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
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant indicates on the Request for Continued Examination (RCE) Transmittal filed on 04 May 2026 has been entered.
Claim Status
In the reply filed on 20 April 2026, Applicant has amended claim 33. Claims 9, 11-32 and 34-48 are previously cancelled and therefore, claims 1-8,10 and 33 are herein pending.
Election/Restrictions
Applicant previously elected without traverse of Group I, claims 1-8,10 and 33 drawn to a method of expanding hepatoblasts with a Wnt pathway activator, a TGF beta inhibitor, and FGF19 in the reply filed on 17 December 2024.
In the reply filed 03 October 2025, Applicant has cancelled withdrawn Groups 2-3 (Claims 11-32 and 34-48).
Therefore, claims 1-8,10 and 33 are herein under examination.
Withdrawn Rejections
Applicant argues that in the prior art Hu et al., (US20190161734A1) discloses the individual components of the expansion media required by independent claim 1 (i.e., an activator of the Wnt pathway, a TGF beta inhibitor, and FGF 19 or an equivalent thereof), Hu does not disclose using all three components together as recited in independent claim 1. Therefore, applicant arguments have been fully considered and are found persuasive. Specifically, Hu discloses that the culturing system can include an enhancer of the WNT pathway (see paragraph [0044]) and a stem cell differentiation inhibitor (see paragraph [0045]) but can be FGF-free (see paragraph [0046]). Therefore, However, Hu did not to teach or reasonably suggest a method of expanding hepatoblasts using all three components (i.e., an activator of the Wnt pathway, a TGF beta inhibitor, and FGF19 or an equivalent thereof) together. Therefore, the prior rejection of claims 1-4, and 33 under 35 U.S.C. 103 as being unpatentable over by Hu et al., (US20190161734A1; published on May 30, 2019; cited in PTO892; hereinafter “Hu”), in view of Harrison et al. (The Lancet, 391(10126), pp.1174-1185; cited in PTO892; hereinafter “Harrison”) is hereby withdrawn.
Accordingly, the prior rejection of claims 1-8, 10 and 33 under 35 U.S.C. 103 as being unpatentable over Hu et al., (US20190161734A1; cited in PTO892; hereinafter “Hu”) in view of Harrison et al. (The Lancet, 391(10126), pp.1174-1185; cited in PTO892; hereinafter “Harrison”) as applied to claims 1-4, and 33 above, and further in view of Wenum et al., (Journal of Cell Communication and Signaling (2018) 12:575–588; cited in PTO892; hereinafter “Wenum”) is hereby withdrawn.
New 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 1-8,10 and 33 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Regarding claim 1, 8 and 33, the term “an equivalent” in the claim is a relative term which renders the claim indefinite. The term “equivalent” 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. It is unclear how to measure the equivalency in claims is compared to FGF19 (i.e., measure the regulating bile acid synthesis the level as compared to what?). Therefore, the claims 1, 8 and 33 are indefinite and dependent claims 2-5 and 10.
Claims 6 and 7 are rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph, as being incomplete for omitting essential steps, “wherein the composition comprises hepatoblasts expanded using the method of claim 1.” See MPEP § 2172.01. Specifically, claim 6 is directed to “A method of expanding hepatoblasts”, which does NOT narrow the scope of claim 1 that is directed to a method of expanding hepatoblasts. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements. The rejection may be obviated by amending the claim 6 to recite: “wherein the composition comprises hepatoblasts expanded using the method of claim 1.”
Claim Rejections - 35 USC § 112(a)
(Written description)
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, 8, and 33 are 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 contains subject matter that 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 pre-AIA the inventor, at the time the application was filed, had possession of the claimed invention.
Under the written description guidelines (see MPEP 2163), the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail so that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
Claims 1 and 8 encompasses a genus of any Wnt pathway, any TGF beta inhibitor, and any FGF19 or any equivalent thereof (hereinafter “any three components”). However, the specification doesn't have adequate support in the disclosure for the any three components. The specification discloses that the methods
typically include culturing the hepatoblasts in the presence the activator of the Wnt pathway is CHIR99021, CHIR98014, BIO, a (potent) GSK-3 inhibitor, or a natural Wnt agonists such as Wnt3, the TGF-beta receptor inhibitor is SB431542, A83-01, or an ALK4 and/or ALK7 inhibitor (e.g., SB525334, SB505124, etc.) and the FGF 19 or an equivalent thereof is an engineered version of FGF 19 referred to as NGM282 (see SPEC p. 1 lns 24-29). More specifically expanding hepatoblasts using CHIR99021 (1 μM), SB431542 (6 μM) and FGF19 (50 ng/ml) for 6 days (see SPEC p. 18 lns 25-31). Furthermore, SPEC discloses that the zonation of hepatoblasts can be facilitated by
manipulating Wnt signaling in the cells together with the treatment of thyroid hormone.
Zone I hepatocyies (or Zone I-like hepatocytes) can be obtained by culturing
hepatoblasts in the presence of an inhibitor of the Wnt pathway. Inhibitors of the Wnt
pathway is known or can be identified by a skilled artisan; representative Wnt pathway inhibitors include, without limitation, XAV939, IWP2, IWP4, or ICRT14. Zone 3 hepatocytes (or Zone 3-like hepatocytes) can be obtained by culturing hepatoblasts in the presence of an activator of the Wnt pathway. Activators of the Wnt pathway are discussed herein and include, without limitation, CHIR99021, CHIR98014, BIO, GSK-3 inhibitors and natural 30 Wnt agonists (e.g., Wnt3). Zone3 hepatocyies express multiple CYP enzymes including, without limitation, CYP2C9, CYP2D6 and CYP3A4, which are highly expressed in pericentral hepatocytes in the liver lobule, whereas Zone I hepatocytes express PCK, G6P. Therefore, SPEC does not support merely three specific activators, namely a Wnt pathway, TGF beta inhibitor, and FGF19 or equivalentfor use in a medium for culturing the hepatoblast. Rather, the SPEC fails to disclose that any arbitrary combination of any three components can be used in a medium according to the instant method. Accordingly, the specification fails to identify or support the use of any three components as claimed.
