DETAILED ACTION
Drawings
The drawings are objected to under 37 CFR 1.83(a). The drawings must show every feature of the invention specified in the claims. However, the Figures do not appear to depict a vacuum (claims 150-152), a filter/scaffold (claims 155-157 and 173), a biological membrane (claim 158-160), a synthetic membrane (claims 161-162), a porous cell culture plate insert (claim 163), and a pressure head generator (claims 168-169). Therefore, these features must be shown or canceled from the claims. No new matter should be entered.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 100-122, 129, 133, 143, 150-153 and 164-177 are rejected under 35 U.S.C. 103 as being unpatentable over Held (US 20040219676) in view of Miura (JP H03251187)1 and Greenberg (US 20120135526).
With respect to claims 100, 122, 153, 173 and 177, Held discloses an apparatus for delivering a payload across a plasma membrane of a cell comprising a pneumatic generator (Figure 1:10) configured to produce a gas under pressure. An atomizer (Figure 1:8) is operatively coupled to the pneumatic generator and is capable of forming a spray. The atomizer is additionally coupled to a reservoir (Figure 1:1) configured to contain an aqueous solution that includes the payload. This is described in paragraphs [0066]-[0082]. Held states that the atomizer is oriented towards a support (Figure 1:14) capable of supporting a population of cells for contacting with a volume of the aqueous solution. The atomizer produces an aerosol, which includes colloidal droplets (i.e. droplets dispersed in a gas). Held, however, does not state that a valve is disposed between the pneumatic generator and the atomizer, wherein the valve is configured to switch between closed and open states with a switching speed of less than 250 milliseconds.
Miura discloses an apparatus for delivering a payload across a plasma membrane comprising a pneumatic generator configured to produce a gas under pressure, an atomizer (Figure 1:4) and a reservoir (Figure 1:2) for containing the payload. Miura teaches that a solenoid valve (Figure 4:13) is between the pneumatic generator and the atomizer and is switchable between a closed position preventing gas from activating the atomizer and an open position for allowing gas under pressure to active the atomizer. Miura states that the switching speed of the valve is less than 250 milliseconds (“the action time of an electromagnetic valve is set to about 0.001 sec with a controller 13 built in the valve” – see English abstract filed by Application on 4/6/2020).
Greenberg discloses an apparatus for delivering a payload across a plasma membrane of a cell positioned on a support (Figure 2:206). The apparatus includes a pneumatic generator (Figure 2:208) configured to produce a gas under pressure, an atomizer (Figure 2:100) operatively coupled to the pneumatic generator and capable of forming a spray, and a payload (Figure 3:306). A valve is between the pneumatic generator and atomizer and is switchable from a closed position and an open position. Greenberg teaches that the valve is a solenoid valve that may be cycled between open and closed positions to produce gas pulses. Paragraph [0067] indicates that gas is delivered from the pneumatic generator to the atomizer in a succession of rapid pulses, such that each pulse may have a duration from 0 to 500 milliseconds (“The potentiometer 618 is configured to allow a user to adjust the duration of the gas pulse, e.g., from 0 to 500 msec…FIG. 6C shows a gas solenoid 620 actuated by trigger network 622, which includes tandem 556 integrated circuit chips and the potentiometer 618. The trigger network 622 is configured to allow the user to control the gas pulse duration”.
Before the effective filing date of the claimed invention, it would have been obvious to ensure that the Held system includes a solenoid valve characterized by a switching speed of less than 250 milliseconds. Miura teaches that this would improve the activation precision of the device and allow one to start and stop cell transfection with greater control. Greenberg shows how rapid pulses controllably transport a biological payload through the atomizer at elevated speeds conducive to delivering a molecule to a tissue for gene therapy. It is prima facie obvious to apply a known technique to a known device ready for improvement to yield predictable results. See MPEP 2143.
With respect to claims 101-110 and 174, Held, Miura and Greenberg disclose the combination as described above. Absent a showing of criticality, it would have been obvious to optimize known result-effective variables, such as solution volume, # of cells and support surface area, through routine experimentation. See MPEP 2144.05. Furthermore, it is well-established that apparatus claims cover what a device is, not what a device does. A claim containing a recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus if the prior art apparatus teaches all the structural limitations of the claim. See MPEP 2114.
