of biological elements after treatment, as recognized by Neal.
Moss ‘274, Caplan, Stewart, Sano, and Neal alone or in combination, fail to teach wherein the pulsed electric field comprises a therapeutic electric field at a tissue depth of between about 0.25 mm to about 1.5 mm.
However, Jackson teaches an ablation method for an wherein the pulsed electric field comprises a therapeutic electric field at a tissue depth of between about 0.25 mm to about 1.5 mm ([0018] “desired depth of ablated tissue is approximately between 0.5 mm and 1 mm” )
It would have been prima facia obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the parameters of Moss ‘274, Caplan, Stewart, Sano, and Neal to incorporate the teaching of Jackson for the pulsed electric field comprises a therapeutic electric field at a tissue depth of between 0.25 mm to about 1.5 mm. One would be motivated to do extend the application of a depth between 0.50 mm and 1 mm for ablation of an esophagus to ablation of a stomach or duodenum because the tissue impedance and damage to tissue is minimal at this depth and because the arrangement of the electrodes controls the depth and pattern of the treatment applied ([0035]), as recognized by Jackson.
Regarding Claim 2, Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson teaches the method of claim 1 (as shown above). Moss further discloses where the frequency is between about 300 kHz and about 400kHz ([0024] “a frequency, for example, of between 0.1 per second (Hz) to 10,000 Hz”).
Moss ‘274 teaches a similar method of treating diabetes by duodenal resurfacing to that of the instant application as explained above, except that the instant application teaches a narrower range that falls within the effective range of Moss ‘274. It would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to use a frequency between 300 kHz and 400 kHz, since it has been held that the general conditions of the claim are disclosed in the prior art, therefore discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 105 USPQ 233. Please note that in the instant application, the Applicant has not disclosed any criticality for the claimed limitation.
Regarding Claim 3, Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson teaches the method of claim 1 (as shown above). Moss ‘274 further discloses where the therapeutic electric field at the tissue comprises a field strength that is between about 1,500 V/cm and about 3,000 V/cm ( [0022] “1 to 5 kilovolts per centimeter (kV/cm)”).
Regarding claim 4, Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson teaches the method of claim 1 (as shown above). Sano further discloses a drive voltage at the electrode array between about 450 V and about 750 V ([0167] “Electrical pulse generators that can be used include those capable of delivering from 0 to about 5,000 V, such as the NanoKnife® system of AngioDynamics®, which for example can deliver from 0-3,000 V.”).
Sano makes it evident that the drive voltage is known in the art of electroporation/pulsed electric fields, Sano also shows that this parameter is result-effective in the art of electroporation. Additionally, upon review of Applicant’s disclosure, there appears to be no criticality to the claimed range of this parameter, particularly that of current density and one of ordinary skill in the art would have had reasonable expectation of success in optimizing these parameters.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274, Caplan, Stewart, Neal, and Jackson to incorporate the optimized drive voltage at the electrode array between about 450 V and about 750 V of Sano, as these prior art references are directed to applying electric stimulation to treat unwanted/untreated tissues or cells. One would be motivated to do this as these parameters can have effects on unwanted cells while sparing health tissues.
Regarding Claim 8-9, Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson teaches the method of claim 1 (as shown above).
Moss ‘274, Caplan, Stewart, Sano, and Nea, alone or in combination, fail to teach where the pulsed electric field is a therapeutic electric field at a compressed tissue depth of between 0.25 mm and about 0.75 mm and at an uncompressed tissue depth of between 0.50 mm and about 1.5 mm.
Jackson teaches an ablation method for an esophagus where a “desired depth of ablated tissue is approximately between 0.5 mm and 1 mm” ([0018]).
It would have been prima facia obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the parameters of Moss ‘274, Caplan, Stewart, Sano, and Neal to incorporate the teaching of Jackson for the pulsed electric field is a therapeutic electric field at a compressed tissue depth of between 0.25 mm and about 0.75 mm and at an uncompressed tissue depth of between 0.50 mm and about 1.5 mm. One would be motivated to do extend the application of a depth between 0.50 mm and 1 mm for ablation of an esophagus to ablation of a stomach or duodenum because the tissue impedance and damage to tissue is minimal at this depth, as recognized by Jackson.
Regarding claims 19, Moss ‘274 discloses a method of treating diabetes with irreversible electroporation (IRE) ([00159]-[00160] “the methods and apparatuses described herein may be used to resurface the mucosal layer of the patient's duodenum. Duodenal resurfacing may be used or treat a patient to improve diabetes.”. [0082] “elongate applicator tools adapted to be inserted into a body lumen or structure, and in particular, into a lumen of an otolaryngological structure (such as an ear, nose, or throat, including anatomical structures, such as turbinates, tonsils, tongue, soft palate, parotid glands), a gastrointestinal tract (e.g., stomach, small intestine, large intestine, duodenum, colon, etc., including the esophagus), and/or a respiratory tract (e.g., trachea, pharynx, larynx, and bronchi), to deliver high voltage (e.g., microsecond, nanosecond, picosecond, etc.) electrical energy to target tissue without damaging surrounding (non-target) tissue”), comprising:
Advancing a pulsed electrical field device (elongate applicator tool 102) into a stomach of a patient ([0082]-[0083] “Described herein are elongate applicator tools adapted to be inserted into a body lumen or structure, and in particular, into a lumen of…a gastrointestinal tract (e.g., stomach, small intestine, large intestine, duodenum, colon, etc., including the esophagus)… to deliver high voltage (e.g., microsecond, nanosecond, picosecond, etc.) electrical energy to target tissue”, [0007] “treating within a body lumen using electric fields, including sub-microsecond (e.g., nanosecond) pulsed electrical fields”), the pulsed electric field device comprising an elongate body (elongate shaft 209), an expandable member coupled to the elongate body ([0020] “the applicator tool may include one or more contact projections (e.g., contact plates, contact posts, balloons, etc.)”),
