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Patent Application 17326897 - Control of Cell Electroporation - Rejection

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Patent Application 17326897 - Control of Cell Electroporation

Title: Control of Cell Electroporation

Application Information

  • Invention Title: Control of Cell Electroporation
  • Application Number: 17326897
  • Submission Date: 2025-05-21T00:00:00.000Z
  • Effective Filing Date: 2021-05-21T00:00:00.000Z
  • Filing Date: 2021-05-21T00:00:00.000Z
  • National Class: 435
  • National Sub-Class: 285200
  • Examiner Employee Number: 95459
  • Art Unit: 1799
  • Tech Center: 1700

Rejection Summary

  • 102 Rejections: 0
  • 103 Rejections: 2

Cited Patents

The following patents were cited in the rejection:

Office Action Text


    DETAILED ACTION
Notice of Pre-AIA  or AIA  Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .

Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection.  Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.  Applicant’s submission filed on September 2, 2024 has been entered.
 
Claim Objections
Claim 23 is objected to because of the following informalities:
Regarding claim 23, in line 6, the phrase “a third threshold value” should be “a third predetermined threshold”. This is for consistency with parent claim 1.
Appropriate correction is required.

Claim Interpretation
	The following limitations are being considered as “controller” limitations:
“a stimulation unit” – for more information about this feature, consult the instant specification at paragraph [0054]
“a comparing element” – for more information about this feature, consult the instant specification at paragraphs [0077] and [0089]
However, these claim limitations will not be interpreted under 35 U.S.C. § 112(f), but rather broadest reasonable interpretation (BRI).

Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):

(b)  CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.


The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:

The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.


Claim 24 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA  35 U.S.C. 112, the applicant), regards as the invention.
Claim 24 recites the limitation “a fourth threshold value” in line 6. This claim limitation skips ahead to “a fourth threshold value”, while claim 1 does not mention a “third threshold value”. In view of this, it is unclear if a “third threshold value” exists. Note that the word “value” should be deleted for the sake of consistency of the term used in parent claim 1.

Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA  35 U.S.C. 102 and 103 (or as subject to pre-AIA  35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA  to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.  
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.

The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary.  Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.

