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 .
Election/Restrictions
Applicant’s election with traverse of Group I (Claims 1-3, 8, 26-33, and 36-38; drawn to a culture device) in the reply filed on May 7, 2024, is acknowledged. Claims 44-45 and 47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Group II), there being no allowable generic or linking claim.
Applicant further elected the following species:
a. hydrophilic substrate surface
In light of the Applicant’s elected species, claim 8 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Response to Arguments
Applicant's arguments filed June 5, 2026, are acknowledged.
Applicant argues that the restriction between inventions should be withdrawn as claims 1 and 44 share the exact same substantive features and claim 44 has been amended to be dependent on claim 44. Applicant argues this would lead to no additional examination burden.
Applicant's arguments have been fully considered but they are not persuasive.
As stated in the Requirement for Restriction mailed on April 7, 2026, Inventions I and II are related as product and process of use. The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case, the product as claimed can be used in a materially different process such as storing multiple samples in the individual culture regions.
Although the product of claim 1 is identified as a culture device, this is considered an intended use and not required in the product. On the contrary, the method of claim 44 would require the device to be a culture device as culturing must occur as part of the method. Therefore, the breadth of the prior art that is applicable to the product is not the same as the breadth of the prior art that is applicable to the method.
As such, the restriction between the product and the method is maintained.
DETAILED ACTION
The amended claims filed on June 5, 2026, have been acknowledged. Claims 4-7, 9, 12-25, 34-35, 39-43, and 46 were cancelled. Claims 38 and 44-45 were amended. In light of the Applicant’s elected invention and species, claims 8, 44-45, and 47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-3, 10-11, 26-33, and 36-38 are pending and examined on the merits.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).The applicant claims foreign priority from CN202110341856.5 and CN202110341842.3 filed on March 30, 2021, and CN202110430174.1 filed on April 21, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received November 14, 2023. While a certified copy of the foreign patent applications CN202110341856.5, CN202110341842.3, and CN202110430174.1 are provided with the instant application, a certified English translation of said foreign patent applications have not been provided.
Information Disclosure Statement
The information disclosure statements (IDS) filed on October 13, 2023, and October 22, 2024, have been considered.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3 and 10-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fukuda et al. (Biomaterial 27: 1479-1486. 2006).
As an initial matter, the interior and exterior areas of the culture are interpreted to include a culture region (the interior) and a non-culture regio (the exterior) as is identified in paragraph 0077 of the instant specification.
Regarding claim 1, Fukuda teaches a micropatterned culture device. Hyaluronic acid (HA) was micropatterned on a glass substrate by using a soft lithographic method called capillary force lithography. The exposed region of a glass substrate was coated with fibronectin (FN). Cells were then selectively adhered to the FN-coated regions. The HA coated surface was complexed with collagen, allowing for the subsequent adhesion of secondary cells. As can be seen in Figures 1-2 and 7, there are multiple culture regions. As can be seen in Figure 7, the adhesion affinity for the ES and AML 12 cells selectively adhered to the FN coated region on HA-patterned culture device whereas the NIH-3T3 cells selectively adhered to the HA coated region (page 1480, column 2, paragraph 2-page 1485, column 2, paragraph 1 and Figures 1-7).
Regarding claim 2, as can be seen in Figures 1-2, the surface roughness of the interior versus the exterior is different (see especially Figure 2D).
Regarding claim 3, Fakuda teaches that the glass surface is hydrophilic due to the presence of hydroxyl groups (page 1482, column 1, paragraph 1). As the claims do not define the interior versus the exterior of the culture region nor the culture region, any definition is considered reasonable. Therefore, the fibronectin coated region could be considered the interior and the HA coated region complexed with collagen can be considered the exterior or it can be vice versa with the HA coated region complexed with collagen considered the exterior and the fibronectin coated region considered the interior. Under the second definition, Figure 2D shows that the collagen coated interior has increased roughness compared to the fibronectin coated region.
Regarding claims 10-11, as can be seen in Figure 2, the patterned HA region surrounding the fibronectin coated interior are ~60 nm in height creating a well with nano scale HA walls surrounding each well (Figures 1-2).
Claims 1, 26-30, and 36 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Birchler et al. (Anal. Chem. 88: 1222-1229. 2016).
As an initial matter, the interior and exterior areas of the culture are interpreted to include a culture region (the interior) and a non-culture regio (the exterior) as is identified in paragraph 0077 of the instant specification.
