DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
The amendment filed 09/25/2025 has been entered. Claims 1-25 are pending in the application. Claims 7-12 are withdrawn.
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.
Claims 1-6, 13-25 are rejected under 35 U.S.C. 103 as being unpatentable over Housley (WO 2016/205895) in view of Hofmann (US 6,241,701) and further in view of Zarif (US 2010/0210994).
Regarding claim 1, Housley discloses a method of controlling electrotransfer delivery of therapeutic molecules to targeted groups of cells using a system comprising an array of two or more physically contiguous electrodes configured to be inserted into biological tissue and a pulse generator configured to selectively drive the two or more physically contiguous electrodes as one or more anodes and one or more cathodes for application of one or more electrical pulses (see page 2, lines 9-15 and page 8, lines 34-36), the method comprising: determining a first selection of the two or more physically contiguous electrodes to drive as the one or more anodes and the one or more cathodes using one or more electric pulses (Page 31, lines 21-34), and for the first selection of the two or more physically contiguous electrodes, determining electrical pulse parameters for the one or more electric pulses to generate a first shaped electric field for a target treatment region adjacent the array (Page 2, lines 28-31 and Page 15, lines 14-28; the controller is configured to calculate the electrical pulse parameters based on a target electric potential gradient in the induced non-uniform electric field), wherein a physical configuration of the two or more physically contiguous electrodes, the first selection of the two or more physically contiguous electrodes as anodes and cathodes, and the electrical pulse parameters, control contours of gradients within the first shaped electric field for the target treatment region adjacent the array (Page 15, lines 14-28); determining a second selection of the two or more physically contiguous electrodes to drive as the one or more anodes and the one or more cathodes using one or more electric pulses (Page 31, lines 21-34; different anode and cathode configurations ), and for the second selection of the two or more physically contiguous electrodes, determining electrical pulse parameters for the one or more electric pulses to generate a second shaped electric field for the target treatment region adjacent the array (Page 2, lines 28-31 and Page 15, lines 14-28; the controller is configured to calculate the electrical pulse parameters based on a target electric potential gradient in the induced non-uniform electric field); controlling the pulse generator to apply a first sequence of one or more unipolar pulses using the first selection of electrodes driven as the one or more anodes and the one or more cathodes to generate the first shaped electric field (Page 32, lines 10-31; Page 40, lines 26-34; Page 41, lines 1-9; monopolar control of current steering is used with the electrode array); and, controlling the pulse generator to apply a second sequence of one or more unipolar pulses using the second selection of electrodes driven as the one or more anodes and the one or more cathodes to provide the second shaped electric field (Page 32, lines 10-31; Page 40, lines 26-34; Page 41, lines 1-9; monopolar control of current steering is used with the electrode array).
Housley is silent regarding determining a duration of a waiting period between generating the first shaped electric field and generating the second shaped electric field and wherein a direction of the second shaped electric field is different from a direction of the first shaped electric field and a polarity of the plurality of unipolar pulses of the second sequence is opposite to a polarity of the plurality of unipolar pulses of the first sequence.
Hofmann teaches an analogous method of electroporation, the method comprising determining a duration of a waiting period between generating a first sequence and generating a second sequence (Col 10, lines 33-47).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method disclosed by Housley to determine and implement a waiting period between the sets or sequences of pulses as taught by Hofmann in order to adjust the electric field parameters to improve efficiency of treatment (Col 10, lines 22-32).
The modified invention of Housley and Hofmann discloses all of the elements of the invention as discussed above, however, is silent regarding wherein a direction of the second shaped electric field is different from a direction of the first shaped electric field and a polarity of the plurality of unipolar pulses of the second sequence is opposite to a polarity of the plurality of unipolar pulses of the first sequence.
Zarif teaches an analogous method of electroporation comprising a pulse generator configured to selectively drive the two or more electrodes as one or more anodes and one or more cathodes for application of one or more electrical pulses, wherein a direction of the second shaped electric field is different from a direction of the first shaped electric field (“multiple directions”, Para 0021) and a polarity of the plurality of pulses of the second sequence is opposite to a polarity of the plurality of pulses of the first sequence (Para 0020; Para 0055).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method to have the first and second shaped electric field be in different directions and to have the polarity of the pulses of the first and second sequences be opposite to one another as taught by Zarif in order to achieve the desired electroporation effects (Para 0055).
