Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
The Amendment filed 09/09/2026 has been entered. Claims 1 and 6-21 remain pending in the application. Claims 10-19 are withdrawn. New grounds of rejections necessitated by amendments are discussed below.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 6-8, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Fernandez-Nieves et al. (US 20170361534 A1; cited in the IDS filed 12/30/2021) in view of Kumagai et al. (US 20210062132 A1; effectively filed 01/29/2018), Sun et al. (CN 107028681 A; see machine translation), Angelini et al. (US 20180021140 A1) and Kwak et al. (Kwak et al., “Microfabrication of Custom Collagen Structures Capable of Guiding Cell Morphology and Alignment”, Biomacromolecules 2015, 16, 1761−1770).
Regarding claim 1, Fernandez-Nieves teaches a cellular micro-masonry system (abstract, “apparatus for three-dimensionally printing”; paragraphs [0007]-[0008]), comprising:
a translation system comprising a placement device (Fig. 5 teaches a micro-capillary with a tip in the XYZ axes), wherein the placement device is a micro-capillary (paragraph [0103] teaches the 3D extrusion system comprising extrusion nozzles; paragraph [0063] and Fig. 5 teaches a micro-capillary, controlled in the XYZ axes, therefore the micro-capillary is part of the translation system) and comprises a shaft and a tip (Fig. 5 shows manipulation of a micro-capillary including a shaft and a tip in the XYZ axes), wherein the translation system approaches a cell in a 3D cell culture medium (interpreted as an intended use, see MPEP 2114; note that “cell in a 3D cell culture medium” is not positively recited structurally; Fig. 5 shows manipulation of a micro-capillary in the XYZ axes, which is structurally capable of approaching a cell in a 3D cell culture medium at a later time since the micro-capillary can move in XYZ axes; paragraph [0077] teaches 3D cell-encapsulating matrices or scaffolds; Fig. 5 and paragraph [0063] teach granular gel support medium), and wherein the translation system provides three cartesian translational degrees of freedom (X, Y, Z) (Fig. 5; paragraph [0103] teaches an XYZ stage, therefore provides three cartesian translational degrees of freedom); and
an imaging system (paragraphs [0088],[0098], [0103]-[0104],[0112] teaches imaging; paragraph [0110] teaches confocal microscopy; therefore, the system includes an imaging system in order to perform imaging and confocal microscopy);
wherein the three-dimensional (3D) cell culture medium (interpreted as an intended use of the translation system, see MPEP 2114; note that “3D cell culture medium” is not positively recited structurally, however, for compact prosecution purposes, paragraph [0077] teaches 3D cell-encapsulating matrices or scaffolds; Fig. 5 and paragraph [0063] granular gel support medium) comprises a plurality of hydrogel particles (paragraph [0077], “hydrogel particles”) and a liquid cell culture medium (paragraphs [0041],[0050], [0077], teaches cell growth medium is used as a solvent for aqueous microgels or hydrogels), wherein the hydrogel particles are swelled with the liquid cell culture medium to form a granular gel (paragraph [0077] teaches when disposed in a solution, hydrogel particles will swell with the solvent and form a granular gel material; paragraph [0110] teaches microgels are swelled);
wherein the 3D culture medium (paragraph [0077] teaches 3D cell-encapsulating matrices or scaffolds include hydrogels and hydrogel particles; Fig. 5a shows a soft granular gel medium) has a yield stress such that the 3D cell culture medium (i.e. 3D cell culture medium) undergoes a temporary phase change from a first solid phase to a second liquid phase upon application of a shear stress greater than the yield stress (interpreted as a functional limitation of the 3D culture medium, see MPEP 2114; paragraph [0098] teaches yield stress materials are solid when applied stress is below the yield stress and fluidize when stresses exceed the yield stress; paragraph [0083] teaches hydrogels include microgels, and yield stress can be varied and tuned; paragraphs [0036]-[0037],[0040],[0062] teaches the material is suitable for temporary phase change; paragraph [0063] and Fig. 5 teaches a granular gel support medium, where the soft granular gel medium is a yield stress material that fluidize at high strains; Fig. 5c shows a yield stress that causes the soft granular gel medium to undergo a phase change from a solid phase, i.e. elastic, to a liquid phase, i.e. yielded fluid).
and wherein the tip of the placement device (Fig. 5 shows manipulation of a micro-capillary with a tip in the XYZ axes) causes the temporary phase change in the 3D cell culture medium to accommodate engagement and placement of the cell in the 3D cell culture medium (interpreted as an intended use of the tip, see MPEP 2114; paragraphs [0067]-[0068] and Fig. 2 teach the movement of the tip causes hydrogel particles of the 3D cell growth medium to fluidize, which is capable of accommodating engagement and placement of cell, e.g. injection of cells, in the 3D cell growth medium).
