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 Arguments
Applicant has cancelled claim 8 in the Remarks filed 6/30/2026.
Applicant’s arguments with respect to claims 1-7 and 12-15 filed 6/30/2026 have been considered but are moot in view of new grounds of rejections necessitated by the amendments to the claims.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-7, 9, 12, 15, and 18 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ingber et al. (US 2021/003561 A1) (hereinafter referred to as Ingber; see PTO-892).
Regarding claim 1, Ingber discloses a cell culture apparatus (abstract) comprising: one or more cell culture chambers (Fig. 2A, device 200) each comprising;
a flexible membrane (Fig. 2A-2B, body 202; [0090], body is elastomeric) comprising one or more microfluidic layers (Fig. 2A-2B, first outer body portion 204 and second outer body portion 206), each microfluidic layer independently comprises one or more microfluidic chambers, microfluidic inlets, and microfluidic outlets disposed therein (Fig. 2B, microfluidic inlets 214 and 212, microfluidic outlets 223 and 229; Fig. 2D, microfluidic chambers 252), fluidly connected through one or more porous membranes (Fig. 2B shows membrane 208 connecting inlets, outlets, and chambers), the microfluidic inlets fluidly connected to a source of one or more pressurized fluids ([0111] discloses pressurized fluid flowing through inlet 214) configured to modulate shear stress on cells through the microfluidic chambers ([0078], “Fluid pressure…can be varied to apply a desired fluid shear stress to one or both cell or tissue layers”),
the flexible membrane separating an upper chamber (Fig. 2D, mesochannel 250A) configured to provide an air-liquid interface ([0018], Fig. 5A), and a pneumatic chamber (Fig. 2D, operating chambers 252 separated from mesochannel 250A by body 202; [0019], [0111], [0117], [0135] pressurized fluid is applied to operating chambers), and being mechanically integrated with the pneumatic chamber ([0135] implicitly discloses that the body and mesochannel are mechanically integrated with operating chambers 252),
wherein the pneumatic chamber is fluidly connected to a pneumatic actuator ([0111] discloses a pressure source providing pressure via apertures 214) comprising a source of one or more pressurized fluids ([0111] implicitly discloses a pressurized fluid source), the pneumatic actuator being configured to selectively adjust the pressure in the pneumatic chamber ([0111] positive pressure or negative pressure), thereby altering the shape of the flexible membrane through mechanical stimulation ([0138] and [0146]-[0147] disclose that the shape of the channel walls, and therefore the shape of the flexible membrane, changes in response to a pressure change; Fig. 24A-24B shows a change in shape), and
wherein the cell culture apparatus is configured to generate and apply various mechanical stimuli comprising bending stress, shear stress, or a combination thereof to one or more cell types ([0017]).
Regarding claim 2, Ingber discloses the apparatus of claim 1, wherein the flexible membrane is comprised of a polymeric material comprising polycarbonate (PC), poly-methyl-meta-acrylate (PMMA), cyclic olefin copolymer (COC), polyimide, polydimethylsiloxane (PDMS), or combinations thereof ([0092] discloses the material of body 202 comprises PDMS).
Claim 2 is phrased in the alternative. Because at least one of the limitations above, e.g., PDMS, is rejected above, no further rejections are required at this time.
Regarding claim 3, Ingber discloses the apparatus of claim 2, wherein the flexible membrane is comprised of PDMS, as set forth above.
Regarding claim 4, Ingber discloses the apparatus of claim 1, wherein the flexible membrane comprises a flat, concave, and/or convex shaped curvature upon mechanical stimulation to modulate bending stress on cells ([0138] and [0146]-[0147] disclose that the shape of the channel walls, and therefore the shape of the flexible membrane, changes; Fig. 24A-24B shows the body comprising a concave shape).
Regarding claim 5, Ingber discloses the apparatus of claim 1.
Ingber implicitly discloses that the body portion may have a thickness of about 25 µm to about 250 µm.
Particularly, Ingber discloses that the height of the mesochannel can range from about 200 nm to about 2 mm ([0129]), that the first outer body portion can have a thickness that is more than the mesochannel by no more than 70 microns ([0098]), and that the second outer body portion can have a thickness of about 50 µm to about 10 mm ([0099]). Ingber shows in Fig. 2D that the thickness of the body portion is the combined height of the first outer body portion and second outer body portion. Therefore, Ingber implicitly discloses that the thickness of the body can have a thickness of about 70 µm to about 15 mm.
It has been held that the prior art anticipates the claimed range when the prior art range overlaps or touches the claimed range (MPEP § 2131.03).
Regarding claim 6, Ingber discloses the apparatus of claim 1, wherein each of the one or more cell culture chambers comprises an extracellular matrix layer comprising a hydrogel selected from the group consisting of collagen, elastin, alginate, and combinations thereof disposed on the flexible membrane ([0223] and [0302]-[0303]).