Generating a pulsed or modulated electric field within the target tissue by applying the pulsed waveform to the target tissue ([0014] “One or more (e.g., a plurality) of electrodes configured for the delivery of high voltage, sub-microsecond electrical pulses (nanosecond pulsing, to deliver a nanosecond pulsed electric field to a target tissue) may be present at an end region of the elongate body.”, [0160] “the applicator may be configured as a catheter that may include one or more tissue-expanding projections that may be used to provide access to the tissue of the duodenum, and completely or partially circumferential mucosal-specific ablation may be provided by nanosecond pulsed electric field.”), thereby irreversible electroporating cells within the target tissue within the stomach ([0158] “the epithelial mucosal surface may be modified, e.g., resurfaced, by the application of nanosecond pulsed field”) wherein the pulsed or modulated waveforms comprise a pulse width between about 1µs to about 4 µs ([0024] “a train of electrical pulses having a pulse width, for example, of between 0.1 nanoseconds (ns) and 1000 nanoseconds.” Examiner notes that 1000 ns – 1 µs, [0105] “In some examples, the pulse duration may be…about 1 μs, about 2 μs, about 3 μs, about 4 μs…”), and produces a current through the target tissue between about 30 A to about 90 A ([0105] “In some examples, the current may be…about 25 A, about 40 A, about 50 A, about 60 A, about 75 A, about 100 A…”) , and is further configured to generate energy at the tissue between about 3 J and about 6 J ([0150] “In some treatments, energy delivered was between 1 J and 12 J”)
Wherein the pulsed or modulated electric field comprises a therapeutic electric field comprising a field strength between about 200 V/cm to about 5000 V/cm ([0022] “this pulsed energy may have high peak voltages, such as 1 to 5 kilovolts per centimeter (kV/cm), 10 kV/cm, 20 kV/cm, 100 kV/cm or higher”)
Wherein the therapeutic electric field comprises a field strength between about 200 V/cm to about 5000 V/cm ([0022] “this pulsed energy may have high peak voltages, such as 1 to 5 kilovolts per centimeter (kV/cm), 10 kV/cm, 20 kV/cm, 100 kV/cm or higher”),
Wherein the therapeutic electric field treats cells within the target tissue with the IRE ([0158] “the epithelial mucosal surface may be modified, e.g., resurfaced, by the application of nanosecond pulsed field”)
Although Moss ‘274 does not explicitly teach these ranges, it would be obvious to one of ordinary skill in the art to use values within these ranges because Moss ‘274’s ranges are shown to be effective and they overlap heavily with the applicant’s ranges, therefore discovering the optimum or workable ranges of a result effective variable involves only routine skill in the art. In re Aller, 105 USPQ 233.
Moss ‘274 fails to teach wherein the expandable member comprises an electrode array comprising a plurality of electrodes, and a temperature sensor configured to measure temperature of a target tissue within the duodenum; increasing a temperature of the target tissue to a phase transition temperature of about 41 degrees C before applying current in the form of a pulsed sawtooth-shaped waveform to the target tissue, wherein the phase transition temperature initiates a change in lipid cell membranes within the target tissue from an ordered gel phase to a liquid crystalline phase; and wherein the pulsed or modulated sawtooth-shaped waveform comprising pulses having a frequency between about 50 kHz and about 950 kHz, a drive voltage at the electrode array between about 400 V and about 950 V, and a current density through the target tissue between about 36 A and about 48A per square centimeter of the tissue; wherein the pulsed or modulated electric field comprises a therapeutic electric filed at a tissue depth of between 0.25mm to about 1.5 mm; wherein the therapeutic electric filed treats cells within the target tissue with the IRE and leaves tissue scaffolding within the target tissue intact; wherein the measured temperature is required to be within the range of about 41 degrees C to about 45 degrees C before applying the pulsed or modulated sawtooth-shaped waveform.
However, Caplan teaches a device for ablating the duodenal mucosa wherein the expandable member (expandable assemblies 130a and 130b) comprises an electrode array comprising a plurality of electrodes ([0131] “Expandable assembly 130a of FIG. 1 includes an ablation element comprising a pair of electrodes, first electrode 136a and second electrode 137a. In some embodiments, three or more electrodes can be included, such as an expandable assembly 130a which includes at least 4 electrodes. Electrodes 136a and/or 137a can be mounted on, within and/or inside of expandable assembly 130a”) and a temperature sensor configured to measure temperature of a target tissue of within the stomach ([0150] “Functional elements 131a and 131b can comprise a sensor configured to provide information related to the tissue treatment performed by expandable assembly 130a and/or 130b, such as a temperature sensor configured to monitor the temperature of treatment provided by expandable assembly 130a and/or tissue proximate expandable assembly 130a”)
It would have been prima facia obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274 to incorporate the teachings of Caplan to have the expandable member comprises an electrode array comprising a plurality of electrodes and a temperature sensor configured to measure temperature of the tissue of the within the stomach as these prior art references and the instant application are directed to delivering energy to body cavities. One would be motivated to do this to prevent damage to the target tissue while being able to make sufficient contact.
Moss ‘274 and Caplan, alone or in combination, fail to teach increasing a temperature of the target tissue to a phase transition temperature of about 41 degrees C before applying current in the form of a pulsed sawtooth-shaped waveform to the target tissue, wherein the phase transition temperature initiates a change in lipid cell membranes within the target tissue from an ordered gel phase to a liquid crystalline phase; and wherein the plurality of pulses comprise a frequency between about 50 kHz and about 950 kHz, a drive voltage at the electrode array between about 400 V and about 950 V, and a current density through the target tissue between about 36 A and about 48A per square centimeter of the tissue; wherein the pulsed electric field comprises a therapeutic electric filed at a tissue depth of between 0.25mm to about 1.5 mm; wherein the therapeutic electric field treats cells within the target tissue with the IRE and leaves tissue scaffolding within the target tissue intact; and wherein the measured temperature is required to be within the range of about 41 degrees C to about 45 degrees C before applying the pulsed sawtooth-shaped waveform.
However, Stewart et al. (US 2022/0338925 A1) teaches a device, system and method for delivering energy to a tissue wherein “heat the cells to a target temperature. Heating the tissue may reduce the threshold electric field strength of the tissue that is required to cause irreversible cell membrane damage. The temperature increase required, and thus the target temperature, to achieve increased electroporation effectiveness may be less than the minimum temperature that would be required to achieve cell death by thermal means alone (approximately 50° C.)… In one embodiment, the tissue may be optimized by heating to a temperature of at least approximately 45° C. and as high as approximately 60° C. That is, the tissue may be heated to a temperature of between approximately 45° C. and approximately 60° C.” ([0080]).
