DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/25/2026 has been entered.
Remarks
This office action fully acknowledges Applicant’s remarks and amendments filed on 25 June 2026.
Claims 1, 19-28, 30-32, and 34-42 are pending.
Claims 2-18, 29, and 33 are cancelled.
No claims are withdrawn.
Claims 34-42 are newly added.
Claim 1 is amended.
Specification
The amendment filed 06/25/2026 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows:
Claim 1: “wherein the system is free of any electrodes adjacent to any of the plurality of constricted portions configured to introduce an electrical field into the conduit, wherein the system is free of any electrical sensors adjacent to any of the plurality of constricted portions configured to measure a cell property”. See also new Claim 38 reciting the same.
Applicant is required to cancel the new matter in the reply to this Office Action.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1,19-28,30-32 and 34-42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows:
Claim 1: “wherein the system is free of any electrodes adjacent to any of the plurality of constricted portions configured to introduce an electrical field into the conduit, wherein the system is free of any electrical sensors adjacent to any of the plurality of constricted portions configured to measure a cell property”. See also new Claim 38 reciting the same.
See further discussion within the “Response to Arguments” section with respect to the ‘Specification- New Matter.’
Applicant is required to cancel the new matter in the reply to this Office Action.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 19-28, 30-32, and 34-42 are rejected under 35 U.S.C. 103 as being unpatentable over Diefenbach (WO 2010/105135 A1), hereinafter “Diefenbach”, in view of Adamo et al. (US 2009/0280518 A1), hereinafter “Adamo”.
Regarding Claim 1, Diefenbach teaches a system for inserting a payload into a cell (Abstract: “Methods, kits and devices are provided for introducing genetic material into cells”), comprising:
(a) an inlet for receiving the cell (page 5: “a continuous pipe having an entry point [the inlet] and an exit point”);
(b) an outlet (page 5: “a continuous pipe having an entry point and an exit point [the outlet]”);
(c) a conduit positioned along a solid substrate connected to the inlet and the outlet, the conduit comprising at least one non-constricted portion and a plurality of constricted portions through which the cell can pass (page 15: “Using this device, the cells were passed through a significantly smaller diameter passageway than has previously been used, with a result that the cell velocity increased as the diameter of the passageway narrowed. The narrowing of the exit tip of the pipette generated the greater fluid velocities for introduction of the genetic material into the living cells.”),
wherein the constricted portions are each in fluid communication with the inlet (As the constricted portions are merely narrowed regions of the pipe having the inlet, the constricted portions are in fluid communication with the inlet.), wherein the constricted portions are arranged in parallel and have a width smaller than a width of the at least one non-constricted portion (As the constricted portion of the pipe and its constricted end-portion of the pipe are both of the same pipe, the constricted portions are thereby arranged in parallel. – page 3: “An embodiment of the apparatus includes a pipe portion with a diameter that varies along the length of the pipe portion, for example, from a larger diameter to a smaller diameter to a larger diameter, the smaller diameter constituting a constriction of the pipe.”),
wherein the system is free of any electrodes adjacent to any of the plurality of constricted portions configured to introduce an electrical field into the conduit, wherein the system is free of any electrical sensors adjacent to any of the plurality of constricted portions configured to measure a cell property (Diefenbach does not mention any sensors or electrodes adjacent to the constricted portions. Diefenbach is commensurately directed to Applicant’s instant objective of deforming a cell so as to insert a payload thereinto.), and
(d) a payload-containing solution comprising the payload to be inserted into the cell (page 4: “passaging the mixture of cells and genetic material [payload] through the apparatus at least once, such that passaging the mixture having the cells and the genetic material through the apparatus introduces the genetic material into the cell. In general, a composition includes a fluid. For example, the fluid includes a solution or a suspension.”), wherein the payload-containing solution is located:
(i) in the conduit (page 11: “Cells moving in a fluid-filled channel or passageway [the conduit] undergo an increase in speed in a constriction of the channel, or in passing through a narrower diameter exit aperture. These cells in suspension experience a sudden change from high pressure to low pressure. Low pressure results in temporary stretching of the cells, creating temporary holes in cell membranes, thus permitting entry of genetic material present in the fluid or solution surrounding the cells, including without limitation exemplary genetic materials cDNA, siRNA, miRNA.”); and/OR
(ii) in an outlet reservoir configured to collect cells passed through the conduit, wherein the outlet reservoir is connected to the outlet; wherein the payload in the payload-containing solution is dissolved and/or suspended in liquid of the payload-containing solution and is exogenous to the cell, and
wherein the payload comprises:
a macromolecule (page 11: “producing transient holes in the membranes that permit entry of plasmid DNA [the macromolecule] in a molecular shape that is long and relatively thin. In fact, the diameter of a single DNA helix is 2nm. A circular cDNA plasmid is subject to coiling and supercoiling, resulting in a structure that has a configuration capable of entering a cell through resulting openings in the cell membrane produced by the method.”), a particle comprising a nanoparticle or a magnetic bead, a carbon nanotube, and/or a detectable marker, wherein the detectable marker comprises a fluorescent labelled molecule, a fluorescent dye, a radionuclide, a quantum dot, a gold nanoparticle, OR a magnetic bead, as in Claim 1.
Further regarding Claim 1, Diefenbach does not specifically teach the system discussed above wherein at least some of the plurality of constricted portions have: a tapered entrance portion, as in Claim 1.
However, Adamo teaches a respective cell deforming device using a constriction ([0007]: “The channel includes a constriction in the channel walls spaced apart from the first end and the second end, where the constriction is configured to deform a cell passing through the channel.”) to deform a cell 100 flowing through a passage containing the constriction (Fig. 1). Therein, said constriction has a tapered entrance portion ([0040]: “the cell deforming feature 50 has a funnel-shaped region that gradually narrows the channel 50 down to the size and shape of the cell deforming feature 50”). Looking to Diefenbach, Diefenbach discloses “The method in Examples herein maintained a constant fluid pressure, so as to avoid sudden, instantaneous changes in fluid pressure which damage cells.” indicating a motivation for one of ordinary skill in the art to simply modify the constriction of Diefenbach so as to have a tapered entrance so as to regulate pressure changes to avoid cell damange from sudden, instantaneous pressure change as set forth by Diefenbach.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the device of Diefenbach wherein at least some of the plurality of constricted portions have a tapered entrance portion, such as suggested by Adamo, so as to regulate/soften pressure changes between the pipe and the constricted portion of Diefenbach, as specifically indicated by Diefenbach.
Further note that such gradual change in pipe diameter resulting in a more gradual pressure change within the pipe is a known principle of hudrodynamica which would be recognized by one of ordinary skill in the art as Bernoulli's Principle wherein the flow rate (Q) (and thereby pressure) through a pipe is the product of the cross-sectional area (A) and the flow velocity (v) (Q = Av). As such, one of ordinary skill in the art would look to Adamo to confirm cells are successfully passed through a pressure-controlling tapered entrance.
Further regarding Claim 1, Diefenbach does not specifically teach the system discussed above wherein at least some of the plurality of constricted portions have: a width of greater than or equal to 3 microns and less than or equal to 198 microns, as in Claim 1.
However, as Diefenbach teaches a diameter of at least one of the constricted portions (the tapered exit portion) at a range of “about 0.1 mm to about 0.5 mm” (page 3) which overlaps with the instant claimed range of 0.003 mm to 0.198 mm, a prima facie case of obviousness exists in view of In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990), absent contrary evidence of criticality or non-obviousness of the claimed range. Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to select the overlapping portion of the range so as to maximally achieve the benefits of non-damaging single cell compression through a capillary. Further, as each of the references is drawn to cell compression by constriction of a pipe, one of ordinary skill in the art would find it obvious to optimize the constriction diameter respective to the particular cell-type being examined.
