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 .
Claims 1, 2, 4, 5, 7, 9-20 and 24-26 are pending in this application, Claims 9-18 are acknowledged as withdrawn, Claims 1, 2, 4, 5 , 7, 19, 20 and 24-26 were examined on their merits.
The rejection of Claim(s) 1, 3, 4, 6 and 22 under 35 U.S.C. § 103 as being unpatentable over Auth et al. (2001), cited in the IDS, as evidenced by Kibbey (1994), in view of Zuo (2012), both of record, has been withdrawn due to the Applicant’s amendments to the claims filed 02/23/2026.
The rejection of Claim(s) 1, 2, 3, 4, 6, 22 and 23 under 35 U.S.C. § 103 as being
unpatentable over Auth et al. (2001), cited in the IDS, as evidenced by Kibbey (1994), in
view of Zuo (2012), both of record, and further in view of Hashimoto et al. (2008), of record, has been withdrawn due to the Applicant’s amendments to the claims filed 02/23/2026.
The rejection of Claim(s) 1, 3, 4, 5, 6, 21 and 22 under 35 U.S.C. § 103 as being unpatentable over Auth et al. (2001), cited in the IDS, as evidenced by Kibbey (1994), in view of Zuo (2012), both of record, and further in view of Tanimizu et al. (2007), of record, has been withdrawn due to the Applicant’s amendments to the claims filed 02/23/2026.
The rejection of Claim(s) 1, 3, 4, 6, 7 and 22 under 35 U.S.C. § 103 as being
unpatentable over Auth et al. (2001), cited in the IDS, as evidenced by Kibbey (1994), in
view of Zuo (2012), both of record, and further in view of Mitaka et al. (2002), of record, has been withdrawn due to the Applicant’s amendments to the claims filed 02/23/2026.
The rejection of Claim(s) 1, 3, 4, 6, 19, 20 and 22 under 35 U.S.C. § 103 as being unpatentable over Auth et al. (2001), cited in the IDS, as evidenced by Kibbey (1994), in view of Zuo (2012), both of record, and further in view of Katsuda et al. (2018), of record, has been withdrawn due to the Applicant’s amendments to the claims filed 02/23/2026.
Response to Amendment
The Declaration under 37 CFR 1.132 filed 02/23/2026 is insufficient to overcome the rejection of claims 1, 2, 4, 5, 7 and 19-23 based upon Auth et al. (2001) as set forth in the last Office action because:
The Declarant asserts that in Auth (2001) bile canaliculi formed by hepatocytes are not present due to hepatocyte degradation (citing Fig. 6 of the reference) and therefore no connection is formed between the bile canaliculi and the bile ducts (acknowledged by Declarant as being induced to form) (Declaration, Pg. 2, #1).
This is not found to be persuasive because Auth et al. (2005), cited in the New Rejections below, teaches that a coculture of human hepatocytes and biliary epithelial cells (BEC) cultured for over 30 days showed albumin secretion for two weeks and preserved albumin protein expression (thus maintaining differentiation functions of the hepatocytes) (Pg. 410, Abstract and Pg. 414, Figs. 2A-B) and the formation of bile canaliculi between adjacent hepatocytes and junctional complexes formed between adjacent liver epithelial cells (Pg. 417, Fig. 5). The Examiner notes that the description of Fig. 6 of Auth states:
Gradually, from these hollow cystic BEC structures (Fig. 6b). tubular ducts with an identifiable lumen developed and continued to increase in size and number, despite progressive deterioration of the HC layer from around 2 weeks in culture (Fig. 6c)
Thus, while Auth (2001) indicates that there is some progressive deterioration of hepatocytes in the coculture beyond two weeks, Auth (2005) indicates that cocultures of hepatocytes and BEC persisted up to 30 days as well as the hepatocytes therein forming bile canaliculi. Thus it would reasonably expected that the coculture of hepatocytes and BEC of Auth (2001) would also show the formation of bile ducts as well as bile canaliculi and the connection thereof, even if there was some hepatocyte degradation over time.