It would have been prima facia obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274 and Caplan to incorporate the teachings of Stewart to increase a temperature of the target tissue to a phase transition temperature of about 41 degrees C before applying current in the form of a pulsed sawtooth-shaped waveform to the target tissue, wherein the phase transition temperature initiates a change in lipid cell membranes within the target tissue from an ordered gel phase to a liquid crystalline phase, as these prior art references are directed to treating cells by delivering energy. One would be motivated to do this increase the depth of electroporation ablation, as recognized by Stewart ([0080]).
Although Stewart does not explicitly teach these ranges and values, it would be obvious to one of ordinary skill in the art to use values within these ranges because Stewart’s ranges are shown to be effective and they overlap heavily with the applicant’s ranges, therefore discovering the optimum or workable ranges of a result effective variable involves only routine skill in the art. In re Aller, 105 USPQ 233.
Additionally, Examiner would like to note that phase transition temperature, wherein the phase transition temperature initiates a change in lipid cell membranes within the target tissue from an ordered gel phase to a liquid crystalline phase to be a recitation of the recited heating, therefore, achieving the required heating would also achieve the phase transition result.
Moss’274, Caplan, and Stewart, alone or in combination, fail to teach wherein the plurality of pulses comprise a frequency between about 50 kHz and about 950 kHz, a drive voltage at the electrode array between about 400 V and about 950 V, and a current density through the target tissue between about 36 A and about 48A per square centimeter of the tissue; wherein the pulsed electric field comprises a therapeutic electric filed at a tissue depth of between 0.25mm to about 1.5 mm; wherein the therapeutic electric field treats cells within the target tissue with the IRE and leaves tissue scaffolding within the target tissue intact.
However, Sano teaches medical therapies involving administering electrical treatment energy through a train of electrical pulses for treating unwanted cells while sparing healthy tissue ([0003]) wherein the pulsed waveform comprises a pulse width between about 1 µs to about 4µs ([0162]-[0164] “the pulse length may range from about 0.25 microseconds to about 100 microseconds, including 0.5, 1, 2, 3, 4…μs, or any range in between these values”), applying current in the form of a pulsed sawtooth-shaped waveform ([0161] “a pulse shape that is…sawtooth…”), wherein the plurality of pulses comprise a frequency between about 50 kHz and about 950 kHz ([0170]), a drive voltage at the electrode array between about 400 V and about 950 V ([0167] “Electrical pulse generators that can be used include those capable of delivering from 0 to about 5,000 V, such as the NanoKnife® system of AngioDynamics®, which for example can deliver from 0-3,000 V.”), a current between about 30A to about 90A ([0171] “The resulting current in the treated tissue can range for example from about 1 A to about 80 A, or from about 20 A to about 60 A, or from about 30 A to about 50 A, such as 40 A.”), and a current density through the tissue between about 36 A and about 48 A per square centimeter of the tissue ([0158] “The electrode may have a surface area of 0.1-5 sq. cm or 1-2 sq. cm, for example.”, [0171] “The resulting current in the treated tissue can range for example from about 1 A to about 80 A, or from about 20 A to about 60 A, or from about 30 A to about 50 A, such as 40 A.”, Examiner notes that current density = current through the tissue/surface area of treated tissue, therefore if we consider the resulting current in the treated tissue to be 40 A and the surface area of the treated tissue (i.e. electrode surface area, as the electrode is in contact with tissue) to be 1 sq.cm., the current density would be 40 A per square centimeters), wherein the therapeutic electric field comprises a field strength between about 200 V/cm to about 5,000 V/cm ([0167]).
Sano makes it evident that these parameters: pulse shape, pulse width, frequency, drive voltage, current, current density, and field strength are known in the art of electroporation/pulsed electric fields, Sano also shows that these parameters are result-effective in the art of electroporation. Additionally, upon review of Applicant’s disclosure, there appears to be no criticality to the claimed range of these parameters, particularly that of current density and one of ordinary skill in the art would have had reasonable expectation of success in optimizing these parameters.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274 and Caplan to incorporate the optimized pulses having a pulsed sawtooth-shaped waveform, frequency between 50 kHz and about 950 kHz , drive voltage at the electrode array between about 400 V and about 950 V, and current density through the tissue between about 36 A and about 48 A per square centimeter of the tissue of Sano, as these prior art references are directed to applying electric stimulation to treat unwanted/untreated tissues or cells. One would be motivated to do this as these parameters can have effects on unwanted cells while sparing health tissues.
Moss ‘274, Caplan, Stewart, and Sano, alone or in combination, fail to teach wherein the pulsed electric field comprised a therapeutic electric filed at a tissue depth of between about 0.25 mm to about 1.5 mm, while leaving tissue scaffolding within the mucosal layer intact.
However, Neal teaches a method for delivering specialized pulsed electric field (PEF) energy to treat an area of diseased tissue wherein “the extracellular matrices are preserved, and the target tissue maintains its structural architecture including blood vessels and lymphatics. Thus sensitive structure, such as biological lumens are able to be preserved...” ([0265], extracellular matrices are interpreted to be the tissue scaffolding).
It would have been prima facia obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274, Caplan, Stewart and Sano to incorporate the teaching of Neal to wherein the therapeutic electric field is configured to treat cells while leaving tissue scaffolding within the mucosal layer intact. One would be motivated to do this in order to maintain the integrity and functionality of the tissue which allows for the treatment of tissues considered untreatable, tissues near sensitive structures, and for the influx of biological elements after treatment, as recognized by Neal.
Moss ‘274, Caplan, Stewart, Sano, and Neal alone or in combination, fail to teach wherein the pulsed electric field comprises a therapeutic electric field at a tissue depth of between about 0.25 mm to about 1.5 mm.
However, Jackson teaches an ablation method for an wherein the pulsed electric field comprises a therapeutic electric field at a tissue depth of between about 0.25 mm to about 1.5 mm ([0018] “desired depth of ablated tissue is approximately between 0.5 mm and 1 mm” )
It would have been prima facia obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the parameters of Moss ‘274, Caplan, Stewart, Sano, and Neal to incorporate the teaching of Jackson for the pulsed electric field comprises a therapeutic electric field at a tissue depth of between 0.25 mm to about 1.5 mm. One would be motivated to do extend the application of a depth between 0.50 mm and 1 mm for ablation of an esophagus to ablation of a stomach or duodenum because the tissue impedance and damage to tissue is minimal at this depth and because the arrangement of the electrodes controls the depth and pattern of the treatment applied ([0035]), as recognized by Jackson.
