DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Applicant's amendments filed 12/02/2025 to claims 5, 7, 8, 11, 16, 18, and 19 have been entered. Claims 9, 10, 15, and 17 are canceled. Claims 1-8, 11-14, 16, and 18-21 remain pending, of which claims 5-8, 11-14, and 20 are being considered on their merits. Claims 1-4, 16, 18, 19, and 21 remain withdrawn from consideration. References not included with this Office action can be found in a prior action.
Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
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.
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 5-8, 11-14, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Hu (WO 2016/200340; provided in the IDS dated 3/16/2022) in view of Atala (WO 2017/070007; provided in the IDS dated 3/16/2022) and Clevers (WO 2017/220586; provided in the IDS dated 3/16/2022).
Hu teaches a method of producing a substantially spheroid liver organoid, comprising differentiating liver stem cells into human hepatocytes under low-adhesion culture conditions in the presence of a culture medium comprising a TGFß receptor inhibitor, an activator of adenylyl cyclase forskolin, and a Notch inhibitor, wherein the human hepatocytes are cultured in the medium for 7 days and then an additional 14 days until a substantially spheroid liver organoid is obtained (¶0120 and Fig. 24; ¶0238), reading in-part on claim 5, and the culture times of claims 5, 6, and 8. Hu teaches a liver culture medium comprising SB431542 (¶0217), forskolin (¶0150), and DAPT (¶0091), reading in-part on the embodiment of SB431542 for a TGFß inhibitor for claims 5 and 14, the embodiment of DAPT for a notch inhibitor for claim 5, and on claims 11-14.
Regarding claims 5 and 14, Hu does not teach IWP2 and LDN193189. Regarding claims 5 and 6, Hu does not teach a plurality of cells comprising hepatocytes, human hepatic stellate cells, human liver sinusoidal endothelial cells, human cholangiocytes, and human Kupffer cells. Regarding claim 20, Hu does not teach wherein the three or more cell types are hepatocytes, human hepatic stellate cells, human liver sinusoidal endothelial cells at a ratio of 2.5:1:1.
Atala teaches an artificial liver construct composition comprising hepatocytes, Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells, and cholangiocyte cells (Abstract), reading on claims 5 and 6. Atala teaches a preferred embodiment comprising human cells (p5, lines 3-6), reading on claims 5 and 6. Atala teaches that the combination of different liver cell types improves the performance and duration of performance of liver organ construct (p12, lines 16-25), reading on claims 5 and 6. Atala teaches the liver cells in a ratio of 70-90% hepatocytes, 5-20% Kupffer cells, 2-10% hepatic stellate cells, 2-10% sinusoidal endothelial cells, and 1-4% cholangiocytes (p6, lines 9-21), reading in-part on claim 20.
Clevers teaches methods of obtaining a liver organoid by differentiating progenitor cells (claims 1, 15, 16). Clevers teaches a differentiation medium comprising IWP2 (p50, lines 3-13 and p57, lines 4-11) and LDN193189 (p57, lines 4-11), reading on claims 5 and 14.
Regarding the cell types of claims 5 and 6, it would have been obvious to a person of ordinary skill in the art before the invention was filed to add the hepatocytes, Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells, and cholangiocyte cells of Atala to the liver spheroid composition of Hu. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Atala and Hu are directed towards liver construct compositions. The skilled artisan would have been motivated to do so because Atala teaches that the combination of liver cell types are predictably advantageous to improves the performance and duration of performance of liver organ construct and so the addition of the liver cells types would therefor predictably improve the performance of the liver spheroid composition of Hu.
Regarding the IWP2 and LDN193189 of claims 5 and 14, it would have been obvious to a person of ordinary skill in the art before the invention was filed to add the IWP2 and LDN193189 of Clevers to the methods of Hu. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Clevers and Hu are directed in-part towards methods of differentiating progenitor/stem cells into liver cell types and the formation of liver organoids. The skilled artisan would have been motivated to do so because "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). See M.P.E.P. § 2144.06. In this case, Clevers teaches that IWP2 and LDN193189 are known components differentiation medium and separately teaches envisions methods of obtaining a liver organoid by differentiating progenitor cells. Therefore, the addition of IWP2 and LDN193189 to Hu’s methods must be held prima facie obvious absent any showing of nonobviousness to the contrary.
Regarding claim 20, optimization within prior art conditions or through routine experimentation will generally not support patentability absent a showing of criticality of the claimed range to the contrary. See M.P.E.P. § 2144.05, particularly subsections II and III. In this case, Atala teaches the liver cells in a ratio of 70-90% hepatocytes, 5-20% Kupffer cells, 2-10% hepatic stellate cells, 2-10% sinusoidal endothelial cells, and 1-4% cholangiocytes and so any further modification of the liver cell ratios must be held as prima facie obvious as optimization or routine experimentation in the methods of Hu absent any showing of criticality to the contrary.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Response to Arguments
Applicant's arguments on pages 5-8 of the reply have been fully considered, but not found persuasive of error for the reasons given below.
In response to applicant’s argument on pages 6-8 of the reply that there is no teaching, suggestion, or motivation to combine Clevers with the methods of Hu, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the skilled artisan would have been motivated to do so because "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). See M.P.E.P. § 2144.06. In this case, Clevers teaches that IWP2 and LDN193189 are known components differentiation medium and separately teaches envisions methods of obtaining a liver organoid by differentiating progenitor cells. Therefore, the addition of IWP2 and LDN193189 to Hu’s methods must be held prima facie obvious absent any showing of nonobviousness to the contrary.
On pages 6-8 of the reply, Applicant alleges that there would be no reasonable expectation of success in combining the teachings of Atala and Clever with methods of Hu. This is not persuasive of error because Applicant appears to be bodily incorporating the teachings and differentiation medium of Clevers into the methods of Hu, which is an improper test for obviousness. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Conclusion
No claims are allowed. No claims are free of the art.
THIS ACTION IS MADE FINAL. 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 SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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/Sean C. Barron/Primary Examiner, Art Unit 1653