The Declarant argues that the sequence of plating and culturing the hepatocytes and BEC is critical in allowing formation and connection of bile canaliculi formed by the hepatocytes and bile ducts formed by BEC without hepatocyte degradation. Declarant cites Example 4 of the Specification as indicating that following MATRIGEL™ overlay sufficient albumin secretion and liver differentiation functions were maintained for about 1 month (Declaration, Pg. 2, #2).
This is not found to be persuasive for the following reasons, initially, the Examiner notes that the broad claim does not require MATRIGEL™ overlay and thus the Declarant’s assertion is not commensurate in scope with the claimed invention. Secondly, there is no provision in the claims against hepatocyte degradation.
Thirdly, Auth (2005) shows that plating hepatocytes followed by addition of BEC also allows formation of bile canaliculi and that the co-cultures were maintained for at least 30 days, showed albumin secretion for two weeks and preserved albumin protein expression (thus maintaining differentiation functions of the hepatocytes) (Pg. 410, Abstract and Pg. 414, Figs. 2A-B).
The Declarant argues that Auth (2001) was directed to controlling morphogenesis of BEC and did not consider the connection between bile canaliculi and bile ducts. Declarant concludes that the ordinary artisan would not expect that changing the plating order of hepatocytes and BEC would result in formation of a connection between the bile canaliculi and the bile ducts (Declaration, Pg. 2, #3).
This is not found to be persuasive for the following reasons, even if Auth (2001) did not consider the connection between bile canaliculi and bile ducts, the reference does teach the formation of bile ducts while Auth (2005)shows that plating hepatocytes followed by addition of BEC also allows formation of bile canaliculi. Thus, the ordinary artisan would reasonably expect a connection between the two as this is what occurs naturally in vivo.
The Declarant presents experiments wherein; i) hepatocytes are first cultured followed by addition of BEC, ii) BEC are cultured followed by hepatocyte addition and iii) simultaneous culture of hepatocytes and BEC.
Declarant notes that: in i) hepatocytes have deteriorated (indicated by loss of HNF4α expression), ii) both cell types are present as well as bile canaliculi and bile duct connecting structures and iii) both cell types are present but neither bile canaliculi, bile ducts and bile duct connecting structures are not present (Declaration, Pgs. 3-4, #4).
This is not found to be persuasive for the following reasons, the Declarant has provided no information as to the culturing conditions in each experiment and it cannot be determined if each experimental group was conducted under the same conditions, much less if the experiments are commensurate in scope with the claimed invention. Therefore, the Examiner can make no conclusive determination and the validity of the data and its applicability to the finding of obviousness.
Claim Objections
Claim 25 is newly objected to because of the following informalities: The word “comprising” should be changed to “comprises”. Appropriate correction is required.
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, 2, 4, 5 , 7, 19, 20 and 24-26 are newly 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(s) contains subject matter which 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 1 now recites, “forming a connection between a bile canaliculus formed on the hepatocytes and a bile duct formed by the biliary epithelial cells”. Applicant cites support for this new limitation may be found at Test Example 8, Paragraph [0052] of the Specification as filed as well as Figures 7A-B. Test Example 8 merely indicates that when the claimed co-culture was exposed to a bile acid analog (CLF) hepatocytes take up the CLF and excrete it into the bile canaliculus before transport to the bile duct. Nowhere in the description is described where the canaliculus is formed (the citation does not specify the bile canaliculus is formed on hepatocytes) or its special relationship (e.g. any connection) to either the hepatocytes or the bile duct/biliary epithelial cells. The passage merely indicates that hepatocytes will uptake an agent and excrete it into a bile canaliculus wherein the agent is somehow transported to the bile duct through some unspecified process.
Neither the claims or the Specification indicate how, where or when the hepatocytes form a bile canaliculus, how, where or when a bile duct is formed or how said canaliculus and said bile duct physically correlate with one another. The figures merely depict “hepatocyte tissue” and “bile duct” and contain no depiction or description of a canaliculus. Applicant is required to indicate with specificity where support for the new limitation may be found or delete the NEW MATTER. Claims 2, 4, 5 , 7, 19, 20 and 24-26 are rejected as being dependent upon rejected Claim 1.