Regarding claim 1, Birchler teaches a microfluidic device for hanging-drop culture comprising a 4 × 6-drop array with a single inlet and single outlet (Figure 1A). Rim-like micropatterns define wetted and nonwetted areas and were fabricated by using standard soft lithography methods. In short, the casting mold was produced from a 4-in. silicon wafer with two patterned SU-8 layers (both 250 μm thick) on top. The mold was used to produce polydimethylsiloxane (PDMS) replica structures. To improve handling of the flexible PDMS devices, they were bonded to a standard microscopy slide containing throughholes to connect the tubing from the top. The substrate was operated in an upside-down configuration so that hanging drops were formed below the circular areas. The hanging drops were interconnected through channels for liquid circulation, to form a bottom-open microfluidic network. A first critical step consists of loading liquid into the empty microfluidic system. Prior to loading, the drop structures of the fabricated chip were rendered hydrophilic (interior), while the rim structures remained hydrophobic (exterior). For harvesting, all cells and spheroids were harvested in parallel onto a specially designed receiver plate, which comprised of an array of hydrophilic spots arranged at the same pitch as the hanging drops (Figure 1D). Superhydrophobic areas surrounded the hydrophilic spots. The hanging-drop chip and the receiver plate were both placed into a custom-assembled harvesting platform. The platform ensured a precise alignment and parallel movement of the chips. The hanging drop network was approached to the receiver plate, so that all drops got into short contact (∼1 s) with the hydrophilic areas, and so that small volumes of liquid including all cells and spheroids were transferred in parallel. Cells and spheroids remained isolated from each other and were accessible for further analysis. The receiver plate was fabricated by photolithographic patterning of a hydrophobic silazane layer on a 4-in. glass substrate. (page 1222, column 1, paragraph 3-page 1224, column 2, paragraph 6 and Figures 1 and 3). As can be seen in Figures 1 and 3, the circular hydrophilic wells of the culture have increased adhesion affinity for generating hanging drop culture droplets compared to the hydrophobic regions.
Regarding claim 26, Birchler, as stated supra, teaches a hanging drop microfluidic platform comprising a 4 × 6-drop array (the cover plate, as seen in Figure 1) with the surface of the substrate corresponding to a lower surface of the cover plate. As can be seen in Figure 1C, the flexible PDMS devices can be bonded to a standard microscopy slide (a base plate) to improve handling or, as can be seen in Figure 1D, cells can be harvested using a receiver plate (a base plate) with superhydrophobic areas surrounded the hydrophilic spots on the upper surface of the receiver plate. The hanging-drop chip and the receiver plate were both placed into a custom-assembled harvesting platform (page 1222, column 1, paragraph 3-page 1224, column 2, paragraph 6 and Figure 1). As the 4x6 drop array cover plate and the glass slide or receiver plate can be moved independently of one another, they are movable with respect to each other.
Regarding claim 27, the hydrophilic interior of the receiver plate (base plate) would have greater affinity for drop formation than the hydrophobic surfaces of the 4x6 hanging drop array cover plate.
Regarding claim 28, the hydrophilic interior of the 4x6 hanging drop array cover plate would have greater affinity for drop formation than the microscope slide and the hydrophobic surfaces of the receiver plate.
Regarding claim 29, Birchler, as stated supra, teaches the 4x6 hanging drop array cover plate and the receiver plate have a plurality of culture regions (Figure 1D).
Regarding claim 30, as part of placing the 4x6 hanging drop array cover plate and the receiver plate in the custom-assembled harvesting platform, the hanging drop array cover plate and the receiver plate will have staggered culture regions before they become aligned for harvesting.
Regarding claim 36, Birchler, as stated supra, teaches that the hanging-drop chip and the receiver plate were both placed into a custom-assembled harvesting platform. The platform ensured a precise alignment and parallel movement of the chips. The hanging drop network was approached (i.e. the cover plate can be moved in relation to the base plate) to the receiver plate, so that all drops got into short contact (∼1 s) with the hydrophilic areas, and so that small volumes of liquid including all cells and spheroids were transferred in parallel. Cells and spheroids remained isolated from each other and were accessible for further analysis (page 1224, column 2, paragraph 6) and Figure 6).
Claims 1-3, 26-30, 32-33, and 38 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent No. 10017725 (Zimmermann).