While Fernandez-Nieves teaches the translation system comprises a computer-controlled syringe pump (paragraph [0103]) and a container for three dimensional cell culture (paragraph [0007]), Fernandez-Nieves fails to teach: wherein a diameter of the shaft is 1 mm and wherein a diameter of the tip is 5 μm; the translation system engages the cell, and translates the cell to a desired location in the 3D cell culture medium; and the translation system provides one radial degree of freedom (R), one azimuthal degree of freedom (Φ), and one polar degree of freedom (θ).
Kumagai teaches a cell transfer device comprising a container accommodating a plurality of cells, and a head with a suction tip that sucks cells (abstract). Kumagai teaches that for research applications, image capturing processing of cells or cell clusters and a treatment of sucking cells and transferring the cells to other locations may be required (paragraph [0003]). Kumagai teaches when cells are placed in a gel-like culture medium, cells are often placed three-dimensionally (paragraph [0005]). Kumagai teaches a culture medium can include a gel-like culture medium capable of three-dimensionally culturing cells, the gel-like culture can include hydrogels (paragraphs [0030],[0033]). Kumagai teaches an embodiment comprising observation of a biological subject with a camera, suction of the biological subject using a tip and transferring and discharging the biological sample, wherein transfer by suction is from a cell transfer device (paragraph [0019]). Kumagai teaches the cell transfer device allows for suction of a cell and transferring the cell to a predetermined location (paragraph [0022]), wherein before suction, the cells are captured by a camera unit for a sorting operation of good quality cells (paragraph [0022]). Kumagai teaches a suction control unit specifies suction position of a cell based on XYZ coordinates (paragraphs [0052]-[0053]).
Since Kumagai teaches a system for processing cells relating to three-dimensional culturing and 3D hydrogels for culturing (abstract; paragraphs [0003],[0005],[0030],[0033]) similar to Fernandez-Nieves, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the translation system of Fernandez-Nieves to incorporate the teachings of sucking and transferring cells at desired positions based on XYZ coordinates for research applications of Kumagai (paragraphs [0003],[0019],[0022], [0052]-[0053]) to provide: the translation system engages the cell, and translates the cell to a desired location in the 3D cell culture medium. Doing so would have a reasonable expectation of successfully improving control, manipulation, and positioning of cells and thus improve additional research of cells or cell clusters in a 3D cell culture medium as discussed by Kumagai (paragraph [0003]).
Furthermore, the claimed limitations are obvious because all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements (i.e. the claimed translation system and 3D cell culture medium and a translation system that approaches, engages, and translates a cell to a location in a 3D cell culture medium) by known methods with no change in their respective functions (i.e. approaching, engaging, translating a cell in a 3D cell culture medium), and the combinations yielded nothing more than predictable results (i.e. providing the translation system to additionally engage the cell, and translate the cell to a desired location in the 3D cell culture medium would yield nothing more than the obvious and predictable result of enabling improved control, manipulation, and positioning of cells and thus improve additional research of cells or cell clusters in a 3D cell culture medium as discussed by Kumagai (paragraph [0003]). See MPEP 2143(A).
Modified Fernandez-Nieves fails to teach: wherein a diameter of the shaft is 1 mm and wherein a diameter of the tip is 5 μm; the translation system provides one radial degree of freedom (R), one azimuthal degree of freedom (Φ), and one polar degree of freedom (θ).