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 24 and 25 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. Claim 24 recites the limitation "the liver epithelial tissue". There is insufficient antecedent basis for this limitation in the claim. The term “a sufficient amount” in Claim 25 is a relative term which renders the claim indefinite. The term “sufficient” 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. The Examiner has construed the claim as any amount of hepatocyte secreted albumin.
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.
Claim(s) 1, 4, 24, 25 and 26 are newly rejected under 35 U.S.C. § 103 as being
unpatentable over Auth et al. (2001), cited in the IDS, as evidenced by Kibbey (1994), in
view of Zuo (2012), both of record, and Auth et al. (2005), as evidenced by Watari et al. (2017), as necessitated by Applicant’s amendments to the claims filed 02/23/2026.
Auth et al. (2001) teaches culturing mature (adult/mature human) hepatocytes on a Type I collagen gel coating having a concentration of 1g/100ml (or 10mg/ml) then inoculating and culturing bile duct epithelial cells on the cultured hepatocytes, then overlaying with a second layer of collagen (Pg. 520, Column 1, Lines 26-29 and 36-47);
wherein hepatocytes (HC) are cultured to sub-confluence (interpreted as any
density below 100% confluence) before adding BEC (biliary epithelial cells) resulting in
a low ratio of BEC:HC, and that BEC require a higher plating density when grown alone
(Pg. 520, Column 1, Lines 26-30);
and wherein the co-culture induces bile duct formation and development of a bile
duct network of bile duct epithelial cells (e.g. forming a hepatic epithelioid tissue having
a structure of connections between hepatocytes and bile duct epithelial cells) (Pg. 520,
Column 1, Lines 11-13), and reading on Claim 1.
The teachings of Auth et al. (2001) were discussed above.
Auth et al. (2001) does not teach wherein a connection is formed between a bile canaliculus formed on the hepatocytes and a bile duct formed by the biliary epithelial cells, as now required by Claim 1;
overlaying the culture with a gel comprising an EHS gel after the inoculating
and culturing of the hepatocytes, as required by Claim 4 and New Claim 25;
wherein the liver epithelial tissue expresses Cldn4 (claudin-4), as now required by New Claim 24;
secreting a sufficient amount of albumin by the hepatocytes and maintaining liver differentiation functions of the hepatocytes for about 1 month from 2 weeks after overlaying the gel, as required by New Claim 25;
or wherein the connection between the bile canaliculus and bile duct enables transportation of bile excreted from the hepatocytes into the bile canaliculus to the bile duct, as required by New Claim 26.
Auth et al. (2005) teaches that a coculture of human hepatocytes and biliary epithelial cells cultured for over 30 days showed albumin secretion for two weeks and preserved albumin protein expression (thus maintaining differentiation functions of the hepatocytes) (Pg. 410, Abstract and Pg. 414, Figs. 2A-B) and the formation of bile canaliculi between adjacent hepatocytes and junctional complexes formed between adjacent liver epithelial cells (Pg. 417, Fig. 5).
Zuo teaches plating hepatocytes on collagen gel then overlaying with 0.25% of
MATRIGEL™ (Pg. 7, Lines 1-3 and Pg. 10 and Pg. 11, #3) wherein the overlay creates a more physiological-like environment, maintains hepatocyte specific morphology and improves CYP450 activities (Pg. 10).
It would have been obvious to those of ordinary skill in the art to modify the co-
culturing bile duct epithelial cells with hepatocytes of Auth et al. (2001) to first culture the bile duct epithelial cells on a collagen gel because Auth et al. (2001) teaches the culture of bile duct epithelial cells on collagen gel (along with hepatocytes). Thus, it would have been further obvious to the ordinary artisan to inoculate and culture the hepatocytes on the cultured bile duct epithelial cells because there are only a finite number of ways to combine two cell types for co-culturing, either cell-1 is plated before adding cell-2 or cell-2 is plated before adding cell-1. See KSR at MPEP 2143, E. The MPEP at 2144.04, IV. C. further states that "selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results".
There would have been a reasonable expectation of success in making this modification because teaches co-culturing the claimed cell types and the selection of which cell type to plate first in preparing the co-culture is no more than the selection from a finite number of identified, predictable solutions.
