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 .
Status of the Claims
Claims 1-9 are pending (claim set as filed on 10/27/2023).
Priority
This application is a 371 of PCT/JP2022/019017 filed on 04/27/2022, which has a foreign application no.: JP 2021-075780 filed on 04/28/2021.
Information Disclosure Statement
The Information Disclosure Statements (IDS) submitted on 10/27/2023 and 05/06/2025 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the Examiner.
Drawings
The drawings filed on 10/27/2023 have been accepted.
Claim Rejections - 35 USC §102, Anticipation
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 1-9 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Takebe (US 2022/0252575 A1 - cited in the IDS filed on 10/27/2023).
Regarding claims 1-3 and 5-9 pertaining to a method of producing sinusoidal endothelial cells, Takebe teaches that “human induced pluripotent stem cells were cultured in AK02N at 5% CO2, 37°C for 6-7 days to form an iPS cell colony with a diameter of 500-700 µm ... Thereafter, the medium was replaced with Stempro-34 SFM (Gibco) (8 ml) supplemented with VEGF (80 ng/ml), SCF (50 ng/ml), Flt-3L (50 ng/ml), IL-3 (50 ng/ml), IL-6 (50 ng/ml) and TPO (5 ng/ml), and the cells were cultured at 5% CO2, 37° C for 2 days ... and the cells were cultured at 5% CO2, 37° C for 2 days to give CD34-positive, CD32-positive, Factor VIII-positive hepatic sinusoidal endothelial cells” (see ¶ [0102]-[0104: Example 6).
Regarding claims 2-4 pertaining to oncostatin (OSM), Takebe teaches “the medium for hepatocytes includes RPMI, HCM and the like. The medium for hepatocytes may contain one or more kinds of additives selected from Wnt3a, activin A, BMP4, FGF2, FBS (bovine fetal serum), HGF (hepatocyte growth factor), oncostatin M (OSM), dexamethasone (Dex), and the like” (see ¶ [0047]).
Claims 1-6 and 8-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Koui (An In Vitro Human Liver Model by iPSC-Derived Parenchymal and Non-parenchymal Cells, 2017 - cited by the ISA and in the IDS filed on 10/27/2023).
Regarding claims 1, 5-6, and 8-9, Koui teaches “In the present study, toward generation of hiPSC-derived (human induced pluripotent stem cells) mature hepatocytes, we generated hiPSC-derived LSECs (liver sinusoidal endothelial cells) and HSCs capable of supporting the proliferation and differentiation of LPCs” (see page 490: Introduction). In particular, Koui teaches the development of efficient culture systems for LSECs progenitors after the induction of hiPSCs (see page 492, right col.).
Regarding claims 2-4 pertaining to oncostatin (OSM), Koui teaches co-culture induction with oncostatin M stimulation (see page 495, bridging ¶ of left & right col.).
Claim Rejections - 35 USC §103, Obviousness
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 non-obviousness.
Claims 2-3 are rejected under 35 U.S.C. 103 as being unpatentable over Koui (An In Vitro Human Liver Model by iPSC-Derived Parenchymal and Non-parenchymal Cells, 2017 - cited by the ISA and in the IDS filed on 10/27/2023) as applied to claims 1-6 and 8-9, and in view of Mandalam (US Patent no. 9,587,223 B2).
Koui’s disclosure is taught above as it pertains to a method for producing liver sinusoidal endothelial cells.
However, Koui does not teach: wherein the one or more substances selected from the IL-6 family comprise at least interleukin 6 (IL-6), ciliary neurotrophic factor (CNTF), or leukemia inhibitory factor (LIF) (claims 2-3).
Mandalam’s general disclosure relates to “the field of cell biology of embryonic cells and liver cells. The disclosure provides new approaches to directed differentiation of human pluripotent stem cells into cells bearing features and important enzymatic functions of hepatocytes” (see col. 1, lines 35-41). Mandalam discloses “markers characteristic of sinusoidal endothelial cells include Von Willebrand factor, CD4, CD14, and CD32” (see col. 17, lines 25-30). Mandalam teaches “other hepatocyte differentiation and maturation factors illustrated in this disclosure include soluble growth factors (peptide hormones, cytokines, ligand-receptor complexes, and other compounds) that are capable of promoting the growth of cells of the hepatocyte lineage. Such factors include but are not limited to epidermal growth factor (EGF), insulin, TGF-α, TGF-β, fibroblast growth factor (FGF), heparin, hepatocyte growth factor (HGF), Oncostatin M (OSM), IL-1, IL-6, insulin-like growth factors I and II (IGF-I, IGF-2), heparin binding growth factor 1 (HBGF-1), and glucagon. The skilled reader will already appreciate that Oncostatin M is structurally related to Leukemia inhibitory factor (LIF), Interleukin-6 (IL-6), and ciliary neurotrophic factor (CNTF)” (see col. 11-12, bridging ¶).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add or employ the claimed substances (e.g., IL-6, LIF, or OSM) such as taught by Mandalam in the method of Koui for producing sinusoidal endothelial cells. The ordinary artisan would have been motivated to do so is because Mandalam teaches that these are known hepatocyte differentiation and maturation factors that are capable of promoting the growth of cells of the hepatocyte lineage. The ordinary artisan would have had a reasonable expectation of success because both of the cited references are in the same field of endeavor directed to the culture and differentiation of hepatocyte cells.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Koui (An In Vitro Human Liver Model by iPSC-Derived Parenchymal and Non-parenchymal Cells, 2017 - cited by the ISA and in the IDS filed on 10/27/2023) as applied to claims 1-6 and 8-9, and in view of Keller (US 2022/0025324 A1).
