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 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 2 and 21 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.
Claims 2 and 21 contains the trademark/trade name GlutaMAX™. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a media reagent and, accordingly, the identification/description is indefinite.
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 printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 and 2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yan et al. (CN 106190951 A1)
Regarding Claims 1 and 2: Yan et al. discloses a method of differentiation from adipose mesenchymal stem cells into liver cells by way of using an induction system comprising multiple different types of cell factors which induce the mesenchymal stem cells into liver cells. The method taught by Yan is comprised of fewer steps than other protocols, making it advantageous. (Pg 1, Abstract) In Example 3 of the claimed invention, Yan teaches use of mouse adipocyte stem cells (ADSC) isolated from the animal, establishing primary culture for expansion of said cells before transferring the cultures to hepatic induction medium. (Pg 7-8, Example 3) The induction medium contains FGF4, HGF, OSM, aFGF, insulin transferrin selenium, EGF, and bFGF, which are all present in the media simultaneously. Analysis of the resulting differentiated hepatic cells revealed albumin markers, Ck-18, CK-19, AFP, and CYP1A1, all known hepatocyte markers. (Pg 8, Example 3) This fully reads on the media composition of claim 1, and further reads on claim 2 by way of incorporation of at least one of PS, GlutaMAX, HEPESS, N2, N-acetylcysteine, [Leu15]-Gastrin 1, HGF, vitamin A free B27 supplement, A83-01, nicotinamide, forskolin, dexamethasone, or a combination thereof, in addition to the use of stem cells in the hepatic differentiation process.
Claim Rejections - 35 USC § 103
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 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.
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.
Claim(s) 1, 2, 20, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al. (CN 106190951 A1) in view of Clevers et al. (US 2014/0243227 A1) and Simian et al. (Organoids: A historical perspective of thinking in three dimensions, 2017)
Regarding Claims 1 and 2: Yan et al. teaches a method of differentiation from adipose mesenchymal stem cells into liver cells by way of using an induction system comprising multiple different types of cell factors which induce the mesenchymal stem cells into liver cells. The method taught by Yan is comprised of fewer steps than other protocols, making it advantageous. (Pg 1, Abstract) In Example 3 of the claimed invention, Yan teaches use of mouse adipocyte stem cells (ADSC) isolated from the animal, establishing primary culture for expansion of said cells before transferring the cultures to hepatic induction medium. (Pg 7-8, Example 3) The induction medium contains FGF4, HGF, OSM, aFGF, insulin transferrin selenium, EGF, and bFGF, which are all present in the media simultaneously. Analysis of the resulting differentiated hepatic cells revealed albumin markers, Ck-18, CK-19, AFP, and CYP1A1, all known hepatocyte markers. (Pg 8, Example 3) This fully reads on the media composition of claim 1, and further reads on claim 2 by way of incorporation of at least one of PS, GlutaMAX, HEPESS, N2, N-acetylcysteine, [Leu15]-Gastrin 1, HGF, vitamin A free B27 supplement, A83-01, nicotinamide, forskolin, dexamethasone, or a combination thereof, in addition to the use of stem cells in the hepatic differentiation process. Yan fails to state that the hepatocytes were cultured in three-dimensional culture.
Simian teaches the history and benefits of organoid culture. (Pg 31, Abstract) Specifically, Simian teaches that it is widely accepted in the art that functional differentiation is dependent on three dimensional culture and that two dimensional culture conditions fail to provide the conditions for cellular organization and cell to cell relationships found in vivo. (Pg 31, How do we define organoids and 3D cultures?) Regarding hepatocytes specifically, Simian teaches a study which noted that hepatocytes cultured in two dimensional culture lost differentiation capabilities after a few days in culture, but when cultured on collagen, the mechanical tension of the cells on the gel caused the gel to detach and created a floating three dimensional substrate for the hepatocytes. During float culture, it was noted that a more permissive environment for differentiation was created and that differentiation of the hepatocytes in culture appeared to be triggered solely due to the three dimensional culture environment. (Pg 33-35, A historical timeline of organoid and 3D cell cultures)
Based on the above discussion, one of ordinary skill in the art has clear motivation to incorporate the teachings of Simian of a three dimensional culture environment with the hepatocyte differentiation protocol as taught by Yan. Motivation to do so is laid out in the teachings of Simian, who state that the act of three dimensional culture itself is required to induce functional differentiation in vitro.
