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 .
Election/Restrictions
Applicants’ election without traverse of invention Group I in reply filed on 03/23/2026 is acknowledged. Claims 1-12 read on the elected group.
Claims Status
Claims 1-22 are pending.
Claims 13-22 are withdrawn.
Claims 1-12 have been examined on the merits.
Drawings
The drawings submitted 10/13/2023 are objected to because they contain color images without a granted petition to accept color images.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
Claim 1 is objected to because of the following informalities:
In c
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 11 is 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.
Claim 11 requires calculating oral bioavailability of at least one treatment using [the recited formula].The formula references ‘area under the curve (oral)’ and ‘area under the curve (dose)’; however it is not clear what curve is being referred to or how it is calculated. Therefore, there is insufficient antecedent basis for the limitations referring to ‘area(s) under the curve’. Overall, it is unclear what values are used for this calculation and therefore this claim is indefinite.
Appropriate action or clarification is required.
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.
Claims 1-10 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Shinohara et al (Scientific reports, 2021; in IDS filed on 3/23/2026) and in view of Chen et al (Lab on chip, 2018).
Shinohara et al teaches a co-culturing cells, human iPSC derived intestinal cells and fresh human hepatocytes isolated from PXB mice with medium circulation in a pneumatic pressure driven micro physiological systems (MPSs) (See, Abstract).
Regarding claim 1, Shinohara et al teaches the use of a micro physiological system with chambers for cell culture. The chamber where the hiPS-intestinal cells are cultured is fluidically connected to the chamber culturing the PXB cell (hepatocyte cells) (See, p3 Figure 1A-C). This co-culture system and method steps, reads on a method of co-culturing primary liver cells and primary intestinal cells,.. a. providing system comprising….
In Figure 1C (See, below), Shinohara et al shows the co-culturing system has at least one three compartment set, comprising a liver compartment (PXB cell), an apical compartment and a basolateral compartment (insert area where the hiPS intestinal cells are indicated). Figure 1 B and C of Shinohara et al shows that the system comprises first fluid circulation path whereby the basolateral compartment is fluidically connected to the liver compartment and the first circulation path is selectively interruptible… Figure 1C, shows view of the chambers, where it is visible that the intestinal cells are seeded on the insert such that there is a barrier between the apical and basolateral portions of the chambers (See, p3 Figure 1C or below). Shinohara et al Figure 1 depicts that the PXB or liver cells are seeded in the liver compartment and the intestinal cells in another compartment and does not indicate that the circulating media has EGF, therefore this reads on b. seeding primary liver cells…, c. adding primary intestinal cells to the apical compartment…d. circulating media throughout the first fluid circulation path does not comprise EGF.
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Adapted from Shinohara et al (Science reports, 2021) Figure 1 from page 3.
Shinohara et al does not teach the use of primary intestinal cells in this co-culture system nor the addition of media to the apical compartment that comprises EGF.
Chen et al teaches an expanded modular gastrointestinal (GI) tract-liver system by co-culturing primary human intestinal epithelial cells (hIECs) and HepG2 C3A liver cells in tissue compartments connected to a fluidic medium flow driven by gravity (See, Abstract).
Figure 2 of Chen et al teaches the GI-Liver model, with a chamber where the primary hIECs are cultured and then the HepG2 C3A liver cells are seeded onto days later, then placed in a fluidic device for profusion (See, p 15 Figure 2).
Chen et al teaches that the primary hIECs are cultured in medium with 5.0 μg/mL of insulin, 25 ng/mL EGF, and B27 supplement (See, p3-4 methods). Chen et al also teaches that in the MPS the coculture includes 50:50 of both mediums (See, 5-6 methods). Therefore, this reads on the intestinal cells in the apical compartment would be cultured with EGF.
Chen et al further teaches their co-culture of primary hIECs and HepG2 C3A cells in medium circulation is a functional model and viable device for at least 14 days with metabolic activities that are comparably better than single organ system (See, p9 paragraph 3-4).
