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 .
Claim status
In the reply filed 03 October 2025, Applicant has amended claims 1, 2, 6, 8 and 10. Claims 9, 11-13, 19-21, 24, and 41-47 are cancelled and therefore, 1, 2, 6, 8 and 10 are pending.
Election/Restrictions
Applicant's previously without traverse of Group I, claims 1, 2, 6, 8 and 10 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In the reply filed 03 October 2025, Applicant has cancelled withdrawn Groups 2-3 (Claims 11-13,19-21,24 and 41-47)
Therefore, claims 1, 2, 6, 8 and 10 are herein under examination.
Priority
This application was filed 12/03/2021 and is a 371 application of PCT/IB2020/ 055249 filed on 06/03/2020, which claims benefit to the Provisional Application 62857180 filed on 06/04/2019. Thus, the earliest possible priority for the instant application is 06/04/2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/03/2025 is are in compliance with the provisions of 37 CFR 1.97.
Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Abstract Objections
Applicant has amended the Abstract filed 03 October 2025 to correspond to the elected claims. Therefore, the objection to the Abstract is withdrawn.
Withdrawn 35 USC § 112
Applicant has amended claim 2, and remove the exemplary language “such as” and therefore, the prior rejection of Claim 2 under 35 U.S.C. § l 12(b) or 35 U.S.C. § 112 (pre-AIA ), second paragraph is withdrawn.
Withdrawn 35 USC § 102
The prior rejection of claims 1-3, and 33 under 35 U.S.C. 102(a)(1) as being anticipated by Hu et al., (US20190161734A1; published on May 30, 2019; cited in PTO892; hereinafter “Hu”) is withdrawn. The withdrawn is in light of Applicant’s amendment of claim 1 to exclusively include the limitation of cancelled claim 9 “wherein the number of hepatoblasts are expanded about 100-fold to about 400-fold within 3 to 5 passages” which was not disclosed by Hu.
The prior rejection of claims 1-3, and 33 under 35 U.S.C. 102(a)(1) as being anticipated by Ng et al., (US20180258400A1; publication date Pub. Date: Sep. 13, 2018; cited in PTO892; hereinafter “Ng”) is withdrawn. The withdrawn is in light of Applicant’s amendment of claim 1 to exclusively include the limitation of cancelled claim 9 “wherein the number of hepatoblasts are expanded about 100-fold to about 400-fold within 3 to 5 passages” which was not taught by Ng.
Modified 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 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 nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, and 33 are rejected 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”). The modified rejection is necessitated by applicant’s claim amendments.
With respect to claims 1-3, and 33, Hu teaches 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], and FGF19 [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].
Regarding claim 1, Hu does not particularly teach the limitation of the specific fold expansion of hepatocytes within passages during the culturing the hepatoblasts in presence of an activator of the Wnt pathway, a TGF beta inhibitor, and FGF19. However, such would be an inherent property of the hepatocytes. MPEP 2112.01(i) states that when the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent.
MPEP 2112.01.“[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Regarding claim 4, Hu does disclose that NGM282 is an FGF19 analogue, However, such was known in the prior art.
With respect to claim 4, Harrison discloses that NGM282 is a non-tumorigenic variant of FGF19.
MPEP 2143 (A) states that combining prior art elements according to known methods to yield predictable results. The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395. Accordingly, it would have been obvious to practice the hepatocytes expansion method of Hu and include the NGM282 as taught by Harrison with a reasonable expectation of success. One of ordinary skill would have been motivated to do so as taught by Harrison because NGM282 can block hepatocarcinogenesis associated with human FGF19 (p. 1175 2nd Col ¶ of Harrison). Therefore, the products and method as taught by Hu et al. in view of Harrison et al. would have been prima facie obvious over the method of the instant application. In regard to the reasonable expectation of success in doing so, include the NGM282 in the hepatocytes culturing method of Hu had a reasonable expectation of success since the steps thereof required no more than pipetting appropriate NGM282 concentration and cell culture technology.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 1-8, 10 and 33 are rejected 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”).
As stated supra, Hu in view of Harrison, teach the 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], and FGF19 [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].
Regarding claim 5, Hu is silent to culturing the hepatoblasts under hypoxic conditions. However, such was known in the prior art.