Claims 1-2, 5, 7-9, 22, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Lopez  (“A Multimodal CMOS MEA for High-Throughput Intracellular Action Potential Measurements and Impedance Spectroscopy in Drug-Screening Applications”) in view of Bahrami (US 20190117964) and Abassi-185 (WO 2006058185).
	Regarding claim 1, Lopez discloses an electrode unit (abstract, CMOS MEA) comprising:
	an electrode configured to contact a biological cell (Figs. 1 and 15, a single cell is on an electrode; pg. 3076, right col. “single-cell resolution”; pg. 3078, under “F. IS Modality”, “a single-cell level”; pg. 3084 “single-cell IS from one electrode”) and provide a first electrical signal to the biological cell (pg. 3078, under “F. IS Modality”, “applied electric field”) and configured for measuring (i) a first impedance of the electrode and the biological cell (pg. 3084 “single-cell IS was also performed to analyze the impedance of the electrode-cell interface … electrode impedance … and the cell membrane impedance”) 
a stimulation unit electrically connected to the electrode (pgs. 3079-3080 under “C. Stimulation Unit”); 
an impedance measurement device (pg. 3077-3078 under “E. Fast Impedance Monitoring Modality” or Fig. 2a, “Impedance Monitoring Circuit” of “Impedance Monitoring” circuit which is part of “Recording Channel”) configured to measure the first impedance of the electrode and the biological cell contacting the electrode (pg. 3084 “single-cell IS was also performed to analyze the impedance of the electrode-cell interface … electrode impedance … and the cell membrane impedance”); 
a comparing element (Fig. 5 caption, “a pair of comparators monitors the electrode voltage”); an adjustment signal (Fig. 5, caption and pg. 3080, right col. “widths … are adaptively adjusted”) if a voltage is greater than a predetermined threshold (pg. 3080, right col. “predefined electrode voltage thresholds” and Fig. 5, thresholds VH and VL),
the stimulation unit being configured to apply (pg. 3079-3080 under “C. Stimulation Unit”), via the electrode (Fig. 4b, electrode is connected to electrical signal Velec as depicted by the circuit related to “Cells”, further proof of electrode being stimulated in Fig. 15), a second electrical signal to the biological cell based on the adjustment value (Fig. 4b, feedback from the current DAC’s “DAC Charge Balancing” of Fig. 5 goes to Velec which is delivered to “Cells”).
Arguably, Lopez discloses: a comparing element (Fig. 5 caption, “a pair of comparators monitors the electrode voltage”) configured to make a determination of the first impedance (pg. 3084 “single-cell IS was also performed to analyze the impedance of the electrode-cell interface … electrode impedance … and the cell membrane impedance”); and configured to produce an adjustment signal (Fig. 5, caption and pg. 3080, right col. “widths … are adaptively adjusted”) if an impedance (as calculated from electrode voltage and current, see pg. 3080 “enables accurate calculation of the impedance magnitude and phase from the measured voltage waveforms”) is greater than a second predetermined threshold (pg. 3080, right col. “predefined electrode voltage thresholds” and Fig. 5, thresholds VH and VL).
Lopez does not disclose:
(i) a first impedance of the electrode and the biological cell measured before providing the first electrical signal to the biological cell and (ii) a second impedance of the electrode and the biological cell measured after providing the first electrical signal to the biological cell;
a comparing element configured to make a determination of whether the first impedance is greater than a first predetermined threshold and configured to produce an adjustment value based on whether an impedance drop is greater than a second predetermined threshold, wherein the impedance drop is a difference between the first impedance and the second impedance
Bahrami discloses:
(i) a first impedance of the electrode and the biological cell measured before providing the first electrical signal to the biological cell (paragraph [0217] “Impedance may be measured before, between and after electroporation electric fields are applied to determine cell conditions…”) and (ii) a second impedance of the electrode and the biological cell measured after providing the first electrical signal to the biological cell (paragraph [0217] “Impedance measurements may be applied again after the first EP electric fields have been applied…”);
a comparing element (paragraph [0217] “calculated and compared”) configured to make a determination of the first impedance (paragraph [0217] “Impedance may be measured before, between and after electroporation electric fields are applied to determine cell conditions…”) and configured to produce an adjustment value (paragraph [0217] “adjust the pulse width”) based on whether an impedance drop (paragraph [0217] “a percentage drop in impedance”) is greater than a second predetermined threshold (paragraph [0217] “may be calculated and compared to a predetermined value to determine whether cells in the electroporation location have been electroporated sufficiently”), wherein the impedance drop is a difference between the first impedance and the second impedance (paragraph [0217] “percentage drop in impedance”).
Notably, Bahrami also cites “a time constant drop is greater than a predetermined threshold” (paragraph [0422]) and relates this time constant drop or an impedance drop to a predetermined value as previously cited for successful electroporation (paragraph [0217]).
In the analogous art of improved tissue-sensing based electroporation, it would have been obvious to one skilled in the art before the effective filing date to modify the electrode unit of Lopez with the impedance measurements and comparisons of Bahrami in order to have impedance measurements between pulses allowing for electrical conditions (such as adjustable pulse widths) to stop the successful electroporation process when the ideal capacitance, time constant, or membrane integrity is reached (Bahrami, paragraph [0217]).
Arguably, modified Lopez does not disclose:
a comparison element configured to make a determination of whether the first impedance is greater than a first predetermined threshold; and,
the first electrical signal based on the determination.
Abassi-185 discloses a comparison element (pg. 17 “impedance analyzer or impedance measurement circuit”) configured to make a determination of whether the first impedance is greater than a first predetermined threshold (pg. 7, lines 19-23 and pgs. 17-18 under definition of “detectable change in impedance between or among said electrodes”, specifically about “the change in impedance is larger than 0.1% to be detectable…”); and,