Regarding claim 7, Ingber discloses the apparatus of claim 6, further comprising one or more perfusion channels, perfusion channel inlets, and perfusion channel outlets (Fig. 2D, perfusion channels 250A and 250B; Fig. 2B, perfusion channel inlets 211 and 218, perfusion channel outlets 212 and 220) each fluidly connected to the hydrogel (Fig. 2B shows inlets, outlets, and channels connected to membrane, which has the hydrogel layer as described above).
The limitation “configured to deliver one or more liquid fluids to the hydrogel” is directed toward the intended manner of operating the claimed perfusion channels, perfusion channel inlets, and perfusion channel outlets and does not differentiate the claimed perfusion channels, perfusion channel inlets, and perfusion channel outlets from the prior art perfusion channels, perfusion channel inlets, and perfusion channel outlets because all structural limitations are taught in the prior art (MPEP § 2114 II). The noted prior art elements would be fully capable of achieving every claimed intended use because the prior art structure is substantially identical to the claimed structure, absent clear evidence to the contrary and absent a showing of unexpected results (MPEP § 2112.01 I).
Regarding claim 9, Ingber discloses the apparatus of claim 1, wherein at least one of the one or more microfluidic chambers further comprises an extracellular matrix layer comprising a hydrogel selected from the group consisting of collagen, elastin, alginate, and combinations thereof ([0223] and [0302]-[0303]).
Regarding claim 12, Ingber discloses the apparatus of claim 1, wherein the one or more pressurized fluids of the pneumatic actuator comprise air, liquid, or a combination thereof ([0017], “desired fluid (e.g., air and/or liquid)”).
Regarding claim 15, Ingber discloses the apparatus of claim 1, wherein the pneumatic chamber is fluidly connected to the pneumatic actuator through an interface component (Fig. 2B, outer body portion 204) comprising: one or more interface inlets (Fig. 2B, apertures 217) configured to receive the one or more pressurized fluids from the pneumatic actuator ([0111]); one or more interface channels (Fig. 2B, space between 217 and 214); one or more interface outlets (Fig. 2B, apertures 223) configured to apply the one or more pressurized fluids to the pneumatic chamber ([0111]); and one or more chamber portion outlets (Fig. 2B, outlet aperture 215).
Regarding claim 18, Ingber discloses the apparatus of claim 1.
Ingber further discloses the apparatus comprising one or more pluralities of cell culture chambers each comprising multiple pneumatic chambers fluidly connected through one or more channels independent from other pluralities of cell culture chambers, and each comprising selectively adjusted pressures generated from the pneumatic actuator independent from other pluralities of cell culture chambers ([0297] describes multiplexing multiple of device 200; Fig. 20 shows an example of multiplexing multiple of device 200; [0400]).
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.
Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Ingber in view of Hansen et al. (US 2018/0163166 A1) (hereinafter referred to as Hansen, previously presented).
Regarding claim 10, Ingber discloses the apparatus of claim 1.
Ingber is silent to a syringe pump fluidly connected to at least one of the one or more microfluidic inlets or microfluidic outlets, the syringe pump comprising a source of one or more pressurized liquid fluids and configured to modulate shear stress on cells through the microfluidic chambers.
However, Hansen in the art of microfluidic cell cultures teaches it is known in the art to use syringe pumps to control flow rates of microfluidic devices ([0285], lines 37-41) and that syringe pumps comprise a source of one or more pressurized liquid fluids ([0282], lines 52-56 discloses that the syringe contains liquid medium and acts as pump; Fig. 5, syringe 19 comprises a fluid which is pressurized upon use).
It would have been obvious to one of ordinary skill in the art to modify the apparatus of modified Redaelli et al. to incorporate a syringe pump fluidly connected to at least one of the one or more microfluidic inlet or microfluidic outlets to control the flow rate and to further comprise a source of one or more pressurized liquid fluids to provide media, to the apparatus, as Hansen shows that such elements are known in the art for the same or similar purpose.
The limitation “configured to modulate shear stress on cells through the microfluidic chambers” is directed toward the intended manner of operating the claimed apparatus and does not differentiate the claimed apparatus from the prior art apparatus because all structural limitations are taught in the prior art apparatus (MPEP §2114 II). The syringe pump and source of one or more pressurized fluids of Hansen would be fully capable of achieving every claimed intended use because Hansen discloses that medium exchange results in a shear stress exerted on cell chambers ([0285]-[0286], [0289]).
Regarding claim 11, the prior art combination teaches the apparatus of claim 10.
The prior art combination does not expressly disclose wherein the syringe pump generates liquid fluid flow rates ranging from about 50 µL/sec to about 150 µL/sec through the microfluidic chambers.
