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 .
DETAILED ACTION
This action is in response to papers filed June 21, 2024. Currently, claims 1-20 are pending. It is noted that claims 1, 17 and 19 are independent claims.
Therefore, claims 1-20 are under examination to which the following grounds of rejection are applicable.
Priority
The instant application is a continuation of International Application PCT/JP2022/047103 filed December 21, 2022. The International Application claims priority to Japanese Applications 2021-208086 filed December 22, 2021, and 2022-091422 filed June 6, 2022. A certified untranslated copy of the Japanese documents 2022-091422 and Japanese Applications 2021-208086 was filed on 10/18/2024.
Therefore, the earliest filing date for the instant application is December, 22, 2021.
Applicant is advised of possible benefits under 35 U.S.C. 119(a)-(d) and (f), wherein an application for patent filed in the United States may be entitled to claim priority to an application filed in a foreign country.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Specification
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim objection
Claim 14 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 13. Claim 14 is no different in scope than claim 13. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 706.03(k).
Claim Rejections - 35 USC § 112(b)
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 1-20 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, it is unclear if “the cells” are drawn to a different population of cells out of the step of “mixing cells” and “collecting cells”. It is recommended to amend the claims such that it states “mixing a population of cells” and “collecting a population of cells” to provide proper antecedent basis.
Claim 1 is indefinite for its recitation of the phrase “such that a three-dimensional cellular tissue is obtained”. It is unclear whether this language requires the formation of the three-dimensional tissue or merely states an intended or desired result of the culturing step. Moreover, in line 5, it recites “such that a mixture…is obtained”. Likewise, it is unclear if the phrase “such that” implies the formation of a mixture comprising the listed components.
Claims 1 and 17 are indefinite in its recitation of “culturing the cell aggregates seeded in the culture medium without suspension” as it is unclear what is meant by “without suspension”. Specifically, it is uncertain whether the limitation requires that the cell aggregates are attached to a substrate, embedded in a matrix or merely under static conditions.
Claim 18 is indefinite in its recitation of “the second cells”. There is not proper antecedent bases for the recitation of “the second cells”.
Claims 2-16 are indefinite insofar that they depend on claim 1.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 19-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claims recite the nature-based product drawn to a three-dimensional cellular tissue comprising vascular endothelial cells and hepatocytes. MPEP 2106 sets forth the multistep process for determining subject matter eligibility.
In accordance with the MPEP § 2016, claimed found to recite a statutory subject matter (e.g., compositions of matter) (Step 1: YES) are the analyzed to determine if the claims recite any steps that equate to an abstract idea, law of nature, or natural phenomenon. Claims 19-20 are drawn to a three-dimensional cellular tissue comprising a first and second layer of cellular tissue in contact with each other. Specifically, the claims recite naturally occurring tissue constructs, as disclosed in Kitano et al. (Published: 2019. Cited in IDS Cite no. 18 filed 6/21/2024. JP2019033732A. Machine Translation provided by Examiner) and Sun et al. (Published: 2020. American journal of physiology. Cell physiology, 318(6), C1200–C1213.). As such, the claims encompass naturally occurring tissue arrangements and does not require characteristics that distinguished the claimed tissue from its naturally occurring counterpart. The claimed three-dimensional liver tissue comprising vascular endothelial cells and hepatocytes has the same structure as the naturally occurring liver tissue. They have merely been isolated and placed into culture. Thus, the claims encompass a product of nature exception.