Regarding Claim 19, the prior art meets the limitations of Claim 1 as discussed above. Further, Diefenbach does not specifically teach the system discussed above wherein at least some of the plurality of constricted portions have a width of greater than or equal to 3 microns and less than or equal to 17 microns, as in Claim 19.
However, as the shear force experienced by the cell, a factor that affects cell survival as well as degree of membrane disruption, is a property that can be modified by adjusting the width of the constricted portion relative to the cell, the precise constriction diameter would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made. As such, without showing unexpected results, the claimed range of constriction diameter values cannot be considered critical.
Thus, one of ordinary skill in the art would have optimized through routine experimentation the constriction to maximally obtain the desired properties of membrane disruption without causing cell death (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223).
Further therein, as the constriction process of Diefenbach is utilized for a variety of cell types, one of ordinary skill in the art would find it obvious to optimize the constriction diameter for the particular cell-type at hand.
Regarding Claim 20, the prior art meets the limitations of Claim 1 as discussed above. Further, Adamo does not specifically teach the system discussed above wherein at least some of the plurality of constricted portions have a width of greater than or equal to 4 microns and less than or equal to 8 microns, as in Claim 20.
However, similarly as above, as the shear force experienced by the cell, a factor that affects cell survival as well as degree of membrane disruption, is a property that can be modified by adjusting the width of the constricted portion relative to the cell, the precise constriction diameter would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made. As such, without showing unexpected results, the claimed range of constriction diameter values cannot be considered critical.
Thus, one of ordinary skill in the art would have optimized through routine experimentation the constriction to maximally obtain the desired properties of membrane disruption without causing cell death (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223).
Further therein, as the constriction process of Diefenbach is utilized for a variety of cell types, one of ordinary skill in the art would find it obvious to optimize the constriction diameter for the particular cell-type at hand.
Regarding Claim 21, the prior art meets the limitations of Claim 20 as discussed above. Further, Diefenbach teaches the system discussed above wherein the microfluidic channel comprises a non-constricted portion and a constricted portion (page 11: “a constriction in a fluid passageway” – page 3: “An embodiment of the apparatus includes a pipe portion with a diameter that varies along the length of the pipe portion, for example, from a larger diameter [non-constricted] to a smaller diameter [constricted] to a larger diameter [non-constricted], the smaller diameter [constricted] constituting a constriction of the pipe.”), as in Claim 21.
Further, Diefenbach does not specifically teach the device discussed above wherein the conduit comprises a plurality of microfluidic channels arranged in parallel and in fluid communication with the inlet, as in Claim 21.
However mere duplication of parts has no patentable significance unless a new and unexpected result is produced – see MPEP 2144.04(VI)(B). Herein, one of ordinary skill in the art would have found it obvious to provide the device taught by Diefenbach with a plurality of the constricted portions so as to provide a structure capable of transforming multiple cells in parallel to increase throughput.
Regarding Claim 22, the prior art meets the limitations of Claim 21 as discussed above. Further, Diefenbach teaches the system discussed above wherein the non-constricted portion and the constricted portion of each of the plurality of microfluidic channels are contiguous (page 3: “An embodiment of the apparatus includes a pipe portion with a diameter that varies along the length of the pipe portion, for example, from a larger diameter [non-constricted] to a smaller diameter [constricted] to a larger diameter [non-constricted], the smaller diameter [constricted] constituting a constriction of the pipe.” Therein, such constricting and opening of the pipe constitutes a contiguous channel.), as in Claim 22.
Regarding Claim 23, the prior art meets the limitations of Claim 20 as discussed above. Further, Diefenbach does not specifically teach the system discussed above wherein the at least some of the plurality of constricted portions having a tapered entrance portion further comprise a tapered exit portion, as in Claim 23.
However, Adamo teaches an embodiment comprising a tapered entrance portion in combination with a tapered exit portion (Fig. 5B and [0041]: “the channel may also have a funnel-shaped region 54 to allow it to more gradually expand out to the channel 30 diameter”). Therein, one of ordinary skill in the art would recognize the pressure-regulating effects of a tapered exit portion having a more gradually changing pressure gradient.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the device of Diefenbach wherein the constricted portion has a tapered entrance portion further comprise a tapered exit portion, such as suggested by Adamo, so as to further regulate the pressure and shear forces experienced by a cell transitioning from a low velocity pipe to a high velocity constricted portion of the pipe and thereby reduce errors and waste due to cell damage and/or cell death as a result of cells experiencing too much shear force through the constriction.