Hansen discloses that shear stress exerted on cells in a microfluidic chamber is a result of different flow rates through adjacent flow channels ([0285]; Fig. 3 shows flow channels with chambers). Hansen further discloses that flow rates may be adjusted depending on the cell types being used ([0285]).
Ingber of the prior art combination discloses that shear stress on cells is induced by subjecting cells to fluid flow ([0012]) and that fluid flow can be varied to apply a desired fluid shear stress on cells ([0078]).
It has been held that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation, when the particular parameter is recognized as a result-effective variable (MPEP § 2144.05). Hansen of the prior art combination discloses the general conditions for using a syringe pump to generate liquid flow rates (Hansen: [0285]) and both Ingber and Hansen of the prior art combination disclose that the parameter is a result-effective variable. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to discover an optimum or workable range for the liquid flow rate generated by the prior art syringe pump by routine experimentation.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Ingber in view of Redaelli et al. (US 2018/0105782 A1) (hereinafter referred to as Redaelli, previously presented).
Regarding claim 13, Ingber discloses the apparatus of claim 1.
Ingber is silent to a range of fluid pressures generated by the pneumatic actuator.
However, Redaelli in the art of microfluidic cell culturing devices discloses that it is known in the art for a pneumatic actuator to generate fluid pressures ranging from about 5 kPa to about 50 kPa through the pneumatic chamber. Particularly, Redaelli discloses that the pressure within the actuation chamber (i.e., pneumatic chamber) during pressurization caused by an actuator (e.g., pneumatic, [0210]) is between 0.01 atm and 10 atm, most preferably 0.5 atm, which is equivalent to between 1.01325 kPa and 1013.25 kPa, most preferably 50.6 kPa ([0083]).
Ingber of the prior art combination discloses that fluid pressure can be varied to apply desired fluid shear stresses on cells ([0017], [0078]) and to mimic a physiological fluid pressure ([0131]).
It has been held that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation, when the particular parameter is recognized as a result-effective variable (MPEP § 2144.05). Redaelli discloses the general conditions for generating a range of fluid pressures using a pneumatic actuator and Ingber discloses that the parameter is a result-effective variable. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to discover an optimum or workable range for the fluid pressures generated by the pneumatic actuator by routine experimentation.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Ingber.
Regarding claim 14, Ingber discloses the apparatus of claim 1.
Ingber of the prior art combination discloses that a range of frequencies applied by a pressure source can be varied to mimic different mechanical movements ([0087]). Ingber further discloses that cell differentiation and maturation is dependent on frequency of mechanical strain, e.g., a frequency of about 0 Hz to about 1 Hz ([0027]) and that physiological mechanical strain can generated by the flow of fluids, i.e., a pneumatic actuator ([0181] and [0369]).
It has been held that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation, when the particular parameter is recognized as a result-effective variable (MPEP § 2144.05). Ingber discloses the general conditions for a range of frequencies generated by a pneumatic actuator and further discloses that the parameter is a result-effective variable. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to discover an optimum or workable range for the frequency of fluid pressure generated by the pneumatic actuator by routine experimentation.
Claims 16 and 17 is rejected under 35 U.S.C. 103 as being unpatentable over Ingber in view of Hung et al. (US 2012/0003732 A1) (hereinafter referred to as Hung, previously presented).
Regarding claim 16, Ingber discloses the apparatus of claim 15.
Ingber is silent to the interface component further comprising one or more apertures defining one or more cell culture chambers.
However, Hung in the art of microfluidic cell culturing teaches it is known in the art to form an interface component comprising one or more apertures defining the one or more cell cultures chambers (Fig. 5, well layer 503 defines one or more upper reservoirs 505 and one or more lower reservoirs 504; [0127] teaches the reservoirs are for culturing cells – see annotated figure below).
PNG
media_image1.png
216
675
media_image1.png
Greyscale
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 interface component of Ingber to further comprise one or more apertures defining one or more cell culture chambers because Hung teaches that the claimed element of an interface component is known in the art, and would predictably improve efficiency by increasing holding capacity.
Regarding claim 17, the prior art combination teaches the apparatus of claim 15.
PNG
media_image2.png
198
242
media_image2.png
Greyscale
Hung of the prior art combination further discloses a base component connecting the one or more cell culture chambers to the interface component (Fig. 4B, glass slide – see figure below).
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 prior art combination apparatus to further comprise a base component because Hung teaches that the claimed base component is known in the art, and the modification would predictably provide support for the device.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ADRIAN J CARREON whose telephone number is (571)272-6818. The examiner can normally be reached Monday - Friday 8:30 AM - 5 PM.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/A.J.C./Examiner, Art Unit 1799
/William H. Beisner/Primary Examiner, Art Unit 1799
Prosecution Insights