MPEP 2106.04(c) states that if a claim includes a nature-based product that does not exhibit markedly different characteristics from its naturally occurring counterpart in its natural state, then the claim recites a “product of nature” exception, and requires further analysis in Step 2A Prong Two to determine whether the claim as a whole integrates the exception into practical application (Step 2A, Prong One: YES)
The judicial exception is not integrated into a practical application because they do not recite any elements in addition to the recited judicial exception. MPEP 2106.04(d), subsection III states that a judicial exception alone is not eligible subject matter; therefore, if there are no additional claim elements besides the judicial, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. As such, claims 19-20 are directed to a natural product with no additional elements to demonstrate the claims as a whole integrate the exception into practical application. (Step 2A, Prong 2: NO).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. MPEP 2106.05, subsection I states that additional elements in the claims must be evaluated to determine whether they amount to an inventive concept, which requires considering them both individually and in combination to ensure that they amount to significantly more than the judicial exception itself. Any additional steps, such as culturing and maintaining vascular endothelial cells or hepatocytes within a cellular tissue are no more than routine in the art and do not transform the nature of the claim to be something distinct from their naturally occurring counterpart. Hence, because claims 19-20 do not contain additional elements to demonstrate the claims as a whole integrate the exception into a practical application, the claim simultaneously does not recite significantly more than the exception itself and there is no meaningful limitation in the claim that transforms the exception into a patent- eligible application. Therefore, claims 19-20 are directed to a judicial exception without significantly more and does not have an eligible subject matter under 35 U.S.C. § 101 (Step 2B: NO)
Claim Rejections - 35 USC § 112
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.
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
three-dimensional cellular tissue containing human hepatocytes, endothelial cells in a mixture of heparin and collagen and tris-hydrochloride buffer solution
does not reasonably provide enablement for any three dimensional-cellular tissue comprising a genus of cells, a genus of a cationic substance, a genus of polyelectrolytes, and a genus of extracellular matrix components. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The criteria for enablement set out In re Wands, MPEP 2162.01(a), considers the following factors:
Breadth of the Claims
The instant claims are directed to a three-dimensional cell structure comprising of preparing a mixture of a cationic substance, an extracellular matrix component, a polyelectrolyte, and cells. Thus, encompassing all three-dimensional cell structures comprising any type of cationic substance, extracellular matrix component, polyelectrolyte and cell population. As such, the breadth of the claims is great.
State of Prior Art
Critser et al. (Published: 2010. Microvasc Res. 2010 Jul;80(1):23-30.), specifies a three- dimensional cellular matrix made of collagen with implanted human umbilical cord endothelial-colony- forming cells (Abstract), page 1 para 1, “The present study determined the ability of 3D collagen matrix physical properties, varied by changing collagen concentration, to influence ECFC [endothelial colony-forming cell] vasculogenesis in vivo. Human umbilical cord blood ECFCs were cultured within matrices for 18 h in vitro…”). Three-dimensional structures comprising of different concentrations of collagen influence matrix physical properties such as fibril density and stiffness, but is also seen with influencing EPC vessel formation, a fundamental aspect of vasculature (Abstract, page 1 para 1, “We report that increasing collagen concentration significantly decreased ECFC derived vessels per area (density), but significantly increased vessel sizes (total cross sectional area).”; page 5 para 3, “Collagen concentration of the polymerized reactions was varied to systematically modulate matrix physical properties (e.g. fibril density and stiffness) known to affect in vitro EPC vessel formation.”). Thus, Critser et al. provides support for the unpredictability of using any collagen concentration in vasculogenesis of a 3D collagen matrix, let alone any extracellular matrix component.
Ahn et al. (Published: 2018. Acta Biomaterialia. Volume 76, August 2018, Pages 154-163) investigates the effect of a cationic polyelectrolyte perfused within a three dimensional microvessel containing cells and pericytes on microvessel behavior, specifically microvessel contraction (page 154 para 1, Abstract, “. We demonstrated that the oxidative stress present when microvessels were exposed to [polyethylenimine] PEI NPs led to rearrangement of microtubules resulting in microvessel contraction.”; page 155 col 2 para 3, “Human umbilical vein endothelial cells (HUVECs; Lonza) were cultured in endothelial growth medium (EGM-2; Lonza)…Human placental pericytes (hPC-PL, Promocell)”). Thus, Ahn provides support for the unpredictability of using any cationic polyelectrolyte in contractile forces and vascularization of 3D collagen matrices. Moreover, it is unclear if other cell types outside of endothelial cells and pericytes can also achieve a vasculature.