Regarding claim 2, the modified invention of Housley, Hofmann, and Zarif discloses the first selection of the two or more physically contiguous electrodes comprises a linear configuration of one or more anodes and one or more cathodes (Page 30, lines 1-3 -Housley; the electrodes can be arranged in a linear array), and the second selection of the two or more physically contiguous electrodes comprises the first selection of the two or more physically contiguous electrodes with the one or more anodes and the one or more cathodes switched to thereby reverse polarity (Page 32, lines 1-9; Page 37, lines 1-9 -Housley; the controller is configured to selectively control polarity).
Regarding claim 3, the modified invention of Housley, Hofmann, and Zarif discloses the array is a two-dimensional array and wherein the first selection of the two or more physically contiguous electrodes comprises a configuration of the one or more anodes and the one or more cathodes (Page 30, lines 1-3 -Housley; the electrodes can be arranged in a two dimensional array), and the second selection of the two or more physically contiguous electrodes comprises a configuration of electrodes including different electrodes from the first selection, selected to generate a change in electric field gradients within the target treatment region (Page 32, lines 10-31 -Housley; electrodes 1-8 are the first selection and electrodes 9-16 are the second selection).
Regarding claim 4, the modified invention of Housley, Hofmann, and Zarif discloses steps of determining one or more further selections of the two or more physically contiguous electrodes to drive as the one or more anodes and the one or more cathodes using the one or more electric pulses (Page 31, lines 21-34 -Housley), and, for the one or more further selections of the two or more physically contiguous electrodes, determining electrical pulse parameters for the one or more electric pulses to generate a further shaped electric field for the target treatment region adjacent the array (Page 2, lines 28-31; Page 15, lines 14-28 -Housley); and for each of the one or more further selections of the two or more physically contiguous electrodes, controlling the pulse generator to apply a further sequence of one or more unipolar pulses using each of the one or more further
Regarding claim 5, the modified invention of Housley, Hofmann, and Zarif discloses a sequence of said each of the one or more further selections the two or more physically contiguous of electrodes and the electrical pulses is chosen to generate a sequence of electric fields where subsequent electric fields each have an electric field gradient through the target treatment region at an incremental angle relative to a preceding electric field (Page 8, line 33- Page 9, line 1-4 -Housley; See Figs 4-8 of Housley wherein the electric field gradient is shown having changes in incremental angle).
Regarding claim 6, the modified invention of Housley, Hofmann, and Zarif discloses increasing or decreasing spacing between the one or more anodes and the one or more cathodes is used to control a radius of the target treatment region (Page 28, lines 25-32 -Housley).
Regarding claim 13, Housley discloses a method of controlling an electrotransfer delivery system, the electrotransfer delivery system comprising an array of two or more physically contiguous electrodes configured to be inserted into biological tissue and a pulse generator configured to selectively drive the two or more physically contiguous electrodes as one or more anodes and one or more cathodes for application of one or more electrical pulses to produce electric fields adjacent the array (see page 2, lines 9-15 and page 8, lines 34-36), the method comprising: determining a first selection of the two or more physically contiguous electrodes to drive as the one or more anodes and the one or more cathodes using one or more electric pulses (Page 31, lines 21-34), and for the first selection of the two or more physically contiguous electrodes, determining electrical pulse parameters for the one or more electric pulses to generate a first shaped electric field for a target treatment region adjacent the array (Page 2, lines 28-31 and Page 15, lines 14-28; the controller is configured to calculate the electrical pulse parameters based on a target electric potential gradient in the induced non-uniform electric field), wherein a physical configuration of the two or more physically contiguous electrodes, the first selection of the two or more physically contiguous electrodes as anodes and cathodes, and the electrical pulse parameters, control contours of gradients within the first shaped electric field for the target treatment region adjacent the array (Page 15, lines 14-28); determining a second selection of the two or more physically contiguous electrodes to drive as the one or more anodes and the one or more cathodes using one or more electric pulses (Page 31, lines 21-34; different anode and cathode configurations ), and, for the second selection of the two or more physically contiguous electrodes, determining electrical pulse parameters for the one or more electric pulses to generate a second shaped electric field for the target treatment region adjacent the array (Page 2, lines 28-31 and Page 15, lines 14-28; the controller is configured to calculate the electrical pulse parameters based on a target electric potential gradient in the induced non-uniform electric field); controlling the pulse generator to apply a first sequence of one or more unipolar pulses using the first selection of electrodes driven as the one or more anodes and the one or more cathodes to generate the first shaped electric field (Page 32, lines 10-31; Page 40, lines 26-34; Page 41, lines 1-9; monopolar control of current steering is used with the electrode array); and controlling the pulse generator to apply a second sequence of one or more unipolar pulses using the second selection of electrodes driven as the one or more anodes and the one or more cathodes to provide the second shaped electric field (Page 32, lines 10-31; Page 40, lines 26-34; Page 41, lines 1-9; monopolar control of current steering is used with the electrode array).