Sun teaches a 3D printing device for a tissue engineering scaffold (paragraph [0002]). Sun teaches the combination of a printing robot arm and printing platform has at least 3 degrees of freedom of movement and can freely move and grasp a nozzle (paragraph [0058]). Sun teaches that a total of 6 degrees of freedom which meets the needs of omnidirectional movement and can more freely shape the concave and inclined structures in the printing bracket (paragraph [0058]). Sun teaches the printing arm with two additional rotational degrees of freedom and the printing platform with one additional rotational degree of freedom facilitates the omnidirectional printing and spraying of the tissue engineering scaffold, and thus improves the printing effect of the inclined structure, and can perform the printing and spraying process evenly and conveniently (paragraph [0074]). Sun teaches the printing module has 3 translational degrees of freedom and 3 rotational degrees of freedom, which is interpreted as structurally capable of provide one radial degree of freedom, one azimuthal degree of freedom, and one polar degree of freedom, and thus has high printing flexibility (paragraph [0079]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the translation system of Fernandez-Nieves to incorporate the teachings of 6 degrees of freedom for a 3D printing device of Sun (paragraphs [0058],[0074],[0079]) to provide the translation system is configured to provide the translation system provides one radial degree of freedom (R), one azimuthal degree of freedom (Φ), and one polar degree of freedom (θ). Doing so would have a reasonable expectation of successfully allowing for omnidirectional movement of the translation system, thus improving printing flexibility of the overall system as taught by Sun (paragraphs [0058],[0074], [0079]).
While Fernandez-Nieves teaches a glass micropipette or microcapillary with a 100 micrometer diameter tip to draw 3D structures (Fig. 5, paragraph [0088]), nozzles made from pulling and shaping glass pipettes to have control over the nozzle diameter and shape (paragraph [0103]), and the pipette has a shaft that decreases in diameter towards the tip (Fig. 5), modified Fernandez-Nieves fails to teach: wherein a diameter of the shaft is 1 mm and wherein a diameter of the tip is 5 μm.
Angelini teaches an apparatus for creating three-dimensional tissue construct by injecting biomaterial in a three-dimensional pattern into a material with translation system comprising a placement device including a microcapillary (abstract; Figs. 10-11). Angelini teaches the three-dimensional writing instrument composed of a syringe pump for injecting material into the GGM, and three linear translation stages that provide relative motion to the injection tip; and injection tips with an inner diameter of 50 μm may be made out of glass microcapillaries, 1 mm inner diameter, i.e. shaft, using a pipette puller (paragraph [0209]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the diameter of the shaft of modified Fernandez-Nieves to incorporate Fernandez-Nieves’s teachings of pulling and shaping glass pipettes to have control over the nozzle diameter and shape (paragraph [0103]) and Angelini’s teachings of a microcapillary for three-dimensional writing that is made out of glass microcapillaries, 1 mm inner diameter, i.e. shaft, using a pipette puller (paragraph [0209]) to provide: wherein a diameter of the shaft is 1 mm. Doing so would have a reasonable expectation of successfully shaping a glass microcapillary to have control over the tip diameter and shape from a 1mm diameter shaft as taught by Angelini.
While Fernandez-Nieves teaches a glass micropipette or microcapillary with a 100 micrometer diameter tip to draw 3D structures (Fig. 5, paragraph [0088]), nozzles made from pulling and shaping glass pipettes to have control over the nozzle diameter and shape (paragraph [0103]), and the pipette has a shaft that decreases in diameter towards the tip (Fig. 5), modified Fernandez-Nieves fails to teach: wherein a diameter of the tip is 5 μm.
Kwak teaches new fabrication techniques for custom collagen patterns, and biomaterial fabrication requires improved techniques for tailoring nano/microstructured patterns (abstract). Kwak teaches extrusion guided microfabrication technique using a microcapillary (Fig. 1a). Kwak teaches 1mm outer diameter borosilicate capillaries were processed to have 5 μm tips using a micropipette puller (page 1762, section “Direct Writing with Collagen…”). Kwak teaches when increasing the tip diameter to 5 μm, it was possible to extrude collagen patterns with larger feature sizes corresponding to the approximate size of the capillary tip diameter in use (page 1764, left column, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the diameter of the tip of modified Fernandez-Nieves to incorporate Fernandez-Nieves’s teachings of pulling and shaping glass pipettes to have control over the nozzle diameter and shape (paragraph [0103]) and Kwak’s teachings of microcapillaries with a 5 μm tips (page 1762, section “Direct Writing with Collagen…”) to provide: wherein a diameter of the tip is 5 μm. Doing so would have a reasonable expectation of successfully shaping the tip to have control over the tip diameter to improve extrusion of patterns with desired sizes as taught by Kwak.
