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 .
Claim Objections
Claim 1 is objected to because of the following informalities:
Regarding claim 1, in lines 9-10, the phrase “the cell culture surface having a thickness” should be amended to “the cell culture surface has a thickness”.
Regarding claim 1, in lines 11-12, the phrase “a plurality of intertwined polymer fibers”, should be amended to “the plurality of intertwined polymer fibers”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The previous 35 U.S.C. § 112(b) rejections are withdrawn in light of the amendments.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 4 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 4, the term “concentration polarization” was used, but is not in the specification or the application at the time it was filed.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 3-4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, in line 11, the phrase “the first pores” is recited. There is insufficient antecedent basis for this limitation in the claim. The limitation should be amended to “the plurality of first pores”.
Regarding claim 1, in line 11, the phrase “the second pores” is recited. There is insufficient antecedent basis for this limitation in the claim. The limitation should be amended to “the plurality of second pores”.
Regarding claim 1, in line 12, the phrase “the first pores” is recited. There is insufficient antecedent basis for this limitation in the claim. The limitation should be amended to “the plurality of first pores”.
Regarding claim 1, in line 13, the phrase “the second pores” is recited. There is insufficient antecedent basis for this limitation in the claim. The limitation should be amended to “the plurality of second pores”.
Regarding claim 3, in lines 1-2, the phrase “The porous microwell of claim 1, wherein a plurality of the porous microwells are located in the region formed by the penetrating part” describes an invention with the preamble “The porous microwell” (from independent claim 1’s preamble “A porous microwell”), but then claims “a plurality of the porous microwells” within the same invention’s claim set. Instead, the following phrase can be used: “The porous microwell of claim 1, wherein a plurality of second porous microwells are located in the region formed by the penetrating part.” This claim language avoids:
an antecedent basis issue; and,
widening the metes and bounds or scope of the independent claim, while still allowing for a plurality of porous microwells to be claimed.
Regarding point 1, to clarify, claim 3 recites limitation “the porous microwells” in line 1. There is insufficient antecedent basis for this limitation in the claim.
Regarding point 2, to clarify, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 3 recites the broad recitation “wherein a plurality of the porous microwells are located in the region formed by the penetrating part”, and the claim also recites “The porous microwell of claim 1” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claim 4, the term “near the surface” in lines 5-6 is a relative term which renders the claim indefinite. The term “near the surface” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Regarding claim 4, the claim recites the limitation “the surface” in lines 5-6. There is insufficient antecedent basis for this limitation in the claim.
Regarding the dependent claims 3-4, these claims are rejected for the same reason as the base claim upon which they depend.
Claim Interpretation
Regarding the following limitations, the manner of operating or intended use of a claimed apparatus does not patentably distinguish it from the prior art. MPEP § 2114(II).
Regarding claim 1, the phrase “a cell culture surface for culturing three-dimensional cell spheroids” is an intended use of the invention.
Regarding claim 4, the claim is a form of intended use or manner of operation of the invention.
Claim Rejections - 35 USC § 103
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 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 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Martin (US 20170218321) (newly cited) in view of Gottardi (US 20190076840) (newly cited).
Regarding claim 1, Martin discloses a porous microwell (paragraph [0039]; Fig. 3A-3D), comprising:
a cell culture surface (paragraph [0039]) for culturing three-dimensional cell spheroids (paragraph [0039]), comprising a plurality of first pores (paragraph [0039] “a porous membrane 420”), and having a connection part (paragraph [0039] “the substrate having an array of microwells 410 is porous”) surrounding the cell culture surface (paragraph [0039]) with a plurality of second pores (paragraph [0041] “porous material or a gas permeable material”);
wherein the porous microwell (paragraph [0039]; Fig. 3A-3D) is located with the connection part (paragraph [0039] “the substrate having an array of microwells 410 is porous”) within a region defined by a penetrating part of a cell culture vessel (paragraph [0036]; Fig. 3A-3D, element 110 “sidewalls”) when viewed from a top (Fig. 3A-3D) or bottom side (Fig. 3A-3D), and is indented in a downward direction (Fig. 3A-3D),
wherein the cell culture surface (paragraph [0039]) forms a membrane (paragraph [0039] “a porous membrane 420”) with the connection part (paragraph [0039] “the substrate having an array of microwells 410 is porous”), where the membrane is formed from a plurality of intertwined polymer fibers (paragraphs [0025]-[0026] and [0039]; also, this would have been either inherent or expected with a porous membrane comprising a porous polymer, which constitutes a plurality of polymer fibers), wherein the first pores and the second pores are formed in a region between a plurality of intertwined polymer fibers (paragraphs [0025]-[0026] and [0039]; also,this would have been either inherent or expected with a porous membrane and/or a porous substrate comprising a porous polymer, which constitutes a plurality of polymer fibers).