It would have been prima facie obvious to a person having ordinary skill in the art to substitute the hiPS-intestinal cells of the method of co-culturing of Shinohara et al with the primary intestinal epithelial cells (hIECs) of co-culturing method of Chen et al. Both Shinohara et al and Chen et al teach methods of co-culturing liver and intestinal cells to study metabolic interactions.
The use of primary intestinal cells of Chen et al in the place of the hiPS intestinal cells of Shinohara et al would have a predictable result of success evidenced by both Shinohara et al and Chen et al, as they use equivalent cells types from differing sources to co-culture in an MPS. This rationale aligns with the principle of KSR for simple substitution of one known element for another to obtain predictable results (See, MPEP 2143).
Regarding claim 2, following the discussion above about claim 1, as seen in Figure 1 B and C below, both compartments have inlet and outlets that create a second fluid circulation path, wherein fluid in the liver compartment is recirculated (See, star 1 in adapted figure).
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Adapted from Shinohara et al (Science reports, 2021) Figure 1 from page 3.
Regarding claim 3, following the discussion above about claim 1, as seen in Figure 1 B and C above, both compartments have inlet and outlets that create a third circulation path, wherein the fluid in the basolateral compartment is recirculated (See, star 2 in adapted figure).
Regarding claim 4 and 6, following the discussion above about claim 1, Shinohara et al teaches that the intestinal cells were cultured on 24 trans-well inserts, specifically ad-MED VitrigelTM 2 from KANTO CHEMICAL CO., INC. insert was used. This reads on primary intestinal cells are seeded on a biomimetic scaffold, because the VitrigelTM 2 inserts have a collagen virtrigelTM membrane.
Regarding claim 5, following the discussion above about claim 1, Shinohara et al teaches that the human hepatocyte cells isolated from PXB mice were cultured on culture wells precoated with collagen type I in the MPS (See, p8 PXB-cell culture). Shinohara et al teaches the liver cells (PBX) are inoculated into the compartment, but Shinohara et al also teaches seeding the intestinal cells onto porous trans-well inserts and transferring them to the MPS. There are a finite number of ways to get the cells into the MPS, either by directly inoculating as Shinohara et al did for the liver cells or transfer a trans-well insert into the compartment with the cells already seeded, into the MPS.
It would have been prima facie obvious to a person having ordinary skill in the art to seed the liver cells onto a collagen coated trans-well as the intestinal cells were in Shinohara et al, to then add them to the MPS system for co-culture. There would have been a reasonable expectation of success, as each compartment is able of housing the cells and allow for circulation. Therefore, it would have been obvious for a person having ordinary skill in the art to try to seed the cells onto the collagen coated trans-well as taught by Shinohara et al. This rationale aligns with the principle of KSR for “obvious to try”, to combine features of an invention with a reasonable expectation of success (See, MPEP 2143 (I)(E)).
Regarding claim 7-9, following the discussion above about claim 1, Shinohara et al teaches that the hepatocyte cells are culture in medium containing 1% antibiotic-antimycotic (drug), 15 μg/mL of L-proline (metabolite), and 0.25 μg/mL of human insulin and the medium was changed every 2 days (See, p 8 PXB-cell culture and Figure 1D). This reads on, adding at least one treatment to at least one compartment of claim 7, as this medium is added to the liver cell compartment for culturing. This also reads on, wherein the treatment is selected from at least one of… of claim 9, as insulin is peptide hormone.
Shinohara et al teaches that the medium for the PXB cells was used for the coculture (See, p8 Coculture of…, Figure 1D). Therefore, Shinohara et al teaches the addition of at least one treatment to the apical compartment and at least one treatment to the liver compartment, which reads on claim 9.
Regarding claim 10, following the discussion above about claim 7, Shinohara et al collected the culture medium of both co-culture and monoculture of the MPS, then the amount of secreted albumin in the culture medium was measured by in an assay (See, p9 Albumin production measurement). The sample collection is seen on the timeline give in Figure 1D of Shinohara et al (See, p3).