Additionally, since Kwak teaches a micro-capillary with a tip diameter of 5 μm (page 1762, section “Direct Writing with Collagen…”), wherein 5 μm overlaps with the claimed tip diameter of 5 μm, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the diameter of the tip of modified Fernandez-Nieves to provide wherein a diameter of the tip is 5 μm. I.e., it would have been prima facia obvious to have selected the overlapping portion of the range (i.e. 5 μm) from the taught range of 5 μm (Kwak, page 1762, section “Direct Writing with Collagen…”) (In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); see MPEP 2144.05 (I)).
Note that “a cell in a 3D cell culture medium” and the specific “3D cell culture medium” are not positively recited structurally and is interpreted as a functional limitation of the claimed system. A claim is only limited by positively recited elements; thus, inclusion of the material or article (“cell”, “3D cell culture medium”) worked upon by a structure (cellular micro-masonry system) being claimed does not impart patentability to the claims (see MPEP 2115).
Note that “cellular micro-masonry”, “approaches a cell in a 3D cell culture medium, engages the cell, and translates the cell to a desired location in the 3D cell culture medium”, “provides three cartesian translation degrees of freedom…”, “undergoes a temporary phase change…”, “causes the temporary phrase change…to accommodate the engagement with and placement of the cell…” are interpreted as intended uses and functional limitations of the claimed system. A recitation of intended uses and functional limitations of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended uses and functional limitations, then it meets the claim. MPEP 2114. In this case the system of modified Fernandez-Nieves comprises all of the elements of claim 1, and therefore is identical to the presently claimed structure. Modified Fernandez-Nieves discloses the claimed translation system, imaging system, and 3D cell culture medium as claimed and therefore, would have the ability to perform the intended uses and functional limitations recited in the claim. See MPEP 2112.01 (I).
Regarding claim 6, Fernandez-Nieves further teaches wherein the concentration of the hydrogel particles is between 0.05% to about 1.0% by weight (paragraph [0077], “approximately 0.5% to 1% hydrogel particles by weight”).
Regarding claim 7, Fernandez-Nieves further teaches wherein the hydrogel particles have a size between about 0.1 um to about 100 um when swollen with the liquid cell culture medium (paragraph [0077]).
Regarding claim 8, Fernandez-Nieves further teaches wherein the 3D cell culture medium further comprises one or more extracellular matrix components (paragraph [0041] teaches 3D structures with supplemental extracellular matrix material; paragraphs [0064]-[0065] teaches a second material is injected into the first material, i.e. 3D cell culture medium, wherein the second material comprise extracellular matrix materials).
Regarding claim 21, Fernandez-Nieves further teaches wherein the translation system is further configured to provide suction, pressure, or both suction and pressure (Fig. 14 and paragraph [0103] teaches the 3D extrusion system comprises a computer-controlled syringe pump, the syringe pump coupled to the translation system; therefore, Fernandez-Nieves’ computer-controlled syringe pump is configured to at least provide pressure).
In an alternative interpretation of claim 8, claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Fernandez-Nieves in view of Kumagai, Sun, Angelini, and Kwak as applied to claim 1 above.
Regarding claim 8, if it is determined that Fernandez-Nieves fails to explicitly teach an embodiment wherein the 3D cell culture medium further comprises one or more extracellular matrix components, Fernandez-Nieves teaches that cells can be printed into 3D structures either with or without supplemental extracellular matrix material (paragraph [0041]). Fernandez-Nieves teaches a second material is injected into the first material, i.e. 3D cell culture medium, wherein the second material comprise extracellular matrix materials (paragraphs [0064]-[0065]). Fernandez-Nieves teaches further components may be added to a carrier fluid to render a silicone surface bioactive, such as collagen (paragraph [0076]). Fernandez-Nieves teaches other materials for a 3D matrix can include collagen (paragraph [0082]). Fernandez-Nieves teaches an example of collagen with a hydrogel (paragraph [0112]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the 3D cell culture medium of modified Fernandez-Nieves to incorporate the various teachings of including extracellular matrix components, such as collagen, to 3D structures of modified Fernandez-Nieves (paragraphs [0041],[0064]-[0065], [0082], [0112]) to provide wherein the 3D cell culture medium further comprises one or more extracellular matrix components. Doing so would have a reasonable expectation of successfully improving bioactivity and cell attachment and growth within the 3D culture medium, as discussed by Fernandez-Nieves (paragraphs [0041],[0076]).