With respect Claims 5-8, Wenum discloses that human hepatic progenitor cell line (i.e., HepaRG cells) are cultured under hypoxia (5%O2), normoxia (21% O2) or hyperoxia (40% O2). Furthermore, Wenum discloses that the cells lost viability under hyperoxia when applied in the proliferation phase, and not when applied in the differentiation phase. In addition, propagation of the liver cells was optimal under hypoxia, while differentiation was clearly inhibited by low oxygen concentration (p. 584 2nd Col 2nd ¶).
With respect claims 6, 8, and 10, Wenum does not particularly teach that the hepatoblasts are ALB+ AFP+ and the specific fold expansion of hepatocytes within passages during the culturing the hepatoblasts under hypoxic conditions. However, such would be an inherent property of the hepatocytes. MPEP 2112.01 (i) states that when the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent.
MPEP 2112.01.“[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Accordingly, it would have been obvious to practice the hepatocytes expansion method of Hu and optimize the oxygen and passages as taught by Wenum with a reasonable expectation of success. One of ordinary skill would have been motivated to do so as taught by Wenum because it will be treating a subject having liver disease are described herein to the subject, such as by contacting the liver stem cell with the liver of the subject in vivo, or by transplanting a liver stem cell into the liver of the subject ([0138] of Hu). The skilled artisan would have had a reasonable expectation of success in combining the teachings of Hu et al. and Wenum et al. because each of these teachings both successfully generated hepatocytes. Therefore, the products and method as taught by Hu et al. in view of Wenum et al. would have been prima facie obvious over the method of the instant application. In regard to the reasonable expectation of success in doing so, culturing the hepatoblasts under hypoxic conditions method of Wenum had a reasonable expectation of success since the steps thereof required no more than adjusting appropriate oxygen concentration and cell culture technology.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 03 October 2025 are acknowledged.
Applicant’s arguments with respect to Claims 1-4, and 33 rejection under 35 U.S.C. 10 over Hu (see remark p. 6-7) is withdrawn in view of the amendments to the claims. Applicant' s arguments are moot.
Applicant argue that the pending claims require expansion of hepatoblasts under various conditions (i.e., independent claims 1 and 8 in the presence of expansion media and independent claims 6 and 8 under hypoxic conditions) and the degree of expansion under each of those conditions is now recited in each of the independent claims. There is nothing in Hu or Wenum that describe the expansion media required by independent claims 1 and 8 or the hypoxia required by independent claims 6 and 8 as well as the accompanying increase in the number of hepatoblasts under such conditions.
Specifically, while Hu discloses the individual components of the expansion media recited in independent claims 1 and 8, Hu does not disclose using all three components together. Specifically, Hu discloses that the culturing system can be FGF-free (see paragraph [0046]) and further discloses that FGF19 is used in hepatocyte differentiation medium (paragraph [0132]). Thus, Hu does not suggest using FGF 19 during expansion and, since Wenum is focused on terminally differentiated hepatocytes, Wenum certainly does not cure this deficiency (see remark pp. 8-9).
Applicant's arguments have been fully considered but they are not persuasive because the modified rejection relies on amendment claims and references applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. In the new rejection, Hu teaches 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], and FGF19 [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]. Furthermore, Wenum discloses that human hepatic progenitor cell line (i.e., HepaRG cells) are cultured under hypoxia (5%O2), normoxia (21% O2) or hyperoxia (40% O2). Furthermore, Wenum discloses that the cells lost viability under hyperoxia when applied in the proliferation phase, and not when applied in the differentiation phase. In addition, propagation of the liver cells was optimal under hypoxia, while differentiation was clearly inhibited by low oxygen concentration (p. 584 2nd Col 2nd ¶). Accordingly, it would have been obvious POSITA would have been motivated to practice the hepatocytes expansion method of Hu and optimize the oxygen and passages as taught by Wenum with a reasonable expectation of success because it will be treating a subject having liver disease are described herein to the subject, such as by contacting the liver stem cell with the liver of the subject in vivo, or by transplanting a liver stem cell into the liver of the subject ([0138] of Hu). Therefore, POSITA would have had a reasonable expectation of success in combining the teachings of Hu et al. and Wenum et al. because each of these teachings both successfully generated hepatocytes.
Although Hu teaches cell culture system for culturing liver stem cells [0042-0046] and the hepatocyte differentiation medium comprises FGF19 [0046], therefore, a pure stem cell population maintained in culture will increase the stem cell expansion efficiency [0150]. Therefore, Hu does suggest using FGF 19 during expansion of hepatocyte.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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