Regarding Claim 24, the prior art meets the limitations of Claim 20 as discussed above. Further, Diefenbach teaches the system discussed above wherein the outlet is connected to the outlet reservoir configured to collect cells passed through the conduit (page 16: “Following passaging with nucleic acid, the cells were collected by centrifugation at 3000 rpm in a microcentrifuge and the supernatant was removed from the cell pellet, and was replaced with fresh culture medium.”), as in Claim 24.
Regarding Claim 25, the prior art meets the limitations of Claim 1 as discussed above. Further, Diefenbach teaches the system discussed above wherein the microfluidic channel comprises a non-constricted portion and a constricted portion (page 11: “a constriction in a fluid passageway” – page 3: “An embodiment of the apparatus includes a pipe portion with a diameter that varies along the length of the pipe portion, for example, from a larger diameter [non-constricted] to a smaller diameter [constricted] to a larger diameter [non-constricted], the smaller diameter [constricted] constituting a constriction of the pipe.”), as in Claim 25.
Further, Diefenbach does not specifically teach the device discussed above wherein the conduit comprises a plurality of microfluidic channels arranged in parallel and in fluid communication with the inlet, as in Claim 25.
However mere duplication of parts has no patentable significance unless a new and unexpected result is produced – see MPEP 2144.04(VI)(B). Herein, one of ordinary skill in the art would have found it obvious to provide the device taught by Diefenbach with a plurality of the channels so as to provide a structure capable of transforming multiple cells in parallel to increase throughput.
Regarding Claim 26, the prior art meets the limitations of Claim 25 as discussed above. Further, Diefenbach, when modified with a plurality of the channels as discussed above regarding Claim 25, teaches the system discussed above wherein the non-constricted portion and the constricted portion of each of the plurality of microfluidic channels are contiguous given that the inlet portion is not duplicated and thereby provides fluid communication through each of the duplicated channels, as in Claim 26.
Regarding Claim 27, the prior art meets the limitations of Claim 1 as discussed above. Further, Diefenbach does not specifically teach the system discussed above wherein the at least some of the plurality of constricted portions having a tapered entrance portion further comprise a tapered exit portion, as in Claim 27.
However, Adamo teaches an embodiment comprising a tapered entrance portion in combination with a tapered exit portion (Fig. 5B and [0041]: “the channel may also have a funnel-shaped region 54 to allow it to more gradually expand out to the channel 30 diameter”). Therein, one of ordinary skill in the art would recognize the pressure-regulating effects of a tapered exit portion having a more gradually changing pressure gradient.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the device of Diefenbach wherein at least some of the plurality of constricted portions having a tapered entrance portion further comprise a tapered exit portion, such as suggested by Adamo, so as to further regulate the pressure and shear forces experienced by a cell transitioning from a low velocity pipe to a high velocity constricted portion of the pipe and thereby reduce errors and waste due to cell damage and/or cell death as a result of cells experiencing too much shear force through the constriction.
Regarding Claim 28, the prior art meets the limitations of Claim 20 as discussed above. Further, Diefenbach teaches the system discussed above wherein the outlet is connected to the outlet reservoir configured to collect cells passed through the conduit (page 16: “Following passaging with nucleic acid, the cells were collected by centrifugation at 3000 rpm in a microcentrifuge and the supernatant was removed from the cell pellet, and was replaced with fresh culture medium.”), as in Claim 28.