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Martin, Annotated Fig. 1A
Martin does not disclose:
the cell culture surface having a thickness thinner than the connection part, and
a first porosity formed by the first pores is greater than a second porosity formed by the second pores.
Regarding feature 1, the limitation “the cell culture surface having a thickness thinner than the connection part” is obvious under MPEP § 2144.04(IV)(A), which states that “where the only difference between the prior art and the claims was a recitation of relative dimensions … [and the claimed device] would not perform differently than the prior art device, the claimed device was not patentably distinct from the prior art device”. It would have been obvious to one skilled in the art before the effective filing date to modify the thickness of the microwell to be less than the thickness of the connection part in order to promote more fluid transfer through the microwell so that the proper nutrients can more easily flow to the cells and the cellular wastes could be removed more easily.
Regarding feature 2, Martin does not disclose a first porosity formed by the first pores is greater than a second porosity formed by the second pores.
Gottardi discloses a first porosity (paragraph [0123] “≥20 μm pores”) formed by the first pores (paragraph [0123] “lower porous screen”) is greater than a second porosity (paragraph [0123] “20 μm pores”) formed by the second pores (paragraph [0123] “upper porous screen”).
In the analogous art of culture containers, it would have been obvious to one skilled in the art before the effective filing date to modify the first and second porosity of Martin’s microwells and the first and second porosity of Gottardi’s mesh openings in order to allow the specific portions of the culture vessel to have a shape or property through which the cell culture solution perfuses across the porous screen and/or delivers nutrients as well as allows cells to adhere to niches (Gottardi, paragraph [0123]).
Regarding claim 3, Martin discloses wherein a plurality of the porous microwells (paragraph [0039]; Fig. 3A-3D) are located in the region formed by the penetrating part (paragraph [0036]; Fig. 3A-3D, element 110 “sidewalls”).
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Martin (US 20170218321) (newly cited) in view of Gottardi (US 20190076840) (newly cited) as applied to claim 1, as evidenced by McCutcheon (“Influence of concentrative and dilutive internal concentration polarization on flux behavior in forward osmosis”) (previously cited).
Regarding claim 4, Martin discloses wherein, when a fluid flows vertically (paragraph [0080] “fluid communication”) through the porous microwell (paragraph [0039]; Fig. 3A-3D) from an upper side (Annotated Fig. 1A) to a lower side (Annotated Fig. 1A) within an accommodating space of a cell culture vessel (paragraph [0023]; Annotated Fig. 1A, element 150 “a reservoir or a well”), and the surface of the porous microwell (paragraph [0039]; Fig. 3A-3D).
Martin does not disclose a concentration polarization occurs near the surface of the porous microwell.
However, this phenomena is inherent to a flow with particles through a filter, and is known as “concentration polarization”, as evidenced by McCutcheon (see pg. 239 under “3.1 Concentrative and dilutive external concentration polarization”, specifically “Water permeates this layer leaving the solute behind in higher concentrations”).
Additionally, regarding the limitation “a concentration polarization occurs near the surface of the porous microwell” the manner of operating or intended use of a claimed apparatus does not patentably distinguish it from the prior art. MPEP § 2114(II). The device of modified Martin would be fully capable of operating in this manner given the porous microwell, an accommodating space of a cell culture vessel, and fluid communication of modified Martin.
Additional Prior Art References
The prior art made of record and not relied upon is considered pertinent to Applicant’s disclosure.
Hansen (US 20160017267) (newly cited) – This invention is a tray for monitoring and culturing cell culture with multiple accommodating zones (paragraphs [0043] and [0058]) or microwells within a well (paragraphs [0039]-[0040]).
Ramsing (US 20110165609) (newly cited) – This invention is a tray for monitoring and culturing cell culture with a single microwell per well (paragraphs [0024] and [0062] “at least two indents”).
Ejiri (US 20140227784) (newly cited) – This invention is a well-within-a-well culture plate (paragraphs [0038]-[0039] and Fig. 3).
Li (US 20170226458) (newly cited) – This invention is a spheroid trap insert (Fig. 4).