Given that different concentrations of collagen result in different fibril density and stiffness of a 3D collagen matrix, the prior art demonstrates that the specification fails to provide a full scope of the claims, and does not provide enablement for all three-dimensional cellular tissues comprising a cationic substance, polyelectrolyte, cells and extracellular matrix component. A skilled artisan would require undue experimentation to practice species outside the working examples described and result at the claimed invention. Thus, the prior art implies that the specification fails to provide the full scope of the claims, as it is only enabled for heparin, collagen, a plurality of endothelial cells and hepatocytes and tris-hydrochloric acid buffer solution.
The Amount of Direction Provided by the Inventor
The specification provides insufficient direction and guidance to enable a person of ordinary skill in the art to practice the full scope of the claimed invention. The Specification details recommended concentrations of cationic substance (para 0031-0033), polyelectrolyte (para 0034-0036) and extracellular matrix component (para 0037-0039), as well as different species of these components that create the three-dimensional cellular tissue. However, these are only suggestive embodiments and it is unclear if different combinations of the recomended groups of cationic substance, polyelectrolyte and extracellular matrix, would successfully result in the production of three-dimensional tissue able to generate a three-dimensional cellular tissues. Moreover, a person with ordinary skill in the art would have to perform undue experimentation with various concentrations and species of these groups in order to arrive at the claimed invention. The specification provides insufficient direction and guidance to enable a person of ordinary skill in the art to practice the full scope of the claimed invention.
Presence or Absence of Working Examples
The Specification only provides working examples for three-dimensional cellular tissues comprising heparin (polyelectrolyte), collagen (extracellular matrix component) and tris-hydrochloride (cationic substance). Moreover, Example 1 prepares three-dimensional tissues with hepatocytes alone (para 0098, “Preparation of Dispersion of Three-Dimensional Cellular Tissue 3.0×10.sup.5 human hepatocytes (PXB Cells (registered trademark)) were suspended in an equal volume mixture solution (heparin/collagen solution) containing 20 μL of 1.0 mg/mL heparin/200 mM tris-HCl buffer solution (pH 7.4) and 20 μL of 0.6 mg/mL collagen/5 mM acetic acid solution (pH 3.7)”). Experimental example 2 utilizes a combination of sinusoidal endothelial cells, hepatic stellate cells, and human hepatocytes (para 0101, “A cell mixture containing 65% of human hepatocytes (PXB Cells (registered trademark)), 25% of sinusoidal endothelial cells (SEC) and 10% of hepatic stellate cells (LX-2) was suspended in an equal volume mixture solution (heparin/collagen solution) containing 20 μL of 1.0 mg/mL heparin/200 mM tris-HCl buffer solution (pH 7.4) and 20 μL of 0.6 mg/mL collagen/5 mM acetic acid solution (pH 3.7).”). Experimental Example 6 utilizes human umbilical endothelial cells and hepatocytes (para 0115, “1.125×10^5 hepatic stellate cells (LX-2) and 3.75×10^4 human umbilical vein endothelial cells (HUVEC) were suspended in a culture medium to obtain a cell suspension. “; para 0117, “3.0×10^5 human hepatocytes (PXB Cells) were suspended in an equal volume mixture solution (heparin/collagen solution) containing 20 μL of 1.0 mg/mL heparin/200 mM tris-HCl buffer solution (pH 7.4) and 20 μL of 0.6 mg/mL collagen/5 mM acetic acid solution (pH 3.7) to obtain a mixture.”).
Although the Specification provides these working examples, it does not include any examples demonstrating the successful preparation of performance of cell aggregates made from other types of polyelectrolytes, cationic substances, cell populations and extracellular matrix components, as encompassed by the claims. Although the claims broadly encompass any type of these components, the specification contains no experimental data, procedures or functional results for the non-heparin, non-tris-hydrochloric acid buffer, extracellular matrix components of different concentrations, cell types, etc. The absence of working examples for these different components is highly significant because the prior art establishes that varying concentrations of collagen, different cationic substances and polyelectrolytes, and cell populations have an influence the behavior of cell aggregates and subsequently, the production of three-dimensional cellular tissue.