Claims 9 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Fernandez-Nieves in view of Kumagai, Sun, Angelini, and Kwak as applied to claim 1 above, and further in view of Vatankhah-Varnoosfaderani et al. (Vatankhah-Varnoosfaderani et al., “Well-Defined Zwitterionic Microgels: Synthesis and Application as Acid-Resistant Microreactors”, Macromolecules 2016, 49, 7204-7210).
Regarding claim 9, while Fernandez-Nieves teaches exemplary materials for 3D matrices include poly(acrylamide), poly(ethylene glycol diacrylate), and poly(acrylic acid) (paragraph [0082]), modified Fernandez-Nieves fails to teach wherein the hydrogel particles are comprised of zwitterionic microgels.
Vatankhah-Varnoosfaderani teaches applications of zwitterionic microgels (abstract). Vatankhah-Varnoosfaderani teaches that hydrogel particles, or microgels, display a wide range of practical applications (page 7204, left column, first paragraph), and that adding zwitterionic functionality will significantly enhance these applications by imparting microparticles with many desirable features such as antifouling, high saline uptake, pH sensitivity, and antipolyelectrolyte effect (page 7204, left column, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the hydrogel particles of modified Fernandez-Nieves to incorporate the teachings of hydrogel microparticles, specifically zwitterionic microgels, of Vatankhah-Varnoosfaderani (abstract; page 7204, left column, first paragraph) to provide wherein the hydrogel particles are comprised of zwitterionic microgels. Doing so would have a reasonable expectation of successfully enhancing application of the hydrogel particles, such as imparting desirable features such as antifouling, high saline uptake, pH sensitivity, and antipolyelectrolyte effect as taught by Vatankhah-Varnoosfaderani (page 7204, left column, first paragraph).
Regarding claim 20, while Fernandez-Nieves teaches exemplary materials for 3D matrices include poly(acrylamide), poly(ethylene glycol diacrylate), and poly(acrylic acid) (paragraph [0082]), modified Fernandez-Nieves fails to teach wherein the 3D cell culture media medium comprises zwitterionic microgels.
Vatankhah-Varnoosfaderani teaches applications of zwitterionic microgels (abstract). Vatankhah-Varnoosfaderani teaches that hydrogel particles, or microgels, display a wide range of practical applications (page 7204, left column, first paragraph), and that adding zwitterionic functionality will significantly enhance these applications by imparting microparticles with many desirable features such as antifouling, high saline uptake, pH sensitivity, and antipolyelectrolyte effect (page 7204, left column, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the 3D cell culture media medium of modified Fernandez-Nieves to incorporate the teachings of hydrogel microparticles, specifically zwitterionic microgels, of Vatankhah-Varnoosfaderani (abstract; page 7204, left column, first paragraph) to provide wherein the 3D culture media medium comprises zwitterionic microgels. Doing so would have a reasonable expectation of successfully enhancing application of the hydrogel particles, such as imparting desirable features such as antifouling, high saline uptake, pH sensitivity, and antipolyelectrolyte effect as taught by Vatankhah-Varnoosfaderani (page 7204, left column, first paragraph).
Response to Arguments
Applicant’s arguments, see pages 5-7, filed 09/09/2026, with respect to the rejection(s) of claims 1, 3, 6-9, 20-21 under 35 U.S.C. 103, specifically regarding amended claim 1 and the limitation of “a diameter of the shaft is 1 mm and wherein a diameter of the tip is 5 μm”, have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Fernandez-Nieves et al. (US 20170361534 A1; cited in the IDS filed 12/30/2021) in view of Kumagai et al. (US 20210062132 A1; effectively filed 01/29/2018), Sun et al. (CN 107028681 A; see machine translation), Angelini et al. (US 20180021140 A1) and Kwak et al. (Kwak et al., “Microfabrication of Custom Collagen Structures Capable of Guiding Cell Morphology and Alignment”, Biomacromolecules 2015, 16, 1761−1770).