Koui’s disclosure is taught above as it pertains to a method for producing liver sinusoidal endothelial cells.
However, Koui does not teach: wherein the medium further contains vascular endothelial growth factor (VEGF) (claim 7).
Keller’s general disclosure relates to methods for producing venous endothelial lineage cells and, in particular, to sinusoidal endothelial cell-like cells, compositions that include such cells and uses thereof (see abstract & ¶ [0002]). Keller discloses that “VEGF, bFGF, NOTCH and signaling play a role in the specification of vascular fates in hPSC differentiation cultures” (see ¶ [0005]).
In particular, Keller teaches “methods of producing sinusoidal endothelial cell-like cells (SEC-LCs) are provided. Such methods typically include providing stem cells or angioblasts; and culturing the stem cells or angioblasts under conditions in which SEC-LCs are produced, wherein the conditions comprise: a) culturing the stem cells or angioblasts in the presence of bFGF; or b) culturing the stem cells or angioblasts in the presence of vascular endothelial growth factor (VEGF)-A to produce endothelial cells followed by culturing the endothelial cells in the presence of a TGF-β signaling inhibitor, cyclic AMP ( cAMP) signaling agonist, VEGF-C; or c) culturing the stem cells or angioblasts under hypoxic conditions, thereby producing SEC-LCs” (see ¶ [0006]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add or employ the claimed substances (e.g., VEGF) such as taught by Keller in the method of Koui for producing sinusoidal endothelial cells. The ordinary artisan would have been motivated to do so is because Keller teaches that “VEGF, bFGF, NOTCH and signaling play a role in the specification of vascular fates in hPSC differentiation cultures” (see Keller at ¶ [0005]). The ordinary artisan would have had a reasonable expectation of success because both of the cited references are in the same field of endeavor directed to the culture and differentiation of hepatocyte cells.
Claim Rejections - 35 USC §101, Subject Matter Eligibility
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.
Claim 9 is rejected under 35 U.S.C. 101 because they are drawn to ineligible subject matter (based on the 2019 Revised Patent Subject Matter Eligibility Guidance).
Claim interpretation of base claim 9: the claim, as a whole, is drawn to a composition (i.e., its statutory category of invention) but the recitation of the phrase “obtained by the method of according to claim 1” invokes the interpretation of a product-by-process claim. The MPEP 2113(I) states that “Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process”. Thus, the emphasis in analyzing a product claim is the distinctive structural features.
STEP 1: Is the claim directed to a process, machine, manufacture, or a composition of matter?
YES, the claims are directed to a composition of matter.
STEP 2A: PRONG ONE: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
YES, the claims are considered to be “product of nature” exceptions (i.e., a mixture of naturally occurring products). The courts have held that “products of nature” fall under the laws of nature and/or natural phenomena exceptions.
PRONG TWO: Does the claim recite additional elements that integrate the judicial exception into a practical application?
NO, the additional elements or a combination of elements in the claims does not impose a meaningful limit on the judicial exception. Note that the markedly different characteristics analysis is used to determine if a nature-based product is a “product of nature” exception. Thus, the markedly different characteristics analysis is part of Step 2A, i.e., it helps answer the question of whether a claim is directed to an exception as further explained below.
STEP 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
NO, the claimed invention is directed to a law of nature and/or natural phenomena (i.e., a product of nature) without significantly more. Note that the claims must be interpreted under the broadest reasonable interpretation (BRI) standard when evaluating for a marked difference.
the instant specification discloses that sinusoidal endothelial cells are cells of the liver (see pre-grant specification at ¶ [0003]).
Keller (US 2022/0025324 A1) discloses “Within normal liver tissue
for example, multiple types of endothelial cell types are present and represent the interaction surface between hepatocytes and the rest of the body. Primarily, this interaction occurs within the sinusoidal vascular network across the Liver Sinusoidal Endothelial Cells (LSECs) through their dynamically controlled transcellular fenestrations arranged in sieve plates” (see Keller at ¶ [0003]).
There is no indication that the claimed composition has any markedly different characteristic (e.g., structure, function, phenotype, etc.) that is different than what is found in nature. Thus, it appears that Applicant is claiming a naturally occurring product or at least one that is substantially similar thereto with no marked difference.
Therefore, the claims are interpreted under the BRI standard, wherein the claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claim does not recite any additional elements.
Therefore, the claim, as a whole, is considered as a product of nature which is directed to a judicially recognized exception without amounting to significantly more from what occurs in nature and thus, is not eligible subject matter under 35 U.S.C. §101.
Conclusion
No claims were allowed.
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/NGHI V NGUYEN/Primary Examiner, Art Unit 1653