Quantity of Experimentation Necessary
In view of the material-dependent behavior of specific cell aggregates in the art, such as different species of polyelectrolyte and/or cationic substances resulting in vastly different vascularization, a person of ordinary skill in the art would not reasonably expect the formulation of cell aggregates in the specification to be able to address the full scope of different cell aggregate formulations to form three-dimensional cellular tissue without undue experimentation.
Conclusion
In light of the unpredictability surrounding the claimed subject matter and the lack of adequate guidance, one wishing to practice the presently claimed invention would be unable to do so without engaging undue experimentation. One wishing to practice the presently claimed invention would have to produce additional data and experimentation to determine whether the claimed cell aggregates are capable of achieving the intended results. In the absence of such information, a person of ordinary skill in the art would reasonably require an undue quantity of experimentation.
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.
Claim(s) 1-2, 4-5, 7-8, 11, 15, and 17-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Matsusaki et al. (Published: 2018. Cited in IDS filed 6/21/2024, Cite No 4. US 20180355308 A1.) in view of Kitano et al. (Published: 2019. Cited in IDS filed 6/21/2024, Cite No 19. JP2019033732. Machine Translation Provided by Examiner.)
The applied Matsusaki reference has a common applicant (Toppan Printing) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). The publication dated for Matsusaki is Dec. 13, 2018. The earliest effective filing date of the instant application is December 21, 2022.
Therefor rejection under 35 U.S.C. 103 CANNOT be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02. Because the reference qualifies as prior art under 102(a)(1), the provisions of MPEP 717.02 do not apply.
Regarding claim 1, Matsusaki teaches a method of producing three-dimensional cell tissue (Claim 1), comprising the step of mixing cells with a cationic substance, extracellular matrix component and a polymeric electrolyte to obtain a mixture (Claim 1; Claim 2), and collecting cell aggregates from the mixture (Claim 3; para 0131, “A culture solution of NHDF was centrifuged using a microtube, and a supernatant was removed to recover cells. The recovered cells were mixed with a 0.1% collagen solution (dissolved in a DMEM containing 10% FBS), subjected to rotary stirring at 4° C. for 10 minutes to obtain a suspension of the cells. The number of the used cells was 1×10^5 cells, 1×10^ 6 cells, and 3.5×10^ 6 cells. The cell suspension was centrifuged at room temperature for 1 minute at 400×g, and a supernatant was removed to obtain a cell aggregate.”). Moreover, Matsusaki teaches a cell aggregate was sown into a cell culture insert to construct a cell structure (para [0131]]).
Though Matsusaki teaches a cell layer and culturing the cell culture insert to construct a cell structure, Matsusaki fails to explicitly teach the step of culturing cellular aggregates to obtain a three-dimensional tissue structure.
Kitano teaches an embodiment of a multi-layered three-dimensional liver tissue (para 0057, “The three dimensional liver tissue structure according to the present invention is superior in liver function to a monolayer cultured liver cell layer because the liver cells are laminated in the same manner as the liver tissue in the living body.”), wherein the cell layers are constructed by coating the cells with an adhesive film within a culture vessel comprising an additional cell population to form three-dimensional liver tissue (para 0039, “the coated cells coated with the adhesive film are placed in a cell-culture vessel, and then the coated cells are accumulated by centrifugation or the like, thereby constructing a three dimensional hepatic tissue construct composed of multiple cellular layers.”). Moreover, Kitano teaches seeding the mixture in a cell culture vessel to obtain a three-dimensional cell tissue (claim 2, pp. 3“an extracellular matrix component in a cationic buffer solution to obtain a mixture; (b) a step of seeding the mixture obtained in the step (a) in a cell culture vessel; (c) after the step (b), removing a liquid component from the cell mixture in the cell culture vessel to obtain, as a three dimensional liver tissue structure”) . Kitano discloses suspending the cells in a mixture of heparin and collagen (“To be specific, the cells were suspended in a mixture of heparin / 50mM Tris-HCl buffer (pH7. 4) and an equal amount of collagen / 50mM Tris-HCl buffer (pH7. 4). “ and seeding the suspension into a 96 well plate by centrifugation to form a cell layer; page 24 para [0069] and [0071]). Kitano teaches removing the liquid component from a liquid cell culture such that it forms a layer of cells on a substrate (para 0054, “Instead of the step (c), the following step (c ′) may be performed. (c ′) removing the liquid component from the seeded mixture to form a layer of cells on the substrate.”).