It would have been obvious to those of ordinary skill in the art that the co-culture of hepatocytes and biliary epithelial cells of Auth et al. (2001) which induces bile duct formation and development of a bile duct network of bile duct epithelial cells (e.g. forming a hepatic epithelioid tissue having a structure of connections between hepatocytes and bile duct epithelial cells) would also form a connection between the bile duct network of bile duct epithelial cells and a bile canaliculus formed by the hepatocytes because Auth et al. (2005) teaches that a coculture of human hepatocytes and biliary epithelial cells when cultured for over 30 days showed the formation of bile canaliculi between adjacent hepatocytes. Those of ordinary skill in the art would have been motivated to make this modification in order to prepare a realistic model of the structures and cell types found in the liver. There would have been a reasonable expectation of success in making this modification because both references are drawn to the same field of endeavor, that is, the co-culture of hepatocytes and biliary epithelial cells.
It would have been further obvious to those of ordinary skill in the art to then
overlay the co-culture of hepatocytes and biliary epithelial cells of Auth et al. (2001) with MATRIGEL™ (extracted from EHS [Engelbreth-Holm-Swarm mouse sarcoma, see Kibbey, Pg. 227, Summary]) as taught by Zuo because Zuo teaches that a MATRIGEL™ overlay of hepatocytes creates a more physiological-like
environment, maintains hepatocyte specific morphology and improves CYP450
activities. Those of ordinary skill in the art would have been motivated to make this
modification in order to co-culture hepatocytes and bile duct epithelial cells in a
physiological like environment and induces bile duct formation and development of a
bile duct network of bile duct epithelial cells. There would have been a reasonable
expectation of success in making this modification because the Auth (2001) and Auth (2005) references teach co-culturing bile duct epithelial cells with hepatic cells (hepatocytes) and Zuo teaches the overlay of hepatocytes with MATRIGEL™.
It would have been obvious to those of ordinary skill in the art before the effective
filing date of the claimed invention to modify the method of Auth et al. (2001) to add the hepatocytes (HC) when the biliary epithelial cells (BEC) are sub-confluent (interpreted as any density below 100% confluence, and thereby encompassing the claimed 20-40% of the cultured region) because Auth et al. (2001) teaches co-culturing HC and BECs wherein the BECs are at a low ratio with the HCs and are at a lower plating density than when plated alone.
Thus, the ordinary artisan would recognize that BEC culture density is an art-recognized result-effective variable as the ratio of BEC to HC needs to be low and a lower plating density of BEC is required when co-culturing BEC as opposed to culturing BEC alone. Therefore, the result-effective adjustment of conventional working parameters (e.g. determining an appropriate percent density of BEC prior to adding HC) is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. Those of ordinary skill in the art prior to the instant invention would have been motivated to make this modification in order to have an appropriate percentage of BEC to HC when co-culturing. There would have been a reasonable expectation of success in making this modification because it would have been within the purview of those of ordinary skill in the art to determine and select a percentage of BEC confluence which is optimal for co-culture of BEC and HC.
With regard to Claim 24, Watari et al. teaches that tight junctions are formed in the interstices between adjacent epithelial cells (Pg. 2, 3rd paragraph) and that tight junction barrier formation is mediated by claudin-4 (Pg. 3, 3rd paragraph). As Auth et al. (2005) teaches that a coculture of human hepatocytes and biliary epithelial cells cultured for over 30 days showed junctional complexes (tight junctions) formed between adjacent liver epithelial cells, it would be inherent in the method of Auth et al. (2001) that the coculture of human hepatocytes and biliary epithelial cells would also have tight junction formation mediated by claudin-4 between the adjacent biliary epithelial cells.
With regard to Claim 25, it would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention that the connection formed between the bile duct of Auth et al. (2001) and the canaliculi formed by Auth et al. (2005) would “enable” transport of bile secreted by hepatocytes into the bile duct as this is the function of the bile canaliculi. Those of ordinary skill in the art would have been motivated to make this modification because this would provide an in vitro model of in vivo liver function. There would have been a reasonable expectation of success in making this modification because both Auth references are drawn to the same field of endeavor, that is, the co-culture of hepatocytes and biliary epithelial cells.