Regarding Claim 30, the prior art meets the limitations of Claim 1 as discussed above. Further, Diefenbach teaches the system discussed above wherein the payload comprises a macromolecule, wherein the macromolecule comprises a nucleic acid (page 11: “Cells moving in a fluid-filled channel or passageway [the conduit] undergo an increase in speed in a constriction of the channel, or in passing through a narrower diameter exit aperture. These cells in suspension experience a sudden change from high pressure to low pressure. Low pressure results in temporary stretching of the cells, creating temporary holes in cell membranes, thus permitting entry of genetic material present in the fluid or solution surrounding the cells, including without limitation exemplary genetic materials cDNA, siRNA, miRNA.”), a polynucleotide, a protein, and/OR a polypeptide, as in Claim 30.
Regarding Claim 31, the prior art meets the limitations of Claim 30 as discussed above. Further, Diefenbach teaches the system discussed above wherein the system comprises the cell located in the conduit or the outlet reservoir (page 16: “Following passaging [the cell through the conduit] with nucleic acid, the cells were collected [in a reservoir] by centrifugation at 3000 rpm in a microcentrifuge and the supernatant was removed from the cell pellet, and was replaced with fresh culture medium.”), as in Claim 31.
Regarding Claim 32, the prior art meets the limitations of Claim 30 as discussed above. Further, Diefenbach suggests the system discussed above wherein the macromolecule is purified and/or isolated (Diefenbach discusses transfection of plasmid cDNA into cells to produce recombinant cells comprising an exogenously inserted “a gene” (page 15 line 31) of the cDNA. As such a gene in isolation is inserted into a cell as in Diefenbach, such plasmid gene must have been isolated, such as even by PCR. Further, one of ordinary skill in the art would find it obvious common sense to use a purified/isolated reagent so as to avoid errors due to additional genes/molecules/etc. within the solution.), as in Claim 32.
Regarding Claim 34, the prior art meets the limitations of Claim 1 as discussed above. Further, Diefenbach teaches the system discussed above wherein the system is free of any sensors adjacent to any of the plurality of constricted portions configured to measure a cell property (Diefenbach does not mention any sensors or electrodes configured to measure a cell property adjacent to the constricted portions. Diefenbach is commensurately directed to Applicant’s instant objective of deforming a cell so as to insert a payload thereinto.), as in Claim 34.
Regarding Claim 35, the prior art meets the limitations of Claim 1 as discussed above. Further, Diefenbach teaches the system discussed above wherein the system is free of any sensors configured to measure a cell property (Diefenbach does not mention any sensors or electrodes configured to measure a cell property adjacent to the constricted portions. Diefenbach is commensurately directed to Applicant’s instant objective of deforming a cell so as to insert a payload thereinto.), as in Claim 35.
Regarding Claim 36, the prior art meets the limitations of Claim 1 as discussed above. Further, Diefenbach teaches the system discussed above wherein dissolved and/or suspended undelivered payload is present in solution downstream of at least some of the constricted portions with respect to the inlet (page 15: “Cells were placed in a small volume (50 μl to 100 μl), and a solution having a high concentration of plasmid cDNA (70 μg/ml) containing a gene that encodes green fluorescent protein (GFP) fusion proteins of interest was added to the cells .” – As the payload is provided in a greater concentration than the cells, and that Diefenbach further reports “the present method achieved consistently high transfection efficiencies of 80% to about 100%” (page 12), there must be residual payload present downstream of the constricted portions, as would further be obvious to one for ordinary skill in the art and because transfection occurs or is expected to occur at each of the sequential constricted portions in Diefenbach.), as in Claim 36.
Regarding Claim 37, the prior art meets the limitations of Claim 36 as discussed above. Further, Diefenbach teaches the system discussed above wherein the cell is present in solution with dissolved and/OR suspended undelivered payload is present in solution downstream of at least some of the constricted portions with respect to the inlet (page 15: “Cells were placed in a small volume (50 μl to 100 μl), and a solution having a high concentration of plasmid cDNA (70 μg/ml) containing a gene that encodes green fluorescent protein (GFP) fusion proteins of interest was added to the cells .” – As the payload is provided in a greater concentration than the cells, and that Diefenbach further reports “the present method achieved consistently high transfection efficiencies of 80% to about 100%” (page 12), there must be residual payload present downstream of the constricted portions, as would further be obvious to one for ordinary skill in the art and because transfection occurs or is expected to occur at each of the sequential constricted portions in Diefenbach.), as in Claim 37.