As an initial matter, the interior and exterior areas of the culture are interpreted to include a culture region (the interior) and a non-culture regio (the exterior) as is identified in paragraph 0077 of the instant specification.
Regarding claims 1-3, 26, 28, and 38, Zimmerman teaches a culture vessel which is configured for culturing biological cells in hanging droplets and has a vessel wall with a cover section and a bottom section. The cover section is configured for the provision of a culturing area for receiving the hanging droplets. The culturing area has a surface which, when the culture vessel is used for culturing biological cells, faces vertically downwardly, i.e. in the direction of gravity. The bottom section is configured for receiving a liquid. The vessel wall is formed such that an inner space of the culture vessel is enclosed by the cover section and the bottom section on all sides. The inner space is delimited from the surroundings by the vessel wall. Advantageously, this enables a local setting of culturing conditions such as, for example, the provision of a gaseous culture medium, a specified air humidity and/or a specified temperature in the culture vessel. The culturing area is provided with holding elements which are configured for positioning the hanging droplets.
The holding elements are formed such that when they are wetted with the culture liquid, a collection of liquid and a formation of the hanging droplets are supported on the holding elements. The vessel wall of the culture vessel is configured movable so that the holding elements can be wetted with the liquid from the bottom section. The movability of the vessel wall also means that the liquid from the bottom section temporarily comes into contact with the cover section. The vessel wall of the culture vessel is moved such that the culturing area is wetted by the suspension including the biological cells. Subsequently, a return of the vessel wall takes place wherein the culturing area is separated from the suspension on the bottom section and droplets of the suspension with the cells are gathered on the holding elements.
The holding elements comprise hydrophilic surface regions (hydrophilic islands, hydrophilic spots) (interior) of the culturing area which are separated from one another by hydrophobic surface regions (exterior). The hydrophilic surface regions advantageously enable reliable collection of the droplets of aqueous medium. The size of the droplets can be influenced by the size of the hydrophilic surface regions.
Advantageously, various possibilities exist for the design of the holding elements. If, for example, the culturing area is formed by a surface of a film, the hydrophilic and/or the hydrophobic surface regions are provided by functionalizing the film surface. Alternatively or additionally, the holding elements can comprise hydrophilic step elements, in particular local depressions or projections of the culturing area on which the effect of capillary forces is greater than in unstructured surface regions of the culturing area. If the culturing area is formed, for example, by the surface of a plastics panel or film, the hydrophilic step elements can be formed by ring-shaped, square or cylindrical projections with typical dimensions (cross-section, height) in the sub-mm range (i.e. increased roughness of the interior).
Preferably the holding elements, in particular the hydrophilic surface regions are arranged in a regular pattern, e.g. a matrix arrangement with straight rows and columns of the holding elements.
Advantageously, the movement of the vessel wall for wetting the culturing area can take place without the whole culture vessel being pivoted. The culture vessel has a deformable vessel wall. The cover section and the bottom section are movable relative to one another. During a deformation of the vessel wall (compression of the culture vessel) the spacing of the cover section and the bottom section can be reduced so that the culturing area with the holding elements can be moved close to the bottom section. Advantageously, the deformability of the vessel wall enables the culturing area and the bottom section to be moved toward one another such that the holding elements come into contact with the liquid which is accommodated on the bottom section.
Regarding the limitation, the adhesion affinity of the interior of the plurality of culture regions to the culture is greater than an adhesion affinity of the upper surface of the base plate to the culture, the cover plate has the holding elements that form the hanging drops while the base section does not. Therefore, the cover plate has increased affinity (whole document).