Claim(s) 10-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moss’274 in view of Caplan in view of Stewart in view of Sano in view of Neal in view of Jackson as applied to claim 1 and further in view of Vrba et al. (US 2017/0348049 A1), hereinafter Vrba.
Regarding Claim 10, Moss’274 in view of Caplan in view of Stewart in view of Sano in view of Neal in view of Jackson teaches the method of claim 1 (as shown above). Moss ‘274, Caplan, Stewart, Sano, Neal and Jackson, alone or in combination, fail to teach the method further comprising: modulating delivery of the pulsed waveform based on the measured temperature.
However, Vrba teaches an ablation catheter system using electroporation wherein the method further comprising: modulating delivery of the pulsed waveform based on the measured temperature (Vrba, [0392]"In some of these embodiments, the energy source begins to deliver energy (e.g., turn on) when the temperature sensor registers that the temperature has dropped below a certain lower threshold level, and the energy source terminates energy delivery (e.g., turns off) when the temperature sensor registers that the temperature has exceeded a predetermined upper threshold level.").
It would have been prima facia obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274, Caplan, Stewart, Sano, Neal and Jackson to incorporate the teachings of Vrba to have the method further comprising: modulating delivery of the pulsed waveform based on the measured temperature, as these prior art references are directed to treating cells and tissue by using electrical stimulations. One would be motivated to do this to control the ablation to target cells only and prevent further damage to healthy cells.
Regarding Claim 11, Moss ‘274, Caplan, Stewart, Sano, Neal, Jackson, and Vrba teach the method of claim 10 (as shown above). Moss ‘274, Caplan, Stewart, Sano, Neal and Jackson, alone or in combination, fail to teach the wherein modulating delivery of the pulsed waveform comprises inhibiting delivery of the pulsed waveform.
However, Vrba teaches wherein modulating delivery of the pulsed waveform comprises inhibiting delivery of the pulsed waveform (Vrba, [0392] the energy source terminates energy delivery (e.g., turns off) when the temperature sensor registers that the temperature has exceeded a predetermined upper threshold level.").
It would have been prima facia obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274, Caplan, Sano, Neal and Jackson to incorporate the teachings of Vrba to have modulating delivery of the pulsed waveform comprises inhibiting delivery of the pulsed waveform, as these prior art references are directed to treating cells and tissue by using electrical stimulations. One would be motivated to do this to control the ablation to target cells only and prevent further damage to healthy cells.
Claim(s) 21 and 24-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moss et al. (US 2023/0414274 A1, previously cited), hereinafter Moss ‘274 in view of Caplan et al. (US 2020/0261144 A1), hereinafter Caplan in view of Goshgarian et al. (US 2012/0136350 A1), hereinafter Goshgarian in view of Stewart et al. (US 2022/0338925 A1), hereinafter Stewart in view of Sano et al. (US 2017/0266438 A1), hereinafter Sano in view of Neal, II et al. (US 2022/0387095 A1, previously cited), hereinafter Neal further in view of Jackson et al. (US 2006/0095032 A1, previously cited), hereinafter Jackson.
Regarding claim 21, Moss ‘274 discloses a method of treating a condition with irreversible electroporation (IRE) applied to mucosal lined tissue ([00159]-[00160] “the methods and apparatuses described herein may be used to resurface the mucosal layer of the patient's duodenum. Duodenal resurfacing may be used or treat a patient to improve diabetes.”. [0082] “elongate applicator tools adapted to be inserted into a body lumen or structure, and in particular, into a lumen of an otolaryngological structure (such as an ear, nose, or throat, including anatomical structures, such as turbinates, tonsils, tongue, soft palate, parotid glands), a gastrointestinal tract (e.g., stomach, small intestine, large intestine, duodenum, colon, etc., including the esophagus), and/or a respiratory tract (e.g., trachea, pharynx, larynx, and bronchi), to deliver high voltage (e.g., microsecond, nanosecond, picosecond, etc.) electrical energy to target tissue without damaging surrounding (non-target) tissue”), comprising:
Advancing a pulsed electric field (elongate applicator tool 102) into a bodily lumen of a patient ([0082]-[0083] “Described herein are elongate applicator tools adapted to be inserted into a body lumen or structure, and in particular, into a lumen of…a gastrointestinal tract (e.g., stomach, small intestine, large intestine, duodenum, colon, etc., including the esophagus)… to deliver high voltage (e.g., microsecond, nanosecond, picosecond, etc.) electrical energy to target tissue”, [0007] “treating within a body lumen using electric fields, including sub-microsecond (e.g., nanosecond) pulsed electrical fields”), the pulsed electric field device comprising an elongate body (elongate shaft 209), an expandable member coupled to the elongate body ([0020] “the applicator tool may include one or more contact projections (e.g., contact plates, contact posts, balloons, etc.)”),
generating a pulsed or modulated waveform to the electrode array to generate a pulsed or modulated electric field within the target tissue by applying the pulsed waveform to the target tissue, thereby treating the mucosal lined tissue ([0014] “One or more (e.g., a plurality) of electrodes configured for the delivery of high voltage, sub-microsecond electrical pulses (nanosecond pulsing, to deliver a nanosecond pulsed electric field to a target tissue) may be present at an end region of the elongate body.”, [0160] “the applicator may be configured as a catheter that may include one or more tissue-expanding projections that may be used to provide access to the tissue of the duodenum, and completely or partially circumferential mucosal-specific ablation may be provided by nanosecond pulsed electric field.”), wherein the pulsed or modulated waveform comprises a pulse width between about 1µs to about 4 µs ([0024] “a train of electrical pulses having a pulse width, for example, of between 0.1 nanoseconds (ns) and 1000 nanoseconds.” Examiner notes that 1000 ns – 1 µs, [0105] “In some examples, the pulse duration may be…about 1 μs, about 2 μs, about 3 μs, about 4 μs…”), a current between about 30 A to about 90 A ([0105] “In some examples, the current may be…about 25 A, about 40 A, about 50 A, about 60 A, about 75 A, about 100 A…”) , and is further configured to generate energy at the tissue between about 3 J and about 6 J ([0150] “In some treatments, energy delivered was between 1 J and 12 J”)
Wherein the therapeutic electric field comprises a field strength between about 200 V/cm to about 5000 V/cm ([0022] “this pulsed energy may have high peak voltages, such as 1 to 5 kilovolts per centimeter (kV/cm), 10 kV/cm, 20 kV/cm, 100 kV/cm or higher”),
Wherein the therapeutic electric field is configured to treat cells within the target tissue with the IRE ([0158] “the epithelial mucosal surface may be modified, e.g., resurfaced, by the application of nanosecond pulsed field”)
Moss ‘274 fails to disclose wherein the expandable member comprises an electrode array comprising a plurality of electrodes having a semi-elliptical cross-section and a tissue contacting surface configured to achieve full contact with the target tissue or the mucosal lined tissue, and wherein the plurality of electrodes comprises a ratio of a center-to-center distance to an electrode width between directly adjacent electrodes of about 2.3:1 and about 3.3:1, and a temperature sensor configured to measure temperature of the target tissue; increasing a temperature of the target tissue to a phase transition temperature of about 41 degrees C before applying current in the form of a pulsed sawtooth-shaped waveform to the target tissue, wherein the phase transition temperature initiates change in lipid cell membranes within the target tissue from an ordered gel phase to a liquid crystalline phase; and the waveforms in the form of a pulsed sawtooth-shaped waveform to the target tissue, wherein the pulsed or modulated waveform having a frequency between about 50 kHz and about 950 kHz and a drive voltage at the electrode array between 400 V and about 950 V, wherein the pulsed or modulated electric field comprises a therapeutic electric field at a tissue depth of between about 0.25 mm to about 1.5 mm, wherein the therapeutic electric field is configured to treat cells while leaving tissue scaffolding within the target tissue intact, and wherein the measured temperature is required to be within the range of about 41 degrees C to about 45 degrees C before delivering the pulsed sawtooth-shaped waveform.