Regarding Claim 38, Diefenbach teaches a system for inserting a payload into a cell (Abstract: “Methods, kits and devices are provided for introducing genetic material into cells”), comprising:
(a) an inlet for receiving the cell (page 5: “a continuous pipe having an entry point [the inlet] and an exit point”);
(b) an outlet (page 5: “a continuous pipe having an entry point and an exit point [the outlet]”); and
(c) a conduit positioned along a solid substrate connected to the inlet and the outlet, the conduit comprising at least one non-constricted portion and a plurality of constricted portions through which the cell can pass (page 15: “Using this device, the cells were passed through a significantly smaller diameter passageway than has previously been used, with a result that the cell velocity increased as the diameter of the passageway narrowed. The narrowing of the exit tip of the pipette generated the greater fluid velocities for introduction of the genetic material into the living cells.”), wherein the constricted portions are each in fluid communication with the inlet (As the constricted portions are merely narrowed regions of the pipe having the inlet, the constricted portions are in fluid communication with the inlet.), wherein the constricted portions are arranged in parallel and have a width smaller than a width of the at least one non-constricted portion (As the constricted portion of the pipe and its constricted end-portion of the pipe are both of the same pipe, the constricted portions are thereby arranged in parallel. – page 3: “An embodiment of the apparatus includes a pipe portion with a diameter that varies along the length of the pipe portion, for example, from a larger diameter to a smaller diameter to a larger diameter, the smaller diameter constituting a constriction of the pipe.”),
wherein the system is free of any electrodes adjacent to any of the plurality of constricted portions configured to introduce an electrical field into the conduit, wherein system is free of any electrical sensors adjacent any of the plurality of constricted portions configured to measure a cell property (Diefenbach does not mention any sensors or electrodes adjacent to the constricted portions. Diefenbach is commensurately directed to Applicant’s instant objective of deforming a cell so as to insert a payload thereinto.),
as in Claim 38.
Further regarding Claim 38, Diefenbach does not specifically teach the system discussed above wherein at least some of the plurality of constricted portions have: a tapered entrance portion, as in Claim 38.
However, Adamo teaches a respective cell deforming device using a constriction ([0007]: “The channel includes a constriction in the channel walls spaced apart from the first end and the second end, where the constriction is configured to deform a cell passing through the channel.”) to deform a cell 100 flowing through a passage containing the constriction (Fig. 1). Therein, said constriction has a tapered entrance portion ([0040]: “the cell deforming feature 50 has a funnel-shaped region that gradually narrows the channel 50 down to the size and shape of the cell deforming feature 50”). Looking to Diefenbach, Diefenbach discloses “The method in Examples herein maintained a constant fluid pressure, so as to avoid sudden, instantaneous changes in fluid pressure which damage cells.” indicating a motivation for one of ordinary skill in the art to simply modify the constriction of Diefenbach so as to have a tapered entrance so as to regulate pressure changes to avoid cell damange from sudden, instantaneous pressure change as set forth by Diefenbach.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the device of Diefenbach wherein at least some of the plurality of constricted portions have a tapered entrance portion, such as suggested by Adamo, so as to regulate/soften pressure changes between the pipe and the constricted portion of Diefenbach, as specifically indicated by Diefenbach.
Further note that such gradual change in pipe diameter resulting in a more gradual pressure change within the pipe is a known principle of hudrodynamica which would be recognized by one of ordinary skill in the art as Bernoulli's Principle wherein the flow rate (Q) (and thereby pressure) through a pipe is the product of the cross-sectional area (A) and the flow velocity (v) (Q = Av). As such, one of ordinary skill in the art would look to Adamo to confirm cells are successfully passed through a pressure-controlling tapered entrance.