Regarding claims 20 and 21: Yan fails to teach a culture media comprising all of the following: forskolin, PS, GlutaMAX, HEPES, N2 supplement, N-acetylcysteine, [Leu15]-Gastrin I, vitamin A-free B27 supplement, A83-O1, nicotinamide, and dexamethasone. Clevers teaches culture media compositions and methods for expanding and differentiating populations of stem cells for the purpose of generating organoids to use in drug screening, toxicity assays, and regenerative medicine. (57) Simian teaches use of each of the following reagents for use in organoid culture:
Forskolin which helps to prevent organoid collapse (0662)
PS, a known and routine antibiotic used in culture media throughout the art (1035)
GlutaMAX™, incorporated into a medium for the differentiation of liver cells (0230)
Hepes, a known buffer to manipulate pH (0114)
N2 supplement, a known growth factor (0124)
N-acetylcysteine, a known growth factor (0124)
Leu15-Gastrin 1, incorporated as a preferred embodiment of the invention (0110)
B27, a known growth factor (0124)
A83-01, a known ALK inhibitor which improved the expansion rate of stem cells in vitro and allowed for continual expansion of undifferentiated stem cells for 3 months (0009)
Nicotinamide, which both inhibits the expression of a mature hepatocyte marker (CYP3A11) and promotes the hepatoblast marker albumin, aiding in maintaining stemness in culture (0233)
Dexamethasone, a known hepatocyte marker (0751)
It would have been obvious to a person of ordinary skill in the art to combine the teachings of Yan with the teachings of Simian and Clevers. One skilled in the art would have been motivated based on the teachings of Clevers, who (as evidenced by the discussion above) clearly state motive for each component of the culture media as listed in claims 20 and 21.
Response to Arguments
First, Examiner wishes to reiterate on the record that a simple agreement of proposed amendments overcoming an existing 35 U.S.C. 102(a)(1) rejection is not a guarantee of an application being in condition for complete allowance, as an additional complete search of the art is required after any changes are made to the claimset.
Applicant's arguments filed 04/07/2026 have been fully considered but they are not persuasive. Applicant argues that claim 1, as amended, overcomes the 35 U.S.C. 102(a)(1) rejection over Yan et al. due to Yan failing to teach three dimensional culture in addition to failing to teach use of all the media components now required by new claims 20 and 21. However, the claim is a medium and is therefore not limited by intended use.
However, in the interest of compact prosecution, the teachings of Clevers and Simian have been incorporated into the 35 U.S.C. 103 rejection. As claim 2 depends from claim 1 and inherits all the limitations thereof, Applicant argues in favor of allowance based on the same reasoning. Furthermore, Applicant argues that the endproduct of Yan is hepatocytes, not organoids. However, one skilled in the art would be motivated to incorporate the teachings of Simian of three dimensional culture to induce functional differentiation, as discussed above.
Simian teaches the benefits and history of three dimensional culture and how the physical act of three dimensional culture itself is required to induce functional differentiation in vitro. In addition to this, Clevers teaches the benefit of each reagent as it relates to three dimensional organoid culture.
Based on the above discussion, claims 1, 2, 20, and 21 are rejected under 35 U.S.C. 103.
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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNA M THUESON whose telephone number is (571) 272-3680. The examiner can normally be reached M-F 7:30-5 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, Tracy Vivlemore, can be reached on (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/HANNA MARIE THUESON/ Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
Prosecution Insights