However, Caplan teaches a device for ablating the duodenal mucosa wherein the expandable member (expandable assemblies 130a and 130b) comprises an electrode array comprising a plurality of electrodes ([0131] “Expandable assembly 130a of FIG. 1 includes an ablation element comprising a pair of electrodes, first electrode 136a and second electrode 137a. In some embodiments, three or more electrodes can be included, such as an expandable assembly 130a which includes at least 4 electrodes. Electrodes 136a and/or 137a can be mounted on, within and/or inside of expandable assembly 130a”, [0199] “round shaped electrodes 136a”, view Figures 8E-8G: the electrodes 136 and 137 are shown mounted on the expandable member 130) and a tissue contacting surface configured to achieve full contact with the target tissue or the mucosal lined tissue ([0187] “each expandable assembly 130a, 130b and 130c can be expanded to fully contact the mucosal wall without exerting undesired force onto tissue.”, [0191] “Balloon 142 and openings 143 are constructed and arranged such that tissue contacts electrodes 136 and 137”) and a temperature sensor configured to measure temperature of the target tissue ([0150] “Functional elements 131a and 131b can comprise a sensor configured to provide information related to the tissue treatment performed by expandable assembly 130a and/or 130b, such as a temperature sensor configured to monitor the temperature of treatment provided by expandable assembly 130a and/or tissue proximate expandable assembly 130a”).
It would have been prima facia obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274 to incorporate the teachings of Caplan to have the expandable member comprises an electrode array comprising a plurality of electrodes and a tissue-contacting surface configured to achieve full contact with the mucosal lined tissue and a temperature sensor configured to measure temperature of the target tissue, as these prior art references and the instant application are directed to delivering energy to body lumens. One would be motivated to do this to prevent damage to the target tissue while being able to make sufficient contact.
Moss’ 274 and Caplan, alone or in combination, fail to teach a plurality of electrodes having a semi-elliptical cross-section.
However, Goshgarian teaches a catheter-based interventions applying electric fields to body lumens (Abstract) wherein a plurality of electrodes having a semi-elliptical cross-section ([0289] “the third flexure zone 44 is sized and configured to carry at least one substantially semi-spherical active electrode 92a at a location more proximally spaced from its distal end. The semi-spherical active electrode is attached to the third flexure zone 44, such that it is directed toward target tissue…substantially spherical electrodes may be semi-spherical, semi-oblong, semi-ellipsoid, semi-cylindrical with rounded edges, complex contoured along one side of shaft 16, etc.”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274 and substitute the electrodes of Caplan with the electrodes of Goshgarian to have the plurality of electrodes having a semi-elliptical cross-section, as these prior art references and the instant application are directed to a catheter-based intervention in body lumens. One would be motivated do this reduce electrical edge effects and damage to the tissue.
Moss’274, Caplan, and Goshgarian, alone or in combination, fail to teach increasing a temperature of the target tissue to a phase transition temperature of about 41 degrees C before applying current in the form of a pulsed sawtooth-shaped waveform to the target tissue, wherein the phase transition temperature initiates change in lipid cell membranes within the target tissue from an ordered gel phase to a liquid crystalline phase; and the waveforms in the form of a pulsed sawtooth-shaped waveform to the target tissue, wherein the pulsed or modulated waveform having a frequency between about 50 kHz and about 950 kHz and a drive voltage at the electrode array between 400 V and about 950 V, wherein the pulsed or modulated electric field comprises a therapeutic electric field at a tissue depth of between about 0.25 mm to about 1.5 mm, wherein the therapeutic electric field is configured to treat cells while leaving tissue scaffolding within the target tissue intact, and wherein the measured temperature is required to be within the range of about 41 degrees C to about 45 degrees C before delivering the pulsed sawtooth-shaped waveform.
However, Stewart et al. (US 2022/0338925 A1) teaches a device, system and method for delivering energy to a tissue wherein “heat the cells to a target temperature. Heating the tissue may reduce the threshold electric field strength of the tissue that is required to cause irreversible cell membrane damage. The temperature increase required, and thus the target temperature, to achieve increased electroporation effectiveness may be less than the minimum temperature that would be required to achieve cell death by thermal means alone (approximately 50° C.)… In one embodiment, the tissue may be optimized by heating to a temperature of at least approximately 45° C. and as high as approximately 60° C. That is, the tissue may be heated to a temperature of between approximately 45° C. and approximately 60° C.” ([0080]).