With respect to claims 111-114, 175 and 176, Held, Miura and Greenberg disclose the combination as described above. Miura teaches delivering fine particles (e.g. metal particles immobilized with DNA) with diameters as great as 10 microns into cells. An aqueous droplet capable of delivering such a particle would need to be bigger than the particle it carries, for example between 30-50 microns in diameter. Held discusses droplet size in paragraphs [0042]-[0047], and states that the selection of a specific particle size is often a tradeoff between minimizing cell damage and increasing the likelihood of membrane penetration (“The importance of droplet size has been demonstrated with particle bombardment technology where particles of greater than 1 micron in diameter were shown to be unsuitable for introducing DNA into cells of 10 to 20 microns in diameter (Klein, et al., 1988(a); Klein, et al., 1988(b) due to the damage produced by particles of such size. On the other hand, large particles have been reported to be more likely to penetrate the cells (U.S. Pat. No. 5,877,023)”). Although Held includes statements cautioning against large particle (and droplet) sizes, Held is also directed to transfecting bacteria, which are very small (i.e., 2 microns in diameter). Those of ordinary skill would have considered larger droplet sizes (i.e. 30-50 microns) when delivering a payload to much larger mammalian cells (i.e., up to 100 microns in diameter). Accordingly, the selection of a particular droplet diameter when using the Held system is considered to be a result-effective variable to be optimized through routine experimentation, and those of ordinary skill would have chosen droplet diameters between 30 and 50 microns particularly when large animal cells are being treated. Furthermore, it is well-established that apparatus claims cover what a device is, not what a device does. A claim containing a recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus if the prior art apparatus teaches all the structural limitations of the claim. See MPEP 2114.
With respect to claims 115 and 116, Held, Miura and Greenberg disclose the combination as described above. As previously discussed, Miura states that the valve switching speed is as low as 1 millisecond and may be anywhere between 1 msec to 9.999 sec. Similarly, Greenberg teaches a valve response time between 0-500 msec.
With respect to claims 117-121, Held, Miura and Greenberg disclose the combination as described above. Held further discusses contacting the population of cells with the aqueous solution, and then adding a second volume of buffer or culture medium to submerse or suspend the cells. This is described in Examples 1-21. Furthermore, it is well-established that apparatus claims cover what a device is, not what a device does. A claim containing a recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus if the prior art apparatus teaches all the structural limitations of the claim. See MPEP 2114.
With respect to claims 129, 133 and 143, Held, Miura and Greenberg disclose the combination as described above. Held teaches that an aqueous solution is retained within the reservoir 1, wherein the aqueous solution includes any combination of nucleic acids, carbohydrates, growth regulators and peptides.
With respect to claims 150-152, Held, Miura and Greenberg disclose the combination as described above. Held further teaches that the support includes a vessel (Figure 1:13) that comprises a vacuum (Figure 1:15) for removing media from the bottom of the vessel and the top of the cell population.
With respect to claim 164, Held, Miura and Greenberg disclose the combination as described above. Held and Miura are each capable of producing a conical spray zone.
With respect to claims 165-170, Held, Miura and Greenberg disclose the combination as described above. The Held pneumatic generator includes a gas reservoir comprising compressed gas (e.g. bottled gases). A pressure head generator is either an inherent or obvious feature of the Held gas reservoir, and the apparatus may be used to uniformly contact the aqueous solution with the population of cells using the spray. The device may be operated at a variety of pressures, including, for example, 0.5-2.5 bar. Again, it is well-established that apparatus claims cover what a device is, not what a device does. A claim containing a recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus if the prior art apparatus teaches all the structural limitations of the claim. See MPEP 2114.
With respect to claims 171 and 172, Held, Miura and Greenberg disclose the combination as described above. Held teaches in at least paragraph [0002] that the payload may include any combination of nucleic acids, carbohydrates, growth regulators and peptides.
Claims 123-128 and 154-163 are rejected under 35 U.S.C. 103 as being unpatentable over Held (US 20040219676) in view of Miura (JP H03251187) and Greenberg (US 20120135526) as applied to claim 100, and further in view of O’Brien (US 20040033589)
Held, Miura and Greenberg disclose the combination as described above, however do not expressly teach specific cell types for treatment in a vessel comprising a membrane.
O’Brien discloses an apparatus for delivering a payload across a plasma membrane of a cell comprising a pneumatic generator, an atomizer and a support for supporting a population of cells. See Fig. 2 and paragraph [0033]. Paragraphs [0048]-[0055] describe examples in which confluent slices of tissue containing neuronal cells are treated on a support comprising a 3D membrane (“The slices of cerebellum were placed on a membrane support in six well sterile tissue culture plates (0.4 micron Millicell-CM, Millipore)”). At least paragraph [0060] further discusses treating non-adherent cells, such as T-cells.