Applicant's arguments, see pages 6-7, filed 09/09/2026, with respect to the combination of Fernandez-Nieves and Kumagai and Sun, have been fully considered but they are not persuasive.
In response to applicant’s and Declaration’s argument that, as evidenced by Ellison, a capillary tip does not approach the correct position for engaging a cell, thus incorporating Kumagai’s mechanism would not be reasonably expected to succeed in Fernandez-Nieves’ support mechanism, since the capillary insertion would cause the cells to move; and therefore the combination would not provide the claimed invention (Remarks, page 6, paragraphs 2-3; Declaration, sections 7-8), the examiner disagrees.
In response to applicant's arguments against the references individually, specifically applicant’s arguments that Kumagai does not retrieve cells from a granular gel, yield-stress medium, and does not appreciate the technical difficulties involved with the same (Remarks, page 6, third full paragraph), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As discussed by the applicant (Remarks, page 6, third full paragraph), the examiner agrees that Kumagai is silent with respect to the claimed granular gel that has a yield stress. However, Fernandez-Nieves is used to teach the claimed granular gel and medium with a yield stress. Additionally, note that as claimed, the 3D cell culture medium is not positively recited structurally and is a functional limitation of the translation system.
The examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Additionally, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In this case, Kumagai is used in combination with Fernandez-Nieves to arrive at the claimed “the translation system engages the cell, and translates the cell to a desired location in the 3D cell culture medium”.
Kumagai provides teachings and suggestions of a system for processing cells relating to three-dimensional culturing (abstract; paragraphs [0003],[0005],[0030],[0033]), and specifically using a gel-like culture medium for three-dimensionally culturing cells (paragraphs [0030],[0033]). Fernandez-Nieves provides teachings, relating to culturing within the culture medium, of sucking and transferring cells for research applications of Kumagai (paragraphs [0003],[0019],[0022], [0052]-[0053]) and a suction control unit specifies suction position of a cell based on XYZ coordinates (paragraphs [0052]-[0053]). Fernandez-Nieves provides a desire and motivation: for research applications, image capturing processing of cells or cell clusters and a treatment of sucking cells and transferring the cells to other locations may be required (paragraph [0003]).
Since Kumagai teaches a system for processing cells relating to three-dimensional culturing and 3D hydrogels for culturing (abstract; paragraphs [0003],[0005],[0030],[0033]) similar to Fernandez-Nieves, it would have been obvious to one of ordinary skill in the art to have modified the translation system of Fernandez-Nieves to incorporate the teachings of sucking and transferring cells at desired positions based on XYZ coordinates for research applications of Kumagai (paragraphs [0003],[0019],[0022], [0052]-[0053]) to provide: the translation system engages the cell, and translates the cell to a desired location in the 3D cell culture medium. Doing so would have a reasonable expectation of successfully improving control, manipulation, and positioning of cells and thus improve additional research of cells or cell clusters in 3D cell culture medium as discussed by Kumagai (paragraph [0003]).
Therefore, there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art to have modified Fernandez-Nieves’ translation system with the teachings of Kumagai to provide the translation system capable of engaging the cell, and translating the cell to a desired location in 3D cell culture medium to improve control and manipulation of cells and thus improve additional research of cells or cell clusters with a reasonable expectation of success, i.e. providing “the translation system engages the cell, and translates the cell to a desired location in the 3D cell culture medium”.
In response to applicant’s argument that “without a working translation system for individual cell placement, the combination of Fernandez-Nieves, Kumagai, and Sun may be interpreted as suggesting a general idea that cells could be placed individually but does not provide any mechanism by which to do so that will function as intended in a granular gel, yield stress medium, which requires the specific claimed microcapillary placement device as recited in amended claim 1” (Remarks, page 6, last paragraph), the examiner disagrees. As discussed above, upon further consideration, a new ground(s) of rejection is made in view of Fernandez-Nieves et al. (US 20170361534 A1; cited in the IDS filed 12/30/2021) in view of Kumagai et al. (US 20210062132 A1; effectively filed 01/29/2018), Sun et al. (CN 107028681 A; see machine translation), Angelini et al. (US 20180021140 A1) and Kwak et al. (Kwak et al., “Microfabrication of Custom Collagen Structures Capable of Guiding Cell Morphology and Alignment”, Biomacromolecules 2015, 16, 1761−1770). Specifically, as discussed in the new rejection of claim 1 under 35 U.S.C. 103, modified Fernandez-Nieves teaches the cellular micro-masonry system comprising the translation system including the microcapillary placement device and the imaging system as claimed, i.e. modified Fernandez-Nieves teaches the specific claimed microcapillary placement device as recited in amended claim 1.