It would have been prima facia obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274 and Caplan to incorporate the teachings of Stewart to increase a temperature of the target tissue to a phase transition temperature of about 41 degrees C before applying current in the form of a pulsed sawtooth-shaped waveform to the target tissue, wherein the phase transition temperature initiates a change in lipid cell membranes within the target tissue from an ordered gel phase to a liquid crystalline phase, as these prior art references are directed to treating cells by delivering energy. One would be motivated to do this increase the depth of electroporation ablation, as recognized by Stewart ([0080]).
Although Stewart does not explicitly teach these ranges and values, it would be obvious to one of ordinary skill in the art to use values within these ranges because Stewart’s ranges are shown to be effective and they overlap heavily with the applicant’s ranges, therefore discovering the optimum or workable ranges of a result effective variable involves only routine skill in the art. In re Aller, 105 USPQ 233.
Additionally, Examiner would like to note that phase transition temperature, wherein the phase transition temperature initiates a change in lipid cell membranes within the target tissue from an ordered gel phase to a liquid crystalline phase to be a recitation of the recited heating, therefore, achieving the required heating would also achieve the phase transition result.
Moss’274, Caplan, Goshgarian, and Stewart, alone or in combination, fail to teach the waveforms in the form of a pulsed sawtooth-shaped waveform to the target tissue, wherein the pulsed or modulated waveform having a frequency between about 50 kHz and about 950 kHz and a drive voltage at the electrode array between 400 V and about 950 V, wherein the pulsed or modulated electric field comprises a therapeutic electric field at a tissue depth of between about 0.25 mm to about 1.5 mm, wherein the therapeutic electric field is configured to treat cells while leaving tissue scaffolding within the target tissue intact.
However, Sano teaches medical therapies involving administering electrical treatment energy through a train of electrical pulses for treating unwanted cells while sparing healthy tissue ([0003]) wherein the pulsed waveform comprises a pulse width between about 1 µs to about 4µs ([0162]-[0164] “the pulse length may range from about 0.25 microseconds to about 100 microseconds, including 0.5, 1, 2, 3, 4…μs, or any range in between these values”), comprising pulses having a frequency between about 50 kHz and about 950 kHz ([0170]), a drive voltage at the electrode array between about 400 V and about 950 V ([0167] “Electrical pulse generators that can be used include those capable of delivering from 0 to about 5,000 V, such as the NanoKnife® system of AngioDynamics®, which for example can deliver from 0-3,000 V.”), a current between about 30A to about 90A ([0171] “The resulting current in the treated tissue can range for example from about 1 A to about 80 A, or from about 20 A to about 60 A, or from about 30 A to about 50 A, such as 40 A.”), wherein the therapeutic electric field comprises a field strength between about 200 V/cm to about 5,000 V/cm ([0167]).
Sano makes it evident that these parameters: pulse width, frequency, drive voltage, current, current density, and field strength are known in the art of electroporation/pulsed electric fields, Sano also shows that these parameters are result-effective in the art of electroporation. Additionally, upon review of Applicant’s disclosure, there appears to be no criticality to the claimed range of these parameters, particularly that of current density and one of ordinary skill in the art would have had reasonable expectation of success in optimizing these parameters.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274, Caplan, Goshgarian, and Stewart to incorporate the optimized a drive voltage at the electrode array between about 400 V and about 950 V, and a current density through the target tissue or the mucosal lined tissue between about 36 A and about 48 A per square centimeter of the target tissue or the mucosal lined tissue of Sano, as these prior art references are directed to applying electric stimulation to treat unwanted/untreated tissues or cells. One would be motivated to do this as these parameters can have effects on unwanted cells while sparing health tissues.
Moss ‘274, Caplan, Goshgarian, Stewart, and Sano, alone or in combination, fail to teach wherein the pulsed or modulated electric field comprises a therapeutic electric field at a tissue depth of between about 0.25 mm to about 1.5 mm, wherein the therapeutic electric field is configured to treat cells while leaving tissue scaffolding within the target tissue intact.
However, Neal teaches a method for delivering specialized pulsed electric field (PEF) energy to treat an area of diseased tissue wherein “the extracellular matrices are preserved, and the target tissue maintains its structural architecture including blood vessels and lymphatics. Thus sensitive structure, such as biological lumens are able to be preserved...” ([0265], extracellular matrices are interpreted to be the tissue scaffolding).
It would have been prima facia obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274, Caplan, Goshgarian, and Sano to incorporate the teaching of Neal to wherein the therapeutic electric field is configured to treat cells while leaving tissue scaffolding within the mucosal layer intact. One would be motivated to do this in order to maintain the integrity and functionality of the tissue which allows for the treatment of tissues considered untreatable, tissues near sensitive structures, and for the influx of biological elements after treatment, as recognized by Neal.
Moss ‘274, Caplan, Goshgarian, Stewart, Sano, and Neal, alone or in combination, fail to teach wherein the plurality of electrodes comprises a ratio of a center-to-center distance to an electrode width between directly adjacent electrodes of about 2.3:1 and about 3.3:1, wherein the pulsed or modulated electric field comprises a therapeutic electric field at a tissue depth of between about 0.25 mm to about 1.5 mm, and wherein the measured temperature is required to be within the range of about 37 degrees C to about 45 degrees C before delivering the pulsed or modulated waveform.
However, Jackson teaches an ablation method for an esophagus wherein the plurality of electrodes comprises a ratio of a center-to-center distance to an electrode width between directly adjacent electrodes of about 2.3:1 and about 3.3:1 ([0035] “the electrode widths are less than 3 mm, typically a width in the range from 0.1 mm to 3 mm, preferably 0.1 mm to 0.3 mm, and adjacent electrodes are spaced apart less than 3 mm, typically in the range from 0.1 mm to 3 mm, preferably from 0.1 mm to 0.3 mm”), wherein the pulsed or modulated electric field comprises a therapeutic electric field at a tissue depth of between about 0.25 mm to about 1.5 mm ([0018] “desired depth of ablated tissue is approximately between 0.5 mm and 1 mm” )
It would have been prima facia obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the parameters of Moss ‘274, Caplan, Goshgarian, Stewart, Sano, and Neal to incorporate the teaching of Jackson for the pulsed or modulated electric field comprises a therapeutic electric field at a tissue depth of between 0.25 mm to about 1.5 mm. One would be motivated to do extend the application of a depth between 0.50 mm and 1 mm for ablation of an esophagus to ablation of a stomach or duodenum because the tissue impedance and damage to tissue is minimal at this depth and because the arrangement of the electrodes controls the depth and pattern of the treatment applied ([0035]), as recognized by Jackson.