Before the effective filing date of the claimed invention, it would have been obvious to use the Held system to deliver a payload to essentially any cell type supported within a vessel comprising a 3D membrane/scaffold. O’Brien teaches that biolistic gene gun technology is applicable to a wide range of research (“The technique has had a tremendous impact on plant and microbial research. The gene gun in accordance with the present invention makes the technique applicable for mammalian in-vivo as well as in-vitro use”), and those of ordinary skill would have considered modifying both adherent and non-adherent cells.
Claims 130-132 are rejected under 35 U.S.C. 103 as being unpatentable over Held (US 20040219676) in view of Miura (JP H03251187) and Greenberg (US 20120135526) as applied to claim 129, and further in view of Touitou (US 20040242416)
Held, Miura and Greenberg disclose the combination as described above, however do not expressly state that the aqueous solution includes ethanol.
Touitou discloses a method for improving intracellular delivery of a payload by using an aqueous fluid designed to break down the permeability barrier of the cell plasma membrane. Paragraphs [0084]-[0097] describe aqueous solution compositions that include 10-30% ethanol.
Before the effective filing date of the claimed invention, it would have been obvious to include ethanol in the Held aqueous solution. Touitou teaches that ethanol facilitates the delivery of an agent into a cell during transfection. Those of ordinary skill would have been interested in utilizing different methods designed to increase the likelihood of membrane penetration during bombardment when using the Held apparatus, and would have recognized the Touitou ethanol composition as a possible solution.
Claims 134-149 are rejected under 35 U.S.C. 103 as being unpatentable over Held (US 20040219676) in view of Miura (JP H03251187) and Greenberg (US 20120135526) as applied to claims 129 and 133, and further in view of Chiou (US 20150044751), Delahunt (US 20150111216) and Blackman (US 20130309677)
Held, Miura and Greenberg disclose the combination as described above. Although Held, Miura and Greenberg discuss providing payloads comprising essentially any known nucleic acid, carbohydrate, regulator and/or protein/peptide, Held, Miura and Greenberg do not teach the specific agents set forth in claims 134-149.
Chiou discloses an apparatus for transfecting cells. Chiou teaches in paragraphs [0008]-[0016], [0025], [0071] and [0188] that various nucleic acid and antibody compounds are introduced into the cells. Chiou further teaches that diagnostic agents comprising fluorescent molecules, detectable nanoparticles and/or quantum dots are also utilized.
Delahunt discloses a method for assessing a liquid sample using at least one dye when evaluating cells. Paragraphs [0090]-[0098] state that a wide variety of fluorescent dyes may be used, including DAPI (4’,6-diamidino-2-phenylindole), indocyanine green, and methylene blue.
Blackman discloses an in vitro method for exposing cells to different drugs and compounds, including antibodies, antibody fragments and nanoparticles. Blackman states in paragraphs [0184]-[0211] that it is of interest to subject cells to different anti-neoplastic agents (e.g. cisplatin), anti-hyperlipidemic agents (e.g. statin), anti-depressants (e.g. fluoxetine) and incretin mimetics (e.g. liraglutide).
Before the effective filing date of the claimed invention, it would have been obvious to use the Held system to modify cells using known therapeutic agents and to detect a cellular response using known diagnostic agents. Chiou, Delahunt and Blackman teach that it is common in the art to deliver a wide variety of antibodies, nucleic acids and drugs to cells in combination with optically detectable compounds for the purpose of cell modification and identification, and that this has great research and commercial value.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 100-177 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Pat. No. 12,195,748.
Although the claims at issue are not identical, they are not patentably distinct from each other. The claims of U.S. Pat. No. 12,195,748 describe
An apparatus for delivering a payload across a plasma membrane of a cell, the apparatus comprising:
a pneumatic generator configured to produce gas under a pressure;
an atomizer operatively coupled to the pneumatic generator and capable of forming a spray;
a reservoir configured to contain an aqueous solution, the aqueous solution including the payload; and
a valve between the pneumatic generator and atomizer, the valve switchable between a closed position for preventing the gas under the pressure from activating the atomizer and an open position for allowing the gas under the pressure to activate the atomizer to produce the spray, the spray including colloidal droplets, the valve having a switching speed less than 250 milliseconds;
wherein the atomizer is oriented towards a support capable of supporting a population of cells for contacting the population of cells with a volume of the aqueous solution.