Shinohara et al does not measure the concentration of at least one treatment added to the compartment or the culture media but teach that concentrations of albumin (protein) can be extracted from the coculture media.
However, measuring the concentration of at least one treatment of the coculture media would have been routinely optimized by one having ordinary skill in the art based on the ability to extract the concentration of albumin protein. Shinohara et al teaches concentration of albumin. That means the conditions necessarily to achieve the result of obtaining the concentration of at least one treatment of the coculture were result effective variables. Result effective variables would be optimized by routine experimentation by one having ordinary skill in the art (See, MPEP 2144.05).
Regarding claim 12, following the discussion above about claim 1, Shinohara et al teaches a co-culturing cells, fresh human hepatocytes isolated from PXB mice (See, Abstract). Chen et al teaches an expanded modular gastrointestinal (GI) tract-liver system by co-culturing primary human intestinal epithelial cells (hIECs)(See, Abstract). This reads on, wherein the primary liver cells and primary intestinal cells are human.
Therefore, claims 1-10 and 12 are rendered obvious over Shinohara et al and in view of Chen et al.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Shinohara et al (Scientific reports, 2021; in IDS filed on 3/23/2026) and Chen et al (Lab on chip, 2018) as applied to claims 1-10 and 12 above, and further in view of Lau et al (Drug metabolism and disposition, 2004); evidence by Bioavailability and Bioequivalence (EUPATI Open Classroom, 2021, https://web.archive.org/web/20210114063204/https://learning.eupati.eu/mod/book/tool/print/index.php?id=304#ch146).
The teachings of Shinohara et al and Chen et al have been set forth above.
Regarding claim 11, following the discussion above about claim 10, Shinohara et al and Chen et al do not teach a coculturing method that further comprises calculating oral bioavailability of at least one treatment using a formula.
Lau et al teaches that a coculture system with Caco-2 (colorectal cell line) and hepatocytes for the prediction of oral absorption of compounds (See, abstract).
Lau et al tested the bioavailability of 24 known compounds and compared the in vitro results to the in vivo reported results of the compounds See, p938 col 1 paragraph 1). Lau et al teaches that the use of the hybrid system would be advantageous to reduce expenses and time consuming animal studies and decrease attrition in clinical trials (See, p940). Lau et al concluded that the hybrid system would be a useful tool for estimating the range of oral bioavailability in humans (See, p941 col 2 paragraph 2). Figures 5 and 6 of Lau et al show the oral bioavailability calculated as a percentage (F%). The formula for this is
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, as evidenced by EUPATI open classroom.
EUPATI open classroom, teaches that Absolute Bioavailability (See, p8, Figure 4 adapted below), formula for Fabs, which is equivalent to oral bioavailability equation in the instant claim without the multiplication of 100 to create a percentage, that can be omitted by person of ordinary skill in the art. The adapted figure 4 below, shows that absolute bioavailability reads on the equation for oral bioavailability, as AUC is the area under the curve, tablet is equivalent to oral and the other factors the same in the equation.
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art to have modified the method disclosed by Shinohara et al such that oral bioavailability was calculated with the method provided by Lau et al. One would have been motivated to make this modification because it would have been advantageous to further estimate the efficacy and capabilities of the liver-gut coculture MPS, evidenced by Lau et al coculture system being a tool for various compounds.
This conclusion of obviousness is based on teaching suggestion motivation rationale. One would have had a reasonable expectation of success calculating oral bioavailability of Lau et al in the method of Shinohara et al to get the bioavailability of the treatments.
Therefore, claim 11 is rendered obvious over Shinohara et al and Chen et al in further view of Lau et al, evidenced by EUPATI open classroom.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Caroline M Lara whose telephone number is (571)272-4262. The examiner can normally be reached 7:00 to 4:30pm M-Th.
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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