Regarding claim 24, Moss ‘274, Caplan, Goshgarian, Stewart, Sano, Neal, and Jackson teach the method of claim 21 (as shown above). Moss ‘274 further discloses where the mucosal lined tissue is in the esophagus, the small intestine, or the large intestine ([0010] “methods and apparatuses configured for the delivery of electric treatment (e.g., nanosecond pulsed electrical fields) to…a portion of the gastrointestinal tract (e.g., stomach, small intestine, large intestine, duodenum, colon, etc., including, but not limited to the esophagus)”, [0046] “the target region may be a mucosal epithelium of a stomach, small intestine, large intestine, duodenum”).
Regarding claim 25, Moss ‘274, Caplan, Goshgarian, Stewart, Sano, Neal, and Jackson teach the method of claim 21 (as shown above). Moss ‘274 further discloses where the mucosal lined tissue is in the esophagus ([0025] “Any appropriate tissue may be treated, including tissue of one or more walls of a lumen or portion of a lumen (e.g., including but not limited to pharynx, esophagus…”) and the condition is Barrett's esophagus ([0036] “The apparatuses and methods described herein may be specifically configured for treating Barrett's Esophagus”).
Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson, and further in view of Moss et al. (US 11,779,395 B2, previously cited), hereinafter Moss ‘395.
Regarding Claim 5, Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson teach the method of claim 1 (as shown above). Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson, alone or in combination, fail to teach where the pulsed sawtooth-shaped waveform comprises a set of about 50 pulses in groups of between about 8 and about 13, with a delay of between about 4 seconds and about 10 seconds between each group.
However, Moss ‘395 teaches an energy delivery probe that performs ablation by delivering energy through “electrical energy in the form of electrical pulses that can be sufficient to cause non-thermal irreversible electroporation but insufficient to cause thermal damage to target tissue” (Column 18, line 47-50) where “in one aspect the pulse parameters can be 70 pulses (7 sets of 10 pulses each) at 100 microseconds, with delays of 3.5 seconds between each set of 10 pulses” (Column 20, line 24-27).
It would have been prima facia obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson to incorporate the teaching of Moss ‘395 to deliver the pulses in groups with a delay between the group. Although Moss’ 395 does not explicitly state the recited values, it has been held that the general conditions are disclosed and therefore discovering the optimum or workable ranges of a result effective variable involves only routine skill in the art. In re Aller, 105 USPQ 233.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson, further in view of Thompson et al. (US 2021/0128335 A1, previously cited), hereinafter Thompson.
Regarding Claim 12, Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson teaches the method of claim 1 (as shown above).
Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson, alone or in combination, fail to teach where the method comprises of suctioning the tissue to the expandable member at a pressure between 10 mmHg and about 200 mmHg or suctioning the mucosal lined tissue to the expandable member at a pressure between about 10 mmHg and about 200mmHg.
However, Thompson teaches an apparatus and system for performing a sleeve gastrectomy including a bougie for insertion into a stomach which includes a tube portion with a lumen, mesh and a suction pump where “the pump may apply a negative pressure through the lumen 166 causing tissue adjacent to the mesh 164 to be suctioned against the mesh 164. In an embodiment, the negative pressure used to hold the stomach tissue in place may be in a range of about 20 mmHg to about 200 mmHg” ([0097]).
It would have been prima facia obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the parameters of Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson to incorporate the teaching of Thompson to suction the tissue at a pressure between 10 mmHg and about 200 mmHg, as these references and the claimed invention are directed toward an elongate member with an expandable member used in the gastrointestinal tract. One would be motivated to do this as this modification would provide a good contact between the device and the tissue.
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moss ‘274, Caplan, Goshgarian, Stewart, Sano, Neal, and Jackson, further in view of Thompson et al. (US 2021/0128335 A1, previously cited), hereinafter Thompson.
Regarding claim 23, Moss ‘274, Caplan, Goshgarian, Stewart, Sano, Neal, and Jackson teaches the method of claim 21 (as shown above).
Moss ‘274, Caplan, Goshgarian, Stewart, Sano, Neal, and Jackson, alone or in combination, fail to teach where the method comprises of suctioning the tissue to the expandable member at a pressure between 10 mmHg and about 200 mmHg or suctioning the mucosal lined tissue to the expandable member at a pressure between about 10 mmHg and about 200mmHg.
However, Thompson teaches an apparatus and system for performing a sleeve gastrectomy including a bougie for insertion into a stomach which includes a tube portion with a lumen, mesh and a suction pump where “the pump may apply a negative pressure through the lumen 166 causing tissue adjacent to the mesh 164 to be suctioned against the mesh 164. In an embodiment, the negative pressure used to hold the stomach tissue in place may be in a range of about 20 mmHg to about 200 mmHg” ([0097]).
It would have been prima facia obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the parameters of Moss ‘274, Caplan, Goshgarian, Stewart, Sano, Neal, and Jackson to incorporate the teaching of Thompson to suction the tissue at a pressure between 10 mmHg and about 200 mmHg, as these references and the claimed invention are directed toward an elongate member with an expandable member used in the gastrointestinal tract. One would be motivated to do this as this modification would provide a good contact between the device and the tissue.
Claim(s) 15 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson, and further in view of Adler et al. (US 2020/0268475 A1, previously cited), hereinafter Adler.
Regarding Claim 15, Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson teach the method of claim 1 (as shown above). Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson, alone or in combination, fail to teach generating a visual marker on the tissue using a fiducial generator.
However, Adler teaches an ablation method for the treatment of uterine fibroids where “a removable marker device can be utilized in any portion of the body…examples of other portions of the body where such removable fiducial marker devices may be used include, but are not limited to the gastrointestinal system including…stomach….large and small intestine” ([0012]).
It would have been prima facia obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson to incorporate the teaching of Adler to generate a visual marker on the tissue using a fiducial generator. One would be motivated to do this as the application of a fiducial marker is useful for the localization and/or tracking for the application of therapy and they allow for high-precision tracking of the spatial position of another object not readily visible, as recognized by Adler.
Regarding Claim 16, Moss ‘274, Caplan, Stewart, Sano, Neal, Jackson and Adler teaches the method of claim 15 (as shown above). Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson, alone or in combination, fail to teach visualizing the visual marker.