The claims of U.S. Pat. No. 12,195,748 include similar limitations drawn to an apparatus for delivering a payload across a plasma membrane comprising a pneumatic actuator, an atomizer, a reservoir containing an aqueous solution, a valve and a support. The claims of U.S. Pat. No. 12,195,748 further require that the switching speed of the valve is less than 250 milliseconds. See, especially, claims 19-22.
Claims 100-177 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 52 and 62-72 of copending Application No. 18/509,634 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other. The claims of copending App. No. 18/509,634 describe
An apparatus for delivering a payload across a plasma membrane of a cell, the apparatus comprising:
a pneumatic generator configured to produce gas under a pressure;
an atomizer operatively coupled to the pneumatic generator and capable of forming a spray;
a reservoir configured to contain an aqueous solution, the aqueous solution including the payload; and
a valve between the pneumatic generator and atomizer, the valve switchable between a closed position for preventing the gas under the pressure from activating the atomizer and an open position for allowing the gas under the pressure to activate the atomizer to produce the spray, the spray including colloidal droplets, the valve having a switching speed less than 250 milliseconds;
wherein the atomizer is oriented towards a support capable of supporting a population of cells for contacting the population of cells with a volume of the aqueous solution.
The claims of copending App. No. 18/509,634 include similar limitations drawn to an apparatus for delivering a payload across a plasma membrane comprising a pneumatic actuator, an atomizer, a reservoir containing an aqueous solution, a valve and a support. The claims of copending App. No. 18/509,634 further require that the switching speed of the valve is less than 250 milliseconds. See, especially, claim 52.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 27 January 2026 have been fully considered but they are not persuasive.
Applicant argues that Miura does not teach a valve having a switching speed less than 250 milliseconds. Applicant states that Miura instead describes increments at which a valve speed may be set, rather than the claimed operational speeds. It is unclear specifically what distinction Applicant is making. It is believed that Applicant is saying that Miura teaches a valve that may be open for a default period of time (e.g., X.0 seconds) and that this open period may be extended as desired (i.e., “increments at which a valve speed may be set”), such that the open period may be adjusted as needed to X.1 seconds, X.2 seconds, X.3 seconds, etc., (or any added value between 0.0010 to 9.999 seconds), and that Miura does not actually provide a teaching regarding how long the transition (i.e., “switching speed”) between open to closed takes.
In response, it is again emphasized that Miura is describing the claimed switching speed. Miura expressly states that the control can “set the operation time of the solenoid valve in increments of 0.01 to 9.999 seconds”. The “operation time” of a valve refers to the valve’s ability to close or open, which is its “operation”. Miura further states that gas “is ejected together with foreign particle-carrying fine particles from the tip of the nozzle for 0.005 to 0.01 second”. Again, this refers to the time it takes to move the valve from a closed position, to an open position, and then back to a closed position (i.e., the “switching speed”). It is unclear how gas could be ejected for 0.01 seconds without the valve undergoing a full transition from closed to open and then back to closed all in 0.01 seconds. Miura further states that “the action time of an electromagnetic valve is set to about 0.001 sec with a controller 13 built in the valve”, which is believed to be a direct statement relating to switching speed (i.e., “action time”).
The Greenberg reference is additionally cited to show that the claimed switching speed is known in the art. Greenberg, for example, teaches in paragraph [0067] that gas pulses are produced, such that each gas pulse has a duration from 0 to 500 msec (“the potentiometer 618 is configured to allow a user to adjust the duration of the gas pulse, e.g., from 0 to 500 msec”).
Furthermore, a product description from a solenoid valve manufacturer (Tameson) is provided as evidence2 to show that when those of ordinary skill speak about valve switching speed, response time and operation time, they are speaking about the interval required for the valve to transition between open and closed states. This reference additionally presents a table showing how solenoid valves are often characterized by a switching speed of less than 250 msec.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATHAN ANDREW BOWERS whose telephone number is (571)272-8613. The examiner can normally be reached M-F 7am-5pm.
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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/NATHAN A BOWERS/Primary Examiner, Art Unit 1799
1 See English translation provided on 5/26/2023
2 This reference is not prior art, but rather is presented as an evidentiary reference to help interpret the “operation time” disclosed by Miura. See MPEP 2124.