Further, regarding applicant's argument that the combination of prior art “does not provide any mechanism by which to do so that will function as intended in a granular gel, yield stress medium, which requires the specific claimed microcapillary placement device as recited in amended claim 1” (Remarks, page 6, last paragraph), a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. MPEP 2114. In this case the system of modified Fernandez-Nieves comprises all of the elements of claim 1, and therefore is identical to the presently claimed structure. Modified Fernandez-Nieves discloses the claimed translation system and imaging system as claimed and therefore, would have the ability to perform the intended uses and functional limitations recited in the claim. See MPEP 2112.01 (I).
Additionally, note that “a cell in a 3D cell culture medium” are not positively recited structurally and is interpreted as a functional limitation of the claimed system. A claim is only limited by positively recited elements; thus, inclusion of the material or article (“a cell in a 3D cell culture medium”) worked upon by a structure (e.g. tip of the placement device) being claimed does not impart patentability to the claims (see MPEP 2115).
In response to applicant’s discussion that “as seen in the declaration and accompanying reference referred to above, reducing the present invention to practice was not trivial but required a great deal of experimentation and refinement” (remarks, page 6, last paragraph- page 7, first paragraph), the examiner acknowledges the comment. However, as discussed in the new rejection of claim 1 under 35 U.S.C. 103, modified Fernandez-Nieves teaches the cellular micro-masonry system comprising the translation system including the microcapillary placement device and the imaging system as claimed.
In response to applicant’s arguments regarding claims 8, 9 and 20 (Remarks, page 7), the examiner notes that the arguments are tantamount to indicating that claims 8,9 and 20 stand or fall with claim 1. The examiner agrees for the same reasons as discussed above regarding amended claim 1 and the limitation of “a diameter of the shaft is 1 mm and wherein a diameter of the tip is 5 μm”. Therefore, the rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Fernandez-Nieves et al. (US 20170361534 A1; cited in the IDS filed 12/30/2021) in view of Kumagai et al. (US 20210062132 A1; effectively filed 01/29/2018), Sun et al. (CN 107028681 A; see machine translation), Angelini et al. (US 20180021140 A1) Kwak et al. (Kwak et al., “Microfabrication of Custom Collagen Structures Capable of Guiding Cell Morphology and Alignment”, Biomacromolecules 2015, 16, 1761−1770), and Vatankhah-Varnoosfaderani et al. (Vatankhah-Varnoosfaderani et al., “Well-Defined Zwitterionic Microgels: Synthesis and Application as Acid-Resistant Microreactors”, Macromolecules 2016, 49, 7204-7210).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Blanchard (US 20180087021 A1) teaches automated cell culture incubators comprising an integrated manipulation (abstract). Blanchard teaches a manipulator can include a cell picker for manipulating cells by detecting desirable cells at a first location based on a predetermined criterion and transferring the cells from the first location to a second location in the cell culture vessel, wherein an imager may image cells to identify desirable or undesirable cells (paragraph [0061]). Blanchard teaches an imager may image cells in or on a cell culture vessel at an imaging location, and the image used to identify desirable or undesirable cells or groups thereof; and the cell picker may then transfer the desirable or undesirable cells, e.g., by contacting each desired cell or cells with a needle, capillary, pipette, or micromanipulator and effecting a movement of the cell or cells, from their first location to a second location in the cell culture vessel (paragraph [0061]). Blanchard teaches cell culture vessels for culturing cells in suspension includes hydrogels (paragraph [0104]).