Housley is silent regarding determining a duration of a waiting period between generating the first shaped electric field and generating the second shaped electric field and wherein a direction of the second shaped electric field is different from a direction of the first shaped electric field and a polarity of the plurality of unipolar pulses of the second sequence is opposite to a polarity of the plurality of unipolar pulses of the first sequence.
Hofmann teaches an analogous method of electroporation, the method comprising determining a duration of a waiting period between generating a first sequence and generating a second sequence (Col 10, lines 33-47).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method disclosed by Housley to determine and implement a waiting period between the sets or sequences of pulses as taught by Hofmann in order to adjust the electric field parameters to improve efficiency of treatment (Col 10, lines 22-32).
The modified invention of Housley and Hofmann discloses all of the elements of the invention as discussed above, however, is silent regarding wherein a direction of the second shaped electric field is different from a direction of the first shaped electric field and a polarity of the plurality of unipolar pulses of the second sequence is opposite to a polarity of the plurality of unipolar pulses of the first sequence.
Zarif teaches an analogous method of electroporation comprising a pulse generator configured to selectively drive the two or more electrodes as one or more anodes and one or more cathodes for application of one or more electrical pulses, wherein a direction of the second shaped electric field is different from a direction of the first shaped electric field (“multiple directions”, Para 0021) and a polarity of the plurality of pulses of the second sequence is opposite to a polarity of the plurality of pulses of the first sequence (Para 0020; Para 0055).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method to have the first and second shaped electric field be in different directions and to have the polarity of the pulses of the first and second sequences be opposite to one another as taught by Zarif in order to achieve the desired electroporation effects (Para 0055).
Regarding claim 14, the modified invention of Housley, Hofmann, and Zarif discloses the waiting period duration is at least 10ms (Col 10, lines 33-47 -Hofmann; the waiting period can be 1 second).
Regarding claim 15, the modified invention of Housley, Hofmann, and Zarif discloses the first selection of the two or more physically contiguous electrodes comprises a linear configuration of one or more anodes and one or more cathodes (Page 30, lines 1-3 -Housley; the electrodes can be arranged in a linear array), and the second selection of the two or more physically contiguous electrodes comprises the first selection of the two or more physically contiguous electrodes with the one or more anodes and the one or more cathodes switched to thereby reverse polarity (Page 32, lines 1-9; Page 37, lines 1-9 -Housley; the controller is configured to selectively control polarity).
Regarding claim 16, the modified invention of Housley, Hofmann, and Zarif discloses the first selection of the two or more physically contiguous electrodes comprises a linear configuration of one or more anodes and one or more cathodes (Page 30, lines 1-3 -Housley; the electrodes can be arranged in a linear array), and the second selection of the two or more physically contiguous electrodes comprises the first selection of the two or more physically contiguous electrodes with the one or more anodes and the one or more cathodes switched to thereby reverse polarity (Page 32, lines 1-9; Page 37, lines 1-9 -Housley; the controller is configured to selectively control polarity).
Regarding claim 17, the modified invention of Housley, Hofmann, and Zarif discloses the array is a two-dimensional array and wherein the first selection of the two or more physically contiguous electrodes comprises a configuration of the one or more anodes and the one or more cathodes (Page 30, lines 1-3 -Housley; the electrodes can be arranged in a two dimensional array), and the second selection of the two or more physically contiguous electrodes comprises a configuration of electrodes including different electrodes from the first selection, selected to generate a change in electric field gradients within the target treatment region (Page 32, lines 10-31 -Housley; electrodes 1-8 are the first selection and electrodes 9-16 are the second selection).
Regarding claim 18, the modified invention of Housley, Hofmann, and Zarif discloses the array is a two-dimensional array and wherein the first selection of the two or more physically contiguous electrodes comprises a configuration of the one or more anodes and the one or more cathodes (Page 30, lines 1-3 -Housley; the electrodes can be arranged in a two dimensional array), and the second selection of the two or more physically contiguous electrodes comprises a configuration of electrodes including different electrodes from the first selection, selected to generate a change in electric field gradients within the target treatment region (Page 32, lines 10-31 -Housley; electrodes 1-8 are the first selection and electrodes 9-16 are the second selection).
