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 Status
Claims 1 – 39 are pending in this application.
Claim Objections
Claim 7 is objected to because of the following informalities: In claim 7, MRP3 is used twice, which is thought to be a typographical error. Appropriate correction is required.
Claim 31 is objected to because of the following informalities: In claim 31, there is a line through the number (31), which is thought to be a typographical error. 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.
Claims 1 – 2, 4 – 30 and 32 – 39 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 claims 1 – 2, 4 – 30 and 32 – 39, the specification does not provide concrete definitions for the relative terms “low” and “high”. The phrase “in some embodiments” is not a limiting definition. Paragraph 140 contemplates a low concentration is 0.01 – 3 mg/L, but paragraph 146 states a high concentration is 2 – 10 mg/L, thereby defining 2 mg/L as both a “low” and a “high” concentration. Therefore the scope of each claim (independent and dependent) is indefinite.
Claim 34 recites the limitation "the glucocorticoid antagonist” in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 35 recites the limitation "the glucocorticoid antagonist" in line 1. There is insufficient antecedent basis for this limitation in the claim.
For examination purposes claims 34 and 35 will be read as if dependent on claim 33, which recites a glucocorticoid antagonist.
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 print 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 30 – 32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tanimizu et al. (Generation of functional liver organoids on combining hepatocytes and cholangiocytes with hepatobiliary connections ex vivo. Nat Commun. 2021;12(1):3390; cited on IDS, hereinafter Tanimizu).
Regarding claims 30 – 32, Tanimizu teaches contacting liver organoids (HBTOs) with a high concentration of bilirubin (p. 10, Detection of bilirubin in the organoids) at 10 µg/mL, thereby forming the hyperbilirubinemia liver organoid. The elevated levels of UGT1A1 and NRF2 in claim 32 are a result of contacting the liver organoid with a high concentration of bilirubin.
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 33 – 35 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Tanimizu, as applied to claims 30 – 32 above, and further in view of Hong et al. (Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats, Human and Experimental Toxicology, 2015 Vol. 34(1) 32 – 43; hereinafter Hong), Yueh et al. (Nrf2-Keap1 Signaling Pathway Regulates Human UGT1A1 Expression in Vitro and in Transgenic UGT1 Mice, The Journal of Biological Chem, Vol 282, No. 12, pp. 8749 – 8758 (2007); hereinafter Yueh), and Togawa et al. (Induction of Human UGT1A1 by Bilirubin Through AhR Dependent Pathway, Drug Metab Letters, 2, 231-237, 2008; hereinafter Togawa).
Regarding claims 33 – 35 and 39, Tanimizu teaches all of the elements of the current invention as stated above except for the following: contacting a hyperbilirubinemia liver organoid with a glucocorticoid antagonist; and a hyperbilirubinemia liver organoid comprising an inactive UGT1A1 gene or it being a model for Crigler-Najjar Syndrome. However, Hong teaches that mifepristone enhances NRF2 mRNA and protein levels (p. 36, Results – Section 1) in RU486 (mifepristone) transfected mice. Furthermore, Yueh discloses that NRF2 activation leads to the induction of UGT1A1 (Abstract), thereby enhancing cellular UGT1A1 glucuronidation activities. Finally, Togawa teaches that UGT1A1 plays (Abstract) a key role in bilirubin conjugation and increasing the concentration of bilirubin increases UGT1A1 in HepG2 cells. Togawa further discloses that a defect in UGT1A1 (p. 231, Introduction – Paragraph 2) is what characterizes Crigler-Najjar Syndrome.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to take the teachings of Hong to use mifepristone to enhance NRF2 expression in the hyperbilirubinemia liver organoid of Tanimizu, with the motivation from Yueh to induce UGT1A1 for the increase in bilirubin conjugation taught by Togawa. Furthermore, Togawa’s teaching on defective UGT1A1 expression when combined with the hyperbilirubinemia liver organoid of Tanimizu would allow for the liver organoid to be engineered to mimic Crigler-Najjar Syndrome.
Claims 36 – 38 are rejected under 35 U.S.C. 103 as being unpatentable over Tanimizu, as applied to claims 30 – 32 above, and further in view of Flett et al. (Gulonolactone Addition to Human Hepatocellular Carcinoma Cells with Gene Transfer of Gulonolactone Oxidase Restores Ascorbate Biosynthesis and Reduces Hypoxia-Inducible Factor 1. Biomedicines. 2014;2(1):98-109. Published 2014 Mar 5.; hereinafter Flett), and Das et al. (Das AT, Tenenbaum L, Berkhout B. Tet-On Systems For Doxycycline-inducible Gene Expression. Curr Gene Ther. 2016;16(3):156-67; hereinafter Das).
Regarding claims 36 – 38, Tanimizu teaches all of the elements of the current invention as stated above except a hyperbilirubinemia liver organoid comprising a functional and conditionally-expressed GULO protein. However, Flett discloses that humans are unable to synthesize ascorbate due to the lack of a functional gulonolactone oxidase (GULO) enzyme (Abstract), so they transfected a plasmid encoding mouse Gulo cDNA for their study into HepG2 cells. Ascorbate is important for the liver because it protects cells from oxidative damage (p. 99, Introduction) supports detoxification, aids in tissue repair, and helps regulate metabolism. The difference between Flett and the instant application is that Flett’s aim was to restore ascorbate synthesis to human HepG2 cells and determine the effect of internally produced ascorbate on (Hypoxia-Inducible Factor) HIF-1 activation. Also, Das (Abstract) discloses the use of the Tet-On (Tetracycline inducible) system for the conditional expression of a gene is to activate/regulate the expression of the gene in diverse settings.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Tanimizu’s hyperbilirubinemia liver organoid, Flett’s murineGULO (mGULO) plasmid with the motivation of Das for conditional expression, in order to research the activity of the hyperbilirubinemia liver organoid with and/or without the ability to synthesize ascorbate. Doing so would improve efforts to formulate potential therapies for the treatment of hyperbilirubinemia.
Allowable Subject Matter
Claim 3 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
Claim 3 would be allowable because it is free of the art and if incorporated into claim 1, it and the dependent claims will be considered allowable.
Conclusion
Claims 1 – 2, 4 – 30 and 32 – 39 are rejected under 112b. Claim 3 is objected to but has allowable subject matter. The invention as claimed in claims 30 – 39 is anticipated by Tanimizu and prima facie obvious over Tanimizu in view of Hong, Yueh, Togawa, Flett and Das. No claim is currently in allowable condition.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WALTER JACKSON III whose telephone number is (571)272-0247. The examiner can normally be reached Monday-Friday 9:00A - 5:00P.
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/WALTER JACKSON III/ Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638