Martinez et al. (US 20210031434 A1; effectively filed 04/11/2018; cited in the OA filed 03/19/2025) teaches a method and system for arranging cellular materials in hydrogel materials used in 3D bioprinting (abstract). Martinez teaches a robotic arm is configured to move in six degrees of freedom (three translational and three rotational) (paragraph [0087]). Martinez teaches a microfluidic pen may also be used to withdraw cells and/or spheroids from a construct in a predetermined pattern in a 3D extracellular environment (paragraph [0070]). Martinez teaches arranging cellular material in a bioink, gel or hydrogel material before, during and/or after 3D-bioprinting, which includes placing material in or on and/or withdrawing material from e.g. a 3D printed construct (paragraph [0075]). Martinez teaches dispensing, patterning or withdrawing cellular material in the form of single cells, spheroids or cell suspension in the bioink/gel/hydrogel layer (paragraph [0075]). Martinez teaches cellular material is dispensed, patterned, and/or withdrawn by a needle or nozzle in the bioink/gel/hydrogel material (paragraph [0079]).
Blakely et al. (Blakely et al., “Bio-Pick, Place, and Perfuse: A New Instrument for Three-Dimensional Tissue Engineering”, 2015, Tissue Engineering: Part C, Volume 21, Number 7) teaches fabrication of large constructs with a high density of living cells using a Bio-pick, Place, and perfuse instrument (abstract; Fig. 1). Blakely teaches the instrument has a head that provides suction to move a stack of living parts to a location (Fig. 1), and the movement includes x, y, and z directions (page 739, left column, second full paragraph).
Nagai et al. (Nagai et al., “Pick-and-Place Operation of Single Cell Using Optical and Electrical Measurements for Robust Manipulation”, Micromachines 2017, 8(12), 350) teaches a pick and placement operation of a single cell for sample collection wherein a glass pipette is used to trap a cell by suction to transport and release the cell at a desired location (abstract; Fig. 1). Nagai teaches a sharpened glass pipette to manipulate a single cell with an internal diameter of 3-4 microns; wherein a pipette puller was used to make a glass pipette from a glass tube with an outer diameter of 1.0 mm (section 2.3).
Sawyer et al. (US 20180142194 A1) teaches cell growth medium may comprise hydrogel particles swollen with a liquid cell growth medium to form a granular gel yield stress material which undergoes a phase transformation from a solid phase to a liquid-like phase when an applied stress exceeds the yield stress; and cells may be placed in the three-dimensional cell growth medium according to any shape or geometry, and may remain in place within the three-dimensional cell growth medium (abstract). Sawyer teaches the gentle yielding and rapid solidification behavior of this culture medium allows the unrestricted placement and retrieval of cells and cell-assemblies deep within the medium (paragraph [0022]). Sawyer teaches providing a 3D cell growth medium made from a yield stress material may enable facile placement and/or retrieval of a group cells at any desired location within the 3D growth medium; and placement of cells may be achieved by causing a solid to liquid phase change at a desired location in a region of yield stress material such that the yield stress material will flow and be displaced when cells are injected or otherwise placed at the desired location (paragraph [0028]). Sawyer teaches cells may be removed by simply moving a tip of a removal device such as a syringe or pipette to a location where a group of cells is disposed, and applying suction to draw the cells from the cell growth medium (paragraph [0038]). Sawyer teaches 3-D cell growth medium as described herein may be used in a method for three-dimensionally printing or otherwise positioning cells in a desired pattern within a 3D cell growth medium (paragraph [0069]).
Lee et al. (Lee et al., “3D bioprinting processes: A perspective on classification and terminology”, 2018, Int J Bioprint, 4(2): 151) teaches 3D bioprinting technology (abstract) that includes pick and place of spheroids using suction to pick and transfer spheroids (sections 2.4, 2.5; Fig. 6A).
Ke et al. (US 20200131383 A1) teaches 3D printing of a polymer composition (abstract). Ke teaches a print head includes a nozzle that defines a port, the port can have a diameter of a diameter of less than 20 microns, less than 15 microns, less than 12.5 microns, less than 10 microns, and less than 5 microns (paragraph [0160]).
Ghoshi et al. (US 20200197179 A1; effectively filed 04/27/2017) teaches 3D printed constructs for accommodating cells (abstract). Ghoshi teaches 3D printing with a nozzle diameter that may range from 5 micrometers to 500 micrometers (paragraph [0027]).
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 HENRY H NGUYEN whose telephone number is (571)272-2338. The examiner can normally be reached M-F 7:30A-5:00P.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maris Kessel can be reached at (571) 270-7698. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HENRY H NGUYEN/Primary Examiner, Art Unit 1758
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