Further regarding Claim 38, Diefenbach does not specifically teach the system discussed above wherein at least some of the plurality of constricted portions have: a width of greater than or equal to 3 microns and less than or equal to 198 microns, as in Claim 38.
However, as Diefenbach teaches a diameter of at least one of the constricted portions (the tapered exit portion) at a range of “about 0.1 mm to about 0.5 mm” (page 3) which overlaps with the instant claimed range of 0.003 mm to 0.198 mm, a prima facie case of obviousness exists in view of In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990), absent contrary evidence of criticality or non-obviousness of the claimed range. Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to select the overlapping portion of the range so as to maximally achieve the benefits of non-damaging single cell compression through a capillary. Further, as each of the references is drawn to cell compression by constriction of a pipe, one of ordinary skill in the art would find it obvious to optimize the constriction diameter respective to the particular cell-type being examined.
Regarding Claim 39, the prior art meets the limitations of Claim 38 as discussed above. Further, Diefenbach teaches the system discussed above wherein the system is free of any sensors adjacent to any of the plurality of constricted portions configured to measure a cell property (Diefenbach does not mention any sensors or electrodes configured to measure a cell property adjacent to the constricted portions. Diefenbach is commensurately directed to Applicant’s instant objective of deforming a cell so as to insert a payload thereinto.), as in Claim 39.
Regarding Claim 40, the prior art meets the limitations of Claim 38 as discussed above. Further, Diefenbach teaches the system discussed above wherein the system is free of any sensors configured to measure a cell property (Diefenbach does not mention any sensors or electrodes configured to measure a cell property adjacent to the constricted portions. Diefenbach is commensurately directed to Applicant’s instant objective of deforming a cell so as to insert a payload thereinto.), as in Claim 40.
Regarding Claim 41, the prior art meets the limitations of Claim 38 as discussed above. Further, Diefenbach does not specifically teach the system discussed above wherein at least some of the plurality of constricted portions have a width of greater than or equal to 3 microns and less than or equal to 17 microns, as in Claim 141.
However, as the shear force experienced by the cell, a factor that affects cell survival as well as degree of membrane disruption, is a property that can be modified by adjusting the width of the constricted portion relative to the cell, the precise constriction diameter would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made. As such, without showing unexpected results, the claimed range of constriction diameter values cannot be considered critical.
Thus, one of ordinary skill in the art would have optimized through routine experimentation the constriction to maximally obtain the desired properties of membrane disruption without causing cell death (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223).
Further therein, as the constriction process of Diefenbach is utilized for a variety of cell types, one of ordinary skill in the art would find it obvious to optimize the constriction diameter for the particular cell-type at hand.
Regarding Claim 42, the prior art meets the limitations of Claim 38 as discussed above. Further, Adamo does not specifically teach the system discussed above wherein at least some of the plurality of constricted portions have a width of greater than or equal to 4 microns and less than or equal to 8 microns, as in Claim 42.
However, similarly as above, as the shear force experienced by the cell, a factor that affects cell survival as well as degree of membrane disruption, is a property that can be modified by adjusting the width of the constricted portion relative to the cell, the precise constriction diameter would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made. As such, without showing unexpected results, the claimed range of constriction diameter values cannot be considered critical.
Thus, one of ordinary skill in the art would have optimized through routine experimentation the constriction to maximally obtain the desired properties of membrane disruption without causing cell death (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223).
Further therein, as the constriction process of Diefenbach is utilized for a variety of cell types, one of ordinary skill in the art would find it obvious to optimize the constriction diameter for the particular cell-type at hand.
Response to Arguments
Specification – New Matter
Examiner acknowledges that in the interview on 06/23/2026 Examiner indicated that the negative recitation of amended Claim 1 excluding electrodes/sensors from around the constricted portion appeared to be supported by the spec in view of MPEP 2173.05(i), reciting: “If alternative elements are positively recited in the specification, they may be explicitly excluded in the claims.”. However, Examiner indicated that an official analysis and decision would occur only after receiving Applicant’s response and further reviewing Applicant’s disclosure.