However, Adler teaches “deploying fiducial markers at a selected location with the intestine could provide spatial context for both the endoscopic view, and for laparoscopic view” .
It would have been prima facia obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson to incorporate the teaching of Adler of visualizing the visual marker. One would be motivated to do this as the visualization of the visual marker provides spatial context and for the localization and tracking of the portion of the body, as recognized by Adler.
Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson as applied to claim 1 above, and further in view of Haidry, Rehan J., et al. "Duodenal mucosal resurfacing: proof-of-concept, procedural development, and initial implementation in the clinical setting." Gastrointestinal endoscopy 90.4 (2019): 673-681., hereinafter Haidry (citations below are made from attached NPL document).
Regarding Claim 17, Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson teach the method of claim 1 (as shown above). Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson, alone or in combination, fail to teach that a treated duodenum is histologically indistinguishable from native tissue after about 30 days.
However, Haidry teaches duodenal mucosal resurfacing (DMR) using a minimally invasive upper endoscopic hydrothermal ablation procedure to treat insulin-resistant metabolic diseases (pg. 1, Background and Aims) wherein a "duodenal biopsy specimens obtained 3 months postprocedure demonstrated full mucosal regrowth" (pg. 1: Results) or more specifically "histology demonstrated a progressive regenerative mucosal healing process completed by week 6…on day 42 the ablation site was not grossly identifiable with fully regenerated mucosa and unremarkable plicae infolding" (pg. 5-6, Results: DMR safety and feasibility in a large animal model: Mucosa, Figure 3) .
It would have been prima facia obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson to incorporate the teaching of Haidry wherein the treated duodenum is histologically indistinguishable from native tissue after about 30 days, as shown by Haidry. One would be motivated to do this as ablation-induced rejuvenation of the duodenal surface could therefore reverse mucosal changes caused by poor diet, mitigating the excessive insulin-resisting signal from the duodenum (pg. 2, Column 1, lines 5-11) .
Claim(s) 18 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson, and further in view of Rajagopalan et al. (US 10,987,149 B2, previously cited), hereinafter Rajagopalan.
Regarding claim 18 and 20, Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson teach the method of claim 1 and the method of claim 19 (as shown above). Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson, alone or in combination, fail to teach that the pulsed or modulated waveform comprises a first pulsed sawtooth-shaped waveform, and delivering at least a second pulsed sawtooth-shaped waveform to the electrode array to generate a second therapeutic electric field thereby treating at least a portion of the duodenum or stomach previously treated.
However, Rajagopalan teaches a method and a device for the treatment of tissues with an elongate tube and an electrode array for delivering energy to the tissue where “Treatment elements of the present inventive concepts may be configured to deliver energy, such as in a continuous, pulsed, and/or variable energy delivered by an energy delivery element a first energy application is delivered by an energy delivery element. In one configuration, a first energy application is delivered followed by a similar or dissimilar second energy application to the same or different tissue portion” (Column 6, line 38-43, Figure 6: 421-422) where “the target tissue may comprise one or more longitudinal portions of the duodenum. The target tissue may comprise a distal portion of the stomach…”(Column 4, line 24-27).
It would have been prima facia obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274, Caplan, Stewart, Sano, Neal, and Jackson to incorporate the teaching of Rajagopalan to the pulsed or modulated waveform comprises a first pulsed sawtooth-shaped waveform, and delivering at least a second pulsed sawtooth-shaped waveform to the electrode array to generate a second therapeutic electric field thereby treating at least a portion of the duodenum or stomach previously treated. One would be motivated to do deliver two sets waveforms to a portion of the duodenum or stomach previously treated to accommodate for the different target tissue thicknesses or to avoid undesired treatment of non-target tissue, as recognized by Rajagopalan.
Claim(s) 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moss ‘274, Caplan, Goshgarian, Stewart, Sano, Neal, and Jackson, and further in view of Rajagopalan et al. (US 10,987,149 B2, previously cited), hereinafter Rajagopalan
Regarding claim 22, Moss ‘274, Caplan, Goshgarian, Stewart, Sano, Neal, and Jackson teaches the method of claim 21 (as shown above). Moss ‘274, Caplan, Goshgarian, Stewart, Sano, Neal, and Jackson, alone or in combination. fail to teach wherein the pulsed sawtooth-shaped waveform comprises a first pulsed sawtooth-shaped waveform, and delivering at least a second pulsed sawtooth-shaped waveform to the electrode array to generate a second therapeutic electric field thereby treating at least a portion of the duodenum or stomach previously treated
However, Rajagopalan teaches “a first tissue portion treated with a first treatment and/or a first treatment element, and a second tissue portion treated with a second treatment and/or second treatment element. The first and second tissue portions may overlap” (Column 3, lines 14-18), and wherein “a first energy application is delivered followed by a similar or dissimilar second energy application, to the same or different tissue portions. Energy delivery may be varied” (Column 6, lines 41-44).
It would have been prima facia obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Moss ‘274, Caplan, Goshgarian, Stewart, Sano, Neal, and Jackson to incorporate the teachings of Rajagopalan to have the pulsed waveform is a first pulsed waveform, and the method further comprises delivering at least a second pulsed waveform to the electrode array to generate a second pulsed or modulated electric field thereby treating at least a portion of the mucosal lined tissue previously treated. One would be motivated to do this to accommodate for different target tissue thickness, such as different thicknesses of duodenal mucosa or duodenal submucosa, as recognized by Rajagopalan (Column 6, lines 45-48).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Sano et al. (US 2021/0212753 A1) teaches IRE protocols for decellularizing duodenum to treat diabetes ([0109]-[0111]) with NanoKnife ([0102]).
Phillips MA, Narayan R, Padath T, Rubinsky B. Irreversible electroporation on the small intestine. Br J Cancer. 2012 Jan 31;106(3):490-5. doi: 10.1038/bjc.2011.582. Epub 2012 Jan 5. PMID: 22223084; PMCID: PMC3273351. Teaches IRE protocols for small intestine where a temperature is held at 37 degrees Celsius (Materials and Methods, Fine element modelling of electrical parameters to predict damage)
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ATTIYA SAYYADA HUSSAINI/
Examiner, Art Unit 3792
/NIKETA PATEL/Supervisory Patent Examiner, Art Unit 3792
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