It would have been obvious to modify the method of Matsusaki, comprising a cell layer and culturing the cell culture insert to construct a cell structure with the tissue producing method of Kitano, where liver cells are laminated in the same manner as the liver tissue in the living body and to have cell aggregates cultured under static conditions (on a substrate) to promote tissue formation and form a tissue construct. One of ordinary skill in the art would understand culturing the cell mixture within a culture vessel surface (e.g. cell culture plate) would be necessarily culturing the cell aggregates without suspension. There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results.
Regarding claim 2, the combined teachings of Matsusaki and Kitano render obvious the claimed method of claim 1. Moreover, Matsusaki teaches that the seeding of cell aggregates is 10^5 cells (para 0131, "The number of the used cells was 1×10.sup.5 cells, 1×10.sup.6 cells, and 3.5×10.sup.6 cells").
Regarding claim 4 and 7, the combined teachings of Matsusaki and Kitano render obvious the claimed method of claim 1 and 2. Moreover, Matsusaki teaches that the extracellular matrix component is collagen (Claim 26).
Regarding claim 5, 8, 11 and 15, the combined teachings of Matsusaki and Kitano render obvious the claimed method of claim 1, 2, 4 and 7. Moreover, Matsusaki teaches that the concentration of extracellular matrix component is 0.05 mg/mL or more to 0.1 mg/mL or less (within range of instant claim) and the polyelectrolyte component less than 10 mg/mL (Claim 12, "The method of claim 1, wherein a concentration of the extracellular matrix component is from 0.05 mg/mL or more to 0.1 mg/mL or less."; Claim 11, "11. The method of claim 2, wherein a concentration of the polymeric electrolyte is 0.05 mg/mL or more to 0.1 mg/mL or less.").
Regarding claim 17 and 19, the combined teachings of Matusaki and Kitano render obvious the claimed invention. Moreover, Kitano teaches a method of producing three-dimensional liver tissue structure (Claim 1, “A method for producing a three-dimensional liver tissue structure which contains at least hepatocytes”), by suspending a population of cells (para 0069, “Albumin productivity of a three dimensional liver tissue structure constructed by coating hepatocytes with heparin and collagen and then laminating the coated hepatocytes was examined. To be specific, the cells were suspended in a mixture of heparin”), wherein a first cell layer and a second cell layer are in contact such that a three-dimensional tissue is formed (para 0040, “As a result, a three dimensional liver tissue structure having a vascular network structure sandwiched between thick fibroblast layers and having a layer containing hepatocytes in a state of being partitioned from the fibroblast layer and the mesenchymal stem cell layer by a semipermeable membrane can be constructed.”; para 0050, “For example, first, a mixture containing only vascular endothelial cells as cells is prepared in the step (a), and the steps (b) and (c) are performed to obtain a cell structure composed of five vascular endothelial cell layers in a cell culture vessel. Next, as step (a), a mixture containing only hepatocytes as cells is prepared, and steps (b) and (c) are performed to laminate five layers of hepatocyte layers on the vascular endothelial cell layer in the cell culture vessel”).