Upon further review of the case law thereto MPEP 2173.05(i) (See In re Johnson, 558 F.2d 1008, 1019, 194 USPQ 187, 196 (CCPA 1977).) and Applicant’s instant disclosure, it is found herein that Applicant’s assertion that the negative limitation is supported is not persuasive.
Although MPEP 2173.05(i) recognizes that positively recited alternative elements may, in appropriate circumstances, be expressly excluded from the claims, the present disclosure does not positively and particularly identify the constriction not having electrodes, and the constriction having electrodes, as particular alternatives to one another (alternative forms of the same disclosed feature).
Rather, the specification merely describes one embodiment in which electrodes are not mentioned, and another embodiment in which electrodes are discussed. Further, Applicant’s cited section of the specification (“FIG. 38 depicts micrographs illustrating alternate device structures.”) does not disclose the specific use/addition of electrodes to a non-electrode-containing alternative, but rather merely states that an alternative can be seen in Fig. 38, wherein the figure happens to show the electrodes, but no particular discussion of if the electrodes are the alternative to a non-electrode structure is seen as the disclosure is absent a showing of the particular exclusion of electrodes. It is not clear from the disclosure that the electrodes are present in one embodiment and not the other as no particular discussion of the absence and/or addition of the electrodes among the disclosed embodiments is seen. Additionally, while applicant contends that the non-electrode embodiment is operated “purely mechanically”, an electrode-containing embodiment can also be operated purely mechanically by simply not utilizing the electrodes.
Thus, the absence of discussion of electrodes in a particular embodiment is not an affirmative disclosure that electrodes are specifically excluded from that embodiment. See MPEP 2173.05(i): “The mere absence of a positive recitation is not basis for an exclusion.”. Accordingly, Applicant’s reliance on MPEP 2173.05 is misplaced because said section concerns the exclusion of positively disclosed alternatives, not the conversion of an unmentioned feature of one embodiment into affirmative support for a negative limitation based on a highly generic discussion of alternative structures and operation of the device, both being non-specific to the electrodes themselves.
Nonetheless, Examiner has amended the rejections above to teach a structure in which no electrodes are present, wherein the newly cited reference of Diefenbach is more akin to Applicant’s intended use of inserting material into the cell, rather than the previous reference of Adamo for measuring cell properties.
Rejections under 35 USC 103:
Applicant’s arguments are on the alleged grounds that one of ordinary skill in the art would not find it obvious to modify the device of Adamo to perform the claimed payload-delivery function as one of ordinary skill in the art would not find it obvious to apply the lack of (free from) electrode/sensor provisions of the instant amended claims as the device of Adamo is wholly directed to cell measurement and such removal of the sensors/electrodes would render the device of Adamo inoperable for its intended purpose.
However, Applicant’s arguments are moot as they are directed toward a grounds of rejection no longer relied upon. Herein, Examiner sets forth the rejection of Claims 1, 19-28, 30-32, and 34-42 under 35 U.S.C. 103 as being unpatentable over Diefenbach in view of Adamo, as necessitated by Applicant’s amendments specifically omitting any sensor/electrode arrangement to be present within the device. Diefenbach teaches forcing cells through a constriction in a pipe so as to transfect said cells with exogenous plasmid DNA contained within the solution in which the cells are held. Adamo is now merely relied upon as a secondary reference for teaching pipes for cell compression having a tapered entrance and exit portion, as is similarly contemplated by the needs of less sudden cell compression discussed by Diefenbach.
Applicant further argues that none of the additional previously cited prior art references cure the alleged deficiencies of Adamo. However, none of those references are relied upon herein to cure any deficiency in Adamo. As such, Applicant’s argument is moot. By this, claims depending from independent Claims 1 or 38 are not patentable merely by virtue of dependence on the independent claim.
New Claims
New Claims 34-42 are rejected under 35 USC 103 as being unpatentable over Diefenbach in view of Adamo, as discussed above in the body of the rejection.
Conclusion
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/B.J.K./Examiner, Art Unit 1798
/NEIL N TURK/Primary Examiner, Art Unit 1798
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