the first electrical signal based on the determination (pg. 7, lines 19-23 “A predetermined threshold or range of impedance may be required prior to electroporating a cell or cell population”).
In the analogous art of microelectronic devices used for detection of cell impedance and electroporation, it would have been obvious to one skilled in the art before the effective filing date to modify the comparison element of modified Lopez with the comparison element of Abassi-185 in order to detect change in impedance to find when molecule binding reactions occur on electrode surfaces; or to find when cells are attached or not attached to the electrode surface (Abassi-185, pgs. 17-18).
Regarding claim 2, Lopez discloses wherein the electrode unit (abstract, CMOS MEA) is configured to obtain the first impedance without causing electroporation (pg. 3077, has the capability to use IS modality to measure impedance, pg. 3078 “F. IS Modality” without the CVS modality to cause electroporation, pg. 3077 “C. Voltage Stimulation Modality” via “six independent modalities that can be used simultaneously across the different wells, and even within the same well. …electrodes in different wells can be independently selected to use any of the modalities”).
	Regarding claim 5, Lopez discloses wherein the comparing element is configured to produce the adjustment value if the voltage does not reach the second predetermined threshold (Fig. 5, VH), and wherein the stimulation unit is configured to provide the second electrical signal as soon as the adjustment value from the comparing element is received (Fig. 4b, DAC charge balancing of Fig. 5 feeds signal to Velec).
Also, Lopez discloses that an impedance can be calculated (as calculated from electrode voltage and current, see pg. 3080 “enables accurate calculation of the impedance magnitude and phase from the measured voltage waveforms”).
	Lopez does not disclose wherein the comparing element is configured to produce the adjustment value if the impedance drop does not reach the second predetermined threshold, and wherein the stimulation unit is configured to provide the second electrical signal as soon as the adjustment value from the comparing element is received.
	Bahrami discloses wherein the comparing element (paragraph [0217] “calculated and compared”) is configured to produce the adjustment value (paragraph [0217] “adjust the pulse width”) if the impedance drop (paragraph [0217] “a percentage drop in impedance”) does not reach the second predetermined threshold (paragraph [0217] “compared to a predetermined value”), and wherein the stimulation unit is configured to provide the second electrical signal (paragraph [0217], “the next set of electroporation pulsed electric fields”) as soon as the adjustment value from the comparing element is received (paragraph [0217] “adjust pulse width” … “adjusted based on time constants associated with cell membrane capacitance and resistance and the electroporation process can be stopped when an ideal prop in capacitance, time constant, or membrane integrity is reached”).
In the analogous art of improved tissue-sensing based electroporation, it would have been obvious to one skilled in the art before the effective filing date to modify the electrode unit of modified Lopez with the impedance measurements and comparisons of Bahrami in order to have impedance drop measurements between pulses allowing for electrical conditions (such as adjustable pulse widths) to continue the electroporation process until such time that electroporation is stopped because it has been successful when the ideal capacitance, time constant, or membrane integrity is reached (Bahrami, paragraph [0217]).
	Regarding claim 7, Lopez discloses wherein the electrode is a microelectrode (Figs. 1 and 6 electrodes are micron-scale; pg. 3077 “electrodes are arranged with a pitch of 15 µm”)
	Regarding claim 8, Lopez discloses further comprising an electrode array that comprises the electrode (abstract, Figs. 1 and 6).
	Regarding claim 9, Lopez discloses a cell interfacing device comprising the electrode unit of claim 1 (Figs. 1 and 15, pg. 3077 left col.).
	Regarding claim 22, Lopez discloses indicators of attachment and contact of the biological cell to the electrode (pg. 3084, first col.; Fig. 15 “seal resistance”).
	Lopez does not disclose wherein the first predetermined threshold indicates attachment and contact of the biological cell to the electrode.
	Abassi-185 discloses wherein the first predetermined threshold indicates attachment and contact of the biological cell to the electrode (pg. 17, last line to pg. 18, line 9).
In the analogous art of microelectronic devices used for detection of cell impedance and electroporation, it would have been obvious to one skilled in the art before the effective filing date to modify the comparison element of modified Lopez with the comparison element of Abassi-185 in order to detect change in impedance to find when molecule binding reactions occur on electrode surfaces; or to find when cells are attached or not attached to the electrode surface (Abassi-185, pgs. 17-18).
	Regarding claim 25, Lopez discloses the stimulation unit (pgs. 3079-3080 under “C. Stimulation Unit”); the first electrical signal (pg. 3078, under “F. IS Modality”, “applied electric field”); and the first impedance (pg. 3084 “single-cell IS was also performed to analyze the impedance of the electrode-cell interface … electrode impedance … and the cell membrane impedance”).
Lopez does not disclose wherein the stimulation unit is configured to apply the first electrical signal using parameters that are based on the first impedance.
Abassi-185 discloses wherein the stimulation unit is configured to apply the first electrical signal using parameters that are based on the first impedance (pg. 7, lines 19-23 “A predetermined threshold or range of impedance may be required prior to electroporating a cell or cell population”; pgs. 17-18 under definition of “detectable change in impedance between or among said electrodes”, specifically about “the change in impedance is larger than 0.1% to be detectable…”).
In the analogous art of microelectronic devices used for detection of cell impedance and electroporation, it would have been obvious to one skilled in the art before the effective filing date to modify the comparison element of modified Lopez with the comparison element of Abassi-185 in order to detect change in impedance to find when molecule binding reactions occur on electrode surfaces; or to find when cells are attached or not attached to the electrode surface (Abassi-185, pgs. 17-18).