Regarding claim 19, the modified invention of Housley, Hofmann, and Zarif discloses steps of determining one or more further selections of the two or more physically contiguous electrodes to drive as the one or more anodes and the one or more cathodes using the one or more electric pulses (Page 31, lines 21-34 -Housley), and, for the one or more further selections of the two or more physically contiguous electrodes, determining electrical pulse parameters for the one or more electric pulses to generate a further shaped electric field for the target treatment region adjacent the array (Page 2, lines 28-31; Page 15, lines 14-28 -Housley); and for each of the one or more further selections of the two or more physically contiguous electrodes, controlling the pulse generator to apply a further sequence of one or more unipolar pulses using each of the one or more further
Regarding claim 20, the modified invention of Housley, Hofmann, and Zarif discloses a sequence of said each of the one or more further selections the two or more physically contiguous of electrodes and the electrical pulses is chosen to generate a sequence of electric fields where subsequent electric fields each have an electric field gradient through the target treatment region at an incremental angle relative to a preceding electric field (Page 8, line 33- Page 9, line 1-4 -Housley; See Figs 4-8 of Housley wherein the electric field gradient is shown having changes in incremental angle).
Regarding claim 21, the modified invention of Housley, Hofmann, and Zarif discloses increasing or decreasing spacing between the one or more anodes and the one or more cathodes is used to control a radius of the target treatment region (Page 28, lines 25-32 -Housley).
Regarding claim 22, the modified invention of Housley, Hofmann, and Zarif discloses a direction of the gradients within the second shaped electric field is different from a direction of the gradients within the first shaped electric field (As best seen in Figs 4a and 5a of Housley, the direction of gradients in the first shape electric field (Fig 4a) is not identical to the direction of gradients in the second shape electric field (Fig 5a). Thus, they are different)
Regarding claim 23, the modified invention of Housley, Hofmann, and Zarif discloses the waiting period duration is at least 10ms (Col 10, lines 33-47 -Hofmann; the waiting period can be 1 second).
Regarding claim 24, the modified invention of Housley, Hofmann, and Zarif discloses the waiting period duration is less than 6000ms (Col 10, lines 33-47 -Hofmann; the waiting period can be 1 second).
Regarding claim 25, the modified invention of Housley, Hofmann, and Zarif discloses a direction of the gradients within the second shaped electric field is different from a direction of the gradients within the first shaped electric field (As best seen in Figs 4a and 5a of Housley, the direction of gradients in the first shape electric field (Fig 4a) is not identical to the direction of gradients in the second shape electric field (Fig 5a). Thus, they are different).
Response to Arguments
Applicant’s arguments regarding Hoffmann not providing any reason for having a waiting period and Hoffman teaching away from the features in independent claims 1 and 13 have been fully considered but are not persuasive. Col 10, lines 22-32 and 44-47 of Hoffmann detail that the parameters, including the wait period, for electroporation can be changed depending on the type of cell and the type of molecule to enter the cell. This is all for the goal of improving efficiency of treatment. Therefore, one of ordinary skill would understand that a wait period can be added and the time can be adjusted as best suited to a particular cell type and molecule type. Additionally, Hoffman does not teach away from the features recited in claims 1 and 13. MPEP 2145(X)(D)(1) states that "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). As Hoffman merely states that a homogeneous electric field is desirable and does not explicitly state that a wait period would not work with a nonhomogeneous electric field, it does not constitute teaching away.
Applicant’s arguments regarding one of ordinary skill in the art not having any motivation to incorporate the opposite polarity singular pulses taught by Zarif to a sequence of a plurality of unipolar pulses have been fully considered but is not persuasive. As detailed in Para 0055 of Zarif, the pulsing scheme, including the polarity and direction of the pulses, of an electrical voltage pulse or a series of voltage pulses can be modified to achieve a desired electroporation effect. One of ordinary skill would have ample motivation to adjust the polarity of a sequence of unipolar pulses to improve or provide a desired effect.
Applicant’s arguments regarding unexpected or superior results have been fully considered but are not persuasive. Per MPEP 716.02(b)(I), “The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992)”. Applicant has not provided evidence of what would have been expected and how the claimed system provides statistically and practically significant results. Applicant points to 330, Fig 3 to show that the use of a sequence of several unipolar pluses and then a sequence of several unipolar pules of opposite polarity improves the driving of DNA towards the cells. However, 330 is being compared to 310 and 350 which are different modes of electrotransfer. Thus, it is not comparing what would have been expected of a biphasic mode electrotransfer to the claimed biphasic mode electrotransfer and therefore, does not show unexpected results.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As detailed in the rejection above, all of the knowledge and reasoning relied upon is from the cited prior art, therefore, the conclusion of obviousness is not based on improper hindsight.
Conclusion
THIS ACTION IS MADE FINAL. 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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/ANTARIUS S DANIEL/Examiner, Art Unit 3783
/BHISMA MEHTA/Supervisory Patent Examiner, Art Unit 3783