Regarding claim 18 and 20, the combined teachings of Matsusaki and Kitano render obvious the claimed methodology of claims 17 and 19. Moreover, Kitano teaches that the first layer of cells contain vascular endothelial cells and the second layer of cells contains hepatocytes (para 0050, “For example, first, a mixture containing only vascular endothelial cells as cells is prepared in the step (a), and the steps (b) and (c) are performed to obtain a cell structure composed of five vascular endothelial cell layers in a cell culture vessel. Next, as step (a), a mixture containing only hepatocytes as cells is prepared, and steps (b) and (c) are performed to laminate five layers of hepatocyte layers on the vascular endothelial cell layer in the cell culture vessel... In addition, in the step (a), a mixture in which vascular endothelial cells corresponding to five vascular endothelial cell layers and mesenchymal stem cells corresponding to two mesenchymal stem cell layers are all mixed is prepared, the steps (b) and (c) are performed, and hepatocytes corresponding to five hepatocyte layers prepared in the same manner are laminated on the formed multilayer structure”).
***
Claims 1-3, 6, 9-10, 12-14, and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Matsusaki et al. (Published: 2018. Cited in IDS filed 6/21/2024, Cite No 4. US 20180355308 A1.) in view of Kitano et al. (Published: 2019. Cited in IDS filed 6/21/2024, Cite No 19. JP2019033732. Machine Translation Provided by Examiner.), and in further view of Crooks et al. (Published: 2019. US Patent Publication: US 20190231817 A1.)
With regards to claims 1 and 2, the combined teachings of Matsusaki and Kitano render obvious the claimed methodology of claim 1.
However the combined teachings fail to explicitly teach an adhesive culture vessel, as required by claims 3 and 6.
Crooks et al. teaches a culture vessel for three-dimensional cell aggregates (para 0217, “A culture vessel used for culturing the 3D cell aggregates or progeny cells thereof can include, but is particularly not limited to: flask, flask for tissue culture, dish, petri dish, dish for tissue culture, multi dish, micro plate, micro-well plate....), wherein the culture vessel can be cellular adhesive culture vessel comprising a substrate for cell adhesion (para 0218, “The culture vessel can be cellular adhesive or non-adhesive and selected depending on the purpose. The cellular adhesive culture vessel can be coated with any of substrates for cell adhesion such as extracellular matrix (ECM) to improve the adhesiveness of the vessel surface to the cells.”).
It would have been obvious to substitute the culture vessel of Matsusaki with the culture vessel of Crook since the vessel promotes cell adhesion. There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results.
Regarding claim 9 and 12, the combined teachings of Crook, Matsusaki, and Kitano render obvious the claimed methodology of claim 1, 2, 3 and 6. Moreover, Matsusaki teaches that the extracellular matrix component is collagen (Claim 26, “The three-dimensional cell tissue of claim 24, wherein the extracellular matrix component is selected from the group consisting of collagen, laminin, fibronectin, vitronectin, elastin, tenascin, entactin, fibrillin, proteoglycan, and a combination thereof.”) and that the polymeric electrolyte is glycosaminoglycans (para 0031, “The method of [2], wherein the polymeric electrolyte is selected from the group consisting of glycosaminoglycan, dextran sulfate, rhamnan sulfate, fucoidan, carrageenan, polystyrene sulfonic acid, polyacrylamide-2-methylpropanesulfonic acid, polyacrylic acid, and a combination thereof.”).
Regarding claim 10, 13, 14 and 16, the combined teachings of Crook, Matsusaki, and Kitano render obvious the claimed methodology of claims 1, 2, 3, 6 and 7. Moreover, Matsusaki teaches that the concentration of extracellular matrix component is 0.05 mg/mL or more to 0.1 mg/mL or less (within range of instant claim) and the polyelectrolyte component is less than 10 mg/mL (Claim 12, "The method of claim 1, wherein a concentration of the extracellular matrix component is from 0.05 mg/mL or more to 0.1 mg/mL or less."; Claim 11, "11. The method of claim 2, wherein a concentration of the polymeric electrolyte is 0.05 mg/mL or more to 0.1 mg/mL or less.").
Conclusion
No claims allowed.
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/KATRIEL BARCELLANO KASAYAN/Examiner, Art Unit 1634 /MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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