Claims 3 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Lopez  (“A Multimodal CMOS MEA for High-Throughput Intracellular Action Potential Measurements and Impedance Spectroscopy in Drug-Screening Applications”) in view of Bahrami (US 20190117964) and Abassi-185 (WO 2006058185), as applied to claim 1, further in view of Miklavcic (US 2004/0039327).
Regarding claim 3, Lopez discloses wherein the stimulation unit (pg. 3078 “The SUs are used during CVS, CCS, and IS modalities”) is configured to generate electroporation (pg. 3077 “the electrode impedance, which can vary with the applied voltage and across the array, will determine the stimulation current applied”, where the electrode impedance is measured from IS modality pg. 3084 and pg. 3079 “to drive the load of 64 parallel electrodes during CVS”).
	Lopez does not disclose wherein the stimulation unit is configured to strengthen the second electrical signal in response to the electrode unit determining that the first electrical signal has not generated electroporation.
	Miklavcic discloses wherein the stimulation unit is configured to strengthen the second electrical signal in response to the electrode unit determining that the first electrical signal has not generated electroporation (paragraphs [0033]-[0034] and [0038]).
	In the analogous art of continuous control of cell electroporation, it would have been obvious to one skilled in the art before the effective filing date to modify the stimulation unit of modified Lopez with the signal feedback of Miklavcic in order to continuously control the electroporation achieved to permeabilize the cells without causing cell damage (Miklavcic, paragraph [0011] and claim 1).
	Regarding claim 6, Lopez does not disclose wherein the stimulation unit is configured to reduce an energy of the second electrical signal if the impedance measurement device does not detect an increase of the second impedance after applying the first electrical signal.
	Miklavcic discloses wherein the stimulation unit is configured to reduce an energy of the second electrical signal (paragraph [0037]) if the impedance measurement device does not detect an increase of the second impedance after applying the first electrical signal (paragraphs [0031]-[0033]).
	In the analogous art of continuous control of cell electroporation, it would have been obvious to one skilled in the art before the effective filing date to modify the stimulation unit of modified Lopez with the signal feedback of Miklavcic in order to continuously control the electroporation achieved to permeabilize the cells without causing cell damage (Miklavcic, paragraph [0011] and claim 1).