Regarding claims 27 and 29-30, Zimmerman teaches that according to a further advantageous embodiment of the invention, the cover and bottom sections are provided with line-shaped coupling elements. On deformation of the culture vessel such that the cover and bottom sections touch one another, a connection of the cover and bottom sections can be provided along the line-shaped coupling elements. Advantageously, this enables the subdivision of the inner space of the culture vessel into vertical chambers in which, for example, different culturing conditions can be set. For example, Figure 13 shows the bottom and top culture regions with corresponding drops. FIG. 13A shows the culture vessel 100 in the unfolded state in which the hanging droplets 2 are arranged on the culturing area 13 and the bottom section 12 is covered with a liquid 3. In order to prepare the cryopreservation of the droplets 2, a cryoprotectant, for example DMSO, is added via the tube 44 to the liquid 3 or the liquid 3 is replaced with a solution of a cryoprotectant (FIG. 13B). Subsequently, the culture vessel 100 is tilted so that the liquid in the inner space 20 flows to the media interface 43 and can flow away via the tube 44. Herein, droplets 5 with the cryoprotectant remain on the hydrophilic surface regions 19 of the bottom section 12 (FIG. 13C). Subsequently, the culture vessel 100 is brought into the compressed state (FIG. 13D). The cover and bottom sections 11, 12 are brought together under the influence of external forces F until the droplets 2 in which the biological cells have been cultured and the droplets 5 blend together. Since the droplets 2, 5 lie exactly opposite one another and the lateral spacings between the droplets are sufficiently large, the cells remain in the droplets at reproducible positions. The cryopreservation can take place in the compressed state (FIG. 13D) or in the subsequent unfolded-again state (FIG. 13E) of the culture vessel 100 (Figure 13 and column 18, lines 6-42).
As part of the deformability of the vessel wall, the plurality of culture regions of the base plate and cover plate can be staggered.
Regarding claims 32-33, Zimmerman teaches that there are different possibilities for the material selection in order to provide the desired deformability of the vessel wall. the vessel wall can be composed from a flexible film material (a flexible membrane) and an elastically deformable material (a support frame). For example, the flexible film material (i.e. a flexible membrane) can be provided along the lateral extent of the cover and bottom sections, whilst the elastically deformable material is provided in the edge regions between the cover and bottom sections, particularly forming the side section (column 4, line 39-column 5, line 17).
Regarding claims 36-37, “a telescoping mechanism” is broadly interpreted to include gas control mechanisms that inflate gas between the base plate and the cover plate, moving them away from each other as paragraph 0093 of the instant specification discloses that “The gas control valve may be configured to control the gas source to inflate or absorb the gas. By using the gas control mechanism as the telescoping mechanism, the movement between the base plate 112 and the cover plate 114 can be controlled more conveniently and stably.” As such, a gas control mechanism is considered to fall within the “telescoping mechanism” of claim 36.
Zimmerman teaches that at the start of the culturing of biological cells according to the invention, the culture vessel 100 is filled according to FIG. 3C. The liquid 3 is fed via a first tube 44 to the bottom section 12, whilst via a second tube (not shown), a gaseous medium, for example an air-CO2 mixture with 5% CO2 is fed in. Under the effect of the gaseous medium, an internal pressure builds up in the inner space 20 so that the culture vessel 100 reaches the unfolded state (column 12, lines 26-33).
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 1, 26, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent No. 10017725 (Zimmermann) as applied to claims 1 and 26 above, and further in view of United States Patent No. 7033823 (Chang).
The teachings of Zimmermann are as discussed above.
Zimmermann does not teach wherein the periphery of the base plate is connected to the periphery of the cover plate through an extendable corrugated tube.
However, Chang teaches that in FIGS. 12A and 12B depict an embodiment of FIGS. 1A and 1B in cooperation with a driving device Such as a motor or a step motor 1218 connected to a volume-adjusting mechanism such as a shaft driver 1219 and 1220 mounted on the bottom of the second chamber 1230 (a corrugated tube) which is compressible. When the shaft driver rises, as depicted in FIG. 12B, or drops, as depicted in FIG. 12A, second chamber 1230 is periodically and intermittently compressed and decompressed. Compression and decompression of the second chamber 1230 causes growth substrate means 1220 of the first chamber 1210 to be periodically and intermittently submerged in or emerged from the growth medium.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that one could use a corrugated tube as the vessel side wall of the culture device of Zimmermann to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use a corrugated tube as the vessel side wall with a reasonable expectation of success because the vessel side wall of Zimmermann and the corrugated tube of Chang perform the same function and would be recognized as comparable as both can undergo compression and decompression to cause a cell growth substrate to be periodically and intermittently submerged in or emerged from the growth medium. As the corrugated tube of Chang is able to perform the same function as the deformable side vessel wall of Zimmermann, it would have been obvious that the corrugated tube of Chang could be used to form the side vessel wall of Zimmermann for a deformable side wall that allows the cover surface with the holding elements comprising hydrophilic surface regions to interact with the culture media in a collapsed state before returning to a unfolded state for culturing of the resulting hanging drops. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631
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