Claim(s) 1, 2 and 4 are newly rejected under 35 U.S.C. § 103 as being
unpatentable over Auth et al. (2001), cited in the IDS, as evidenced by Kibbey (1994), in
view of Zuo (2012), both of record, and Auth et al. (2005), as applied to Claims 1 and 4 above, and further in view of Hashimoto et al. (2008), of record, as necessitated by Applicant’s amendments to the claims filed 02/23/2026.
The teachings of Auth et al. (2001), Auth et al. (2005) and Zuo were discussed above.
None of the above references teach wherein the collagen gel comprises 2-6
mg/mL of collagen, as required by Claim 2.
Hashimoto et al. teaches a method of culturing biliary epithelial cells (BEC)
wherein cells are seeded onto a 4 mg/mL collagen gel (Pgs. 495-496, Materials and
methods, 2nd paragraph).
It would have been obvious to those of ordinary skill in the art before the
effective filing date of the claimed invention to modify the method of Auth et al. (2001)
comprising culturing BEC on a 10 mg/ml collagen gel to use a collagen gel having 4
mg/mL collagen as taught by Hashimoto et al. because Auth et al. teaches a slightly
higher collagen gel concentration and Hashimoto et al. provides a lower concentration
of collagen also suitable for culturing BEC. Those of ordinary skill in the art would have
been motivated to make this modification in order to provide a suitable collagen
concentration for culturing BEC. There would have been a reasonable expectation of success in making this modification because both references are drawn to the same field of endeavor, that is, methods involving culturing BEC.
Claim(s) 1, 4 and 5 are newly rejected under 35 U.S.C. § 103 as being
unpatentable over Auth et al. (2001), cited in the IDS, as evidenced by Kibbey (1994), in
view of Zuo (2012), both of record, and Auth et al. (2005), as applied to Claims 1 and 4 above, and further in view of Tanimizu et al. (2007), of record, as necessitated by Applicant’s amendments to the claims filed 02/23/2026.
The teachings of Auth et al. (2001), Auth et al. (2005) and Zuo were discussed above.
None of the above references teach wherein the MATRIGEL™ is present at a concentration of 5% (v/v) or more, as required by Claim 5.
Tanimizu et al. teaches a method of culturing a liver progenitor cell line (HPPL) in
collagen and MATRIGEL™ which has a similar composition of ECM proteins as
basement membrane, to type I collagen gel to mimic the in vivo environment around
developing bile ducts (Pg. 1473, Column 1, Lines 1-4 and 15-18) and wherein
MATRIGEL™ was at a concentration of 0, 20, 40, 69 or 80% (Pg. 1474, Fig. 2) wherein concentrations of 20% or more (encompassing the claimed concentration range of 20-100%) induced formation of extended structures and cell aggregates (Pg. 1474, Column 2, Lines 12-14).
It would have been obvious to those of ordinary skill in the art to modify the
method of Auth et al. (2001) and Zuo of culturing bile duct epithelial cells on a collagen gel and then adding hepatocytes and culturing, then overlaying with collagen gel containing 0.25% MATRIGEL™ to use the MATRIGEL™ at a concentration of greater than 5% or greater than 20% as taught by Tanimizu et al. because Tanimizu et al. provides a suitable concentration range of collagen for culturing hepatocytes with beneficial aspects seen at concentrations of 20% or more. Those of ordinary skill in the art would have been motivated to make this modification in order to provide a suitable collagen concentration for culturing hepatocytes with induced formation of extended structures and aggregates.
There would have been a reasonable expectation of success in making this modification because both references are drawn to the same field of endeavor, that is, the culturing of culturing hepatocytes.
Claim(s) 1, 4 and 7 are newly rejected under 35 U.S.C. § 103 as being
unpatentable over Auth et al. (2001), cited in the IDS, as evidenced by Kibbey (1994), in
view of Zuo (2012), both of record, and Auth et al. (2005), as applied to Claims 1 and 4 above, and further in view of Mitaka et al. (2002), of record, as necessitated by Applicant’s amendments to the claims filed 02/23/2026.