Allowable Subject Matter
Claim 23 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.

Claim 24 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.

The following is a statement of reasons for the indication of allowable subject matter:

Regarding claims 23-24, the closest prior art is Lopez (“A Multimodal CMOS MEA for High-Throughput Intracellular Action Potential Measurements and Impedance Spectroscopy in Drug-Screening Applications”) in view of Bahrami (US 20190117964) and Abassi-185 (WO 2006058185) as applied to claim 1, further in view of Abassi-762 (WO 2006017762).
	Regarding claim 23, Lopez discloses the impedance measurement device (pg. 3077-3078 under “E. Fast Impedance Monitoring Modality” or Fig. 2a, “Impedance Monitoring Circuit” of “Impedance Monitoring” circuit which is part of “Recording Channel”), the biological cell (Figs. 1 and 15, a single cell is on an electrode; pg. 3076, right col. “single-cell resolution”; pg. 3078, under “F. IS Modality”, “a single-cell level”; pg. 3084 “single-cell IS from one electrode”), impedance measurements (pg. 3084 “single-cell IS was also performed to analyze the impedance of the electrode-cell interface … electrode impedance … and the cell membrane impedance”); the stimulation unit (pgs. 3079-3080 under “C. Stimulation Unit”), and the first electrical signal (pg. 3078, under “F. IS Modality”, “applied electric field”).
Lopez does not disclose wherein 
the impedance measurement device is configured to measure a third impedance of the electrode and the biological cell after measuring the second impedance, and 
the stimulation unit is configured to update the first electrical signal for future application to another cell based on whether the third impedance is greater than the second impedance by more than a third threshold value.
Regarding feature 1, Abassi-762 discloses the impedance measurement device is configured to measure a third impedance of the electrode and the biological cell after measuring the second impedance (pg. 16, top half of page).
In the analogous art of microelectronic devices used for detection of cell impedance and electroporation, it would have been obvious to one skilled in the art before the effective filing date to modify the impedance measurement device to measure impedances in triplicate over time in order to measure test cells and their activation of proteins, including those dose-dependent functional activation of G-Protein Coupled Receptors (GPCRs) (pg. 16, top half of page).
Regarding feature 2, the prior art of record, alone or in combination, does not teach or fairly suggest the feature within the claim environment.
	Regarding claim 24, 
Lopez does not disclose wherein
the impedance measurement device is configured to measure a third impedance of the electrode and the biological cell after measuring the second impedance, and 
the stimulation unit is configured to update the first electrical signal for future application to another cell based on whether the first impedance is greater than the third impedance by less than a fourth threshold value.
Regarding feature 1, Abassi-762 discloses the impedance measurement device is configured to measure a third impedance of the electrode and the biological cell after measuring the second impedance (pg. 16, top half of page).
In the analogous art of microelectronic devices used for detection of cell impedance and electroporation, it would have been obvious to one skilled in the art before the effective filing date to modify the impedance measurement device to measure impedances in triplicate over time in order to measure test cells and their activation of proteins, including those dose-dependent functional activation of G-Protein Coupled Receptors (GPCRs) (pg. 16, top half of page).
Regarding feature 2, the prior art of record, alone or in combination, does not teach or fairly suggest the feature within the claim environment.

Response to Arguments
Applicant’s arguments filed September 2, 2024 have been fully considered but they are not persuasive.

Regarding the arguments and amendments to the claims, new references Abassi-185 (WO 2006058185) and Abassi-762 has been found to pertain to these arguments and amendments.

Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATHAN G ESPERON whose telephone number is 571-272-9807, and whose fax number is 571-273-8464. The examiner can normally be reached 9 am - 6 pm Monday through Thursday, and 9 am - 6 pm every other Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Marcheschi can be reached at 571-272-1374. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/N.G.E./Examiner, Art Unit 1799


/MICHAEL A MARCHESCHI/Supervisory Patent Examiner, Art Unit 1799


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