Love (US 20190218607) (newly cited) – This invention presents a single cell analysis picowell array (combined Figs. 12C and 12D read on claim 1; paragraphs [0366] and [0673]-[0674]).
Martin (US 20210062127) (newly cited) – This invention includes microplates with interconnected wells (paragraph [0057] and Fig. 10).
Martin (US 20220195366) (newly cited) – This invention includes microwells within a cell culture insert (Figs. 3A-3D).
Martin (US 20240263121) (newly cited) – This invention includes microwells within a cell culture insert (Figs. 3A-3D).
Reis (US 20130029412) (newly cited) – This invention includes a cell culture system with two different porosities.
Ledesma-Durán, et al. (“Relation between the porosity and tortuosity of a membrane formed by disconnected irregular pores and the spatial diffusion coefficient of the Fick-Jacobs model”) (newly cited) – This non-patent literature describes a mathematical relationship including the variables membrane thickness and permeate flux.
Response to Arguments
Applicant’s arguments filed 07/25/2025 have been fully considered but they are unpersuasive and/or moot because the new ground(s) of rejection.
In response to the Applicant remarks (pg. 5 of 9), the phrase “concentration polarization” is not in the originally filed disclosure, but rather the term “a fluid concentration phenomenon” is used in the written description (instant specification, pg. 15). The term “concentration polarization” is not an art-recognized equivalent term to “fluid concentration phenomenon” and no evidence has been provided to show otherwise, so the previously claimed term cannot be amended to “concentration polarization” as a substitute without incurring a 35 U.S.C. § 112(a) written description rejection for new matter.
Regarding claim 1 and its dependent claims, because of the new ground(s) of rejection, the arguments are considered unpersuasive and/or moot. Independent claim 1 is now rejected under Martin (US 20170218321) (newly cited) in view of Gottardi (US 20190076840) (newly cited). Due to the extensive amendments and their nature, new primary references and secondary references were found, but Finality is still applicable to this Office Action’s rejections.
Regarding Applicant arguments (pg. 7 of 9), about the cell culture surface’s thickness being thinner than the connection part’s thickness as a unique technical effect, it would have been obvious to one skilled in the art before the effective filing date to modify the cell culture surface’s thickness to be thinner than the connection part’s thickness in order to promote greater rate of flux across the membrane of the cell culture fluid through the thinner membrane (evidence for this statement of higher flux rate for a thinner membrane can be found in Equations 1, 3, and 7 of McCutcheon, shown below, wherein the experimental permeate water flux “Jw” is dependent on “k”, the mass transfer coefficient, which is dependent on the Sherwood number “Sh”, which is dependent on the length of the channel “L”, which is inherently dependent on the width of the porous membrane).
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McCutcheon, Equations 1, 3, and 7: length of channel “L” is a variable in flux “Jw”
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McCutcheon, Fig. 2a: an osmotic driving force profile in a symmetric dense membrane which illustrates concentrative and dilutive external concentration polarization
For in-depth information on the mathematical relationship between membrane thickness and longitudinal pore length, please consult Ledesma-Durán, et al. (“Relation between the porosity and tortuosity of a membrane formed by disconnected irregular pores and the spatial diffusion coefficient of the Fick-Jacobs model”) from the Additional Prior Art section. See specifically, the text between Equations 12 and 13 (“the longitudinal length of the pore L, i.e., its length measured along the direction of transport x, is not necessarily the same as the actual length of the pore Lz”), but yields a relationship between membrane thickness and the actual length of the pore in Equation 15, and Fig. 1 for a drawing of the difference between the two measurements.
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Ledesma-Durán, Fig. 1: Geometry of the pore-cell system
See also, text under “B. Effective diffusion of a pore-cell system” pgs. 052804-4 to 052804-5 (for a pore that is open at both ends), contains Equation 17:
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Ledesma-Durán, Equation 17:
A Fick’s Law of Diffusion related model of the particle flux, effective diffusion coefficient, cell length, cell width, and difference in concentration on either side of the membrane
Dependent claims’ rejections stem from this rejection, and in the case of claim 4, the evidentiary reference McCutcheon (“Influence of concentrative and dilutive internal concentration polarization on flux behavior in forward osmosis”) (previously cited) is cited as well.
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.
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/N.G.E./Examiner, Art Unit 1799
/MICHAEL A MARCHESCHI/Supervisory Patent Examiner, Art Unit 1799