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 .
Applicant’s arguments and amendments filed on 7/11/2025 have been entered.
Claims 1 and 15 have been amended.
Claims 22-26 are new.
Claims, 4, 6, 17-19 and 21 have been cancelled.
In view of the abandonment of 15/296,912, the ODP rejection is withdrawn.
In view of Applicant’s amendments to the claims, the 103 rejection has been amended. Further new 103 rejections are set forth in view of Applicant’s amendments and new claims.
In view of Applicant cancelling claim 19, the objection to claim 19