The teaching of Hu et al. (US20190161734A1; published on May 30, 2019; cited in PTO892; hereinafter “Hu) discloses a method of expanding (e.g., culturing) hepatoblast [0042-0046] in the presence of an activator of the Wnt pathway (i.e., CHIR99021) [0056] a TGF beta inhibitor (i.e., A83-01) [0057]. In some cases, the hepatocyte differentiation medium further comprises about 10 to 300 ng/ml BMP7, about 5 to 200 ng/ml FGF19, and/or about 1 to 200 ng/ml oncostatin M(OSM) [0132]. Hu discloses that the expanded hepatoblasts will be treating a subject having liver disease, wherein the administered or transplanted cell integrates into and repopulates the liver of the subject [0138], [0150]. Therefore, Hu provide robust evidence that the culturing the hepatoblasts in the presence of CHIR99021, A83-01 and further comprising FGF19. Therefore, it is obvious that prior art does not support to identify the generic Wnt pathway, TGF beta inhibitor, and FGF19 or equivalent thereof together in culture medium for expanding the hepatoblasts. With these additional evidences, the method of treating any three components in a medium for expanding the hepatoblasts is not well established at the time of filling and the ordinary artisan cannot predictably identify any three components in a medium.
In a separate prior art, Bria et al. (Liver Research 1 (2017) 81e87; cited in PTO892; hereinafter “Bria”) discloses the several activation factors are involve to activate the replication of mature hepatocytes such as Hepatocyte growth factor (HGF)/c-Met signaling, transcriptional co-activator Yes-associated protein (YAP), Hippo pathway, such as WW45 (see p. 84 “5.1. Pathways for HPC/OC proliferation” ¶ of Bria). Bria also discloses Phagocytosis of hepatocyte debris by liver macrophages results in expression of Wnt3a. Wnt3a in close proximity to HPC/OCs activates Wnt pathways, leading to transcriptional activation of Numb (a Notch pathway inhibitor) and progenitor differentiation into hepatocytes (see Fig. 3 caption of Bria). TGF-b signaling stimulates several processes including cell differentiation, such as CTGF belongs to the Cyr61/CTGF/Nov (CCN) protein family and can potentiate the fibrogenic activity of TGF-b through direct interaction (see p. 85 “5.3. Pathways for HPC/OC and myofibroblast interaction” ¶ of Bria). Therefore, Bria does not support merely three specific activators, namely a Wnt pathway, TGF beta inhibitor, and FGF19 or equivalent for use in a medium for culturing the hepatoblast. Rather, Bria disclose several activation factors are involve to activate the replication of mature hepatocytes. Accordingly, Bria does not identify or support the use of any three components as claimed.
Similarly, in the patent Lijian et al. (CN110982776A - In-vitro amplification culture method and application of hepatocytes; cited in PTO892; attached Google patent English translation; hereinafter “Lijian”) discloses a method for expanding hepatocytes in vitro, comprising: culturing the hepatocytes with a cell culture medium containing a Wnt signaling pathway activator to expand the hepatocytes, wherein the cell culture medium further contains a component selected from the group consisting of N-acetyl-cysteine, nicotinamide, FGF10, EGF, HGF, [Cell culture medium for Leu15]-gastrin I, A 83-01, Y-27632 and cell growth additives selected from the group consisting of N2 supplements, B27 supplements; or serum The medium is selected from following group as basal medium: DMEM, MEM, RPMI, Neuronal basal or Fischers; Preferably , the DMEM is selected from: Advanced DMEM/F12, DMEM/F12. The method according to any one of claims 1 to 5, wherein the method further comprises: inducing the expanded hepatocytes into mature hepatocytes, comprising: adding Forskolin to the cell culture medium, Dexamethasone, Oncostatin M (see claims 1-6 of Lijian). Therefore, Lijian does not disclose merely three specific activators, namely a Wnt pathway, TGF beta inhibitor, and FGF19 or equivalent for use in a medium for culturing the hepatoblast. Rather, Lijian disclose several activation factors are involve for expanding hepatocytes in vitro. Accordingly, Lijian does not identify or support the use of any three components as claimed.
Therefore, it is concluded that the disclosure of the three species of activator does not constitute a “representative number of species” to show possession of the broad genus presently claimed. Accordingly, the claimed genus of any Wnt pathway, any TGF beta inhibitor, any FGF19 or any equivalent thereof and/or only these three activator together in a medium for expanding the hepatoblasts doesn't have an adequate written description. It concludes that a skilled artisan would find the specification inadequately described. Therefore, the Applicant did not sufficiently possess the broader invention as claimed.
Therefore, the Applicant did not sufficiently possess the broader invention as claimed in claim 1 and dependent claim 33.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 20 April 2026 are acknowledged.
Applicant' s arguments with respect to Claims 1, 2, 4 and 18-20 under 103 over Hu have been considered and persuasive. Applicant’s arguments are moot.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MASUDUR RAHMAN whose telephone number is (571)272-0196. The examiner can normally be reached M-F 8-5 (EST).
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/MASUDUR RAHMAN/ Patent Examiner, Art Unit 1633
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684
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