The teachings of Auth et al. (2001), Auth et al. (2005) and Zuo were discussed above.
None of the above references teach wherein the hepatocytes are murine small
and/or mature hepatocytes, as required by Claim 7.
Mitaka et al. teaches the formation of hepatic tissue in vitro, specifically the co-
culture of hepatic cells (mature hepatocytes, small hepatocytes heptoblasts) and
hepatic nonparenchymal cells to form hepatic organoids that possess differentiated
hepatic functions (Pg. 697, Abstract), the non-parenchymal cells may be biliary
epithelial cells (BEC) (Pg. 698, Fig. 1 and Pg. 699, Column 1, Lines 49-51) and wherein
small hepatocytes may isolated from rat liver (Pg. 700, Table 1).
It would have been obvious to those of ordinary skill in the art to modify the
method of Auth et al. (2001) of culturing human bile duct epithelial cells and mature human hepatocytes to use murine mature hepatocytes or murine small hepatocytes) as taught by Mitaka et al. because animal cells are frequently used to model human systems and Mitaka et al. provides suitable hepatocytes and a source thereof for co-culturing with BEC. Those of ordinary skill in the art would have been motivated to make this modification in order to provide a suitable non-human hepatocyte for co-culturing with BEC in forming hepatic models. There would have been a reasonable expectation of success in making this modification because both references are drawn to the same field of endeavor, that is, co-culturing of hepatocytes and BEC.
Claim(s) 1, 4, 19 and 20 are newly rejected under 35 U.S.C. § 103 as being
unpatentable over Auth et al. (2001), cited in the IDS, as evidenced by Kibbey (1994), in
view of Zuo (2012), both of record, and Auth et al. (2005), as applied to Claims 1 and 4 above, and further in view of Katsuda et al. (2018), of record, as necessitated by Applicant’s amendments to the claims filed 02/23/2026.
The teachings of Auth et al. (2001), Auth et al. (2005) and Zuo were discussed above.
None of the above references teach wherein the hepatocytes are human liver
progenitor cells, as required by Claim 19;
or wherein the human liver progenitor cells are chemically induced hepatocyte
progenitors (hCLiPs), as required by Claim 20.
Katsuda et al. teaches that:
" there is a strong demand for a novel cell source to realize regenerative medicine for liver diseases. Accordingly, researchers have proposed various approaches to supply potential hepatic cell sources, using embryonic stem cells, fetal liver cells, induced pluripotent stem cells, iHep cells, and adult liver progenitor cells (LPCs). These advances have attracted much attention, but there are still hurdles to be overcome, such as ethical issues involved with fetal tissue, relatively immature functionality of the generated hepatic cells compared to mature hepatocytes (MHs), and poor availability of the adult progenitor cells. Therefore, further exploration for novel hepatic cell sources is required to realize liver regenerative medicine. We recently proposed a novel type of LPCs that can stably expand in vitro and exhibit bipotentiality. Thus we named these cells chemically induced liver progenitors (CLiPs)" (Pg. 117, Introduction, Lines 3-16).
It would have been obvious to those of ordinary skill in the art to modify the
method of Auth et al. (2001) of co-culturing human bile duct epithelial cells and human
hepatocytes, to use the liver progenitor hepatocytes as taught by Katsuda et al.
because Auth et al. (2001) uses mature human hepatocytes obtained surgically and Katsuda et al. provides a source of suitable hepatocytes non-surgically obtained and which stably expand in vitro and exhibit bipotentiality. Those of ordinary skill in the art would have been motivated to make this modification in order to provide a suitable hepatocyte for experimentation which advantageously can stably expand in vitro and exhibit bipotentiality.
There would have been a reasonable expectation of success in making
this modification because both references are drawn to the same field of endeavor, that
is, hepatocytes and uses thereof.
Response to Arguments
Applicant’s arguments, see Remarks, filed 02/23/2026, with respect to the rejection(s) of claim(s) 1, 2, 4, 5, 7 and 19-23 under 35 U.S.C. § 103 have been fully considered and are persuasive. Therefore, the rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Auth et al. (2005) as set forth above.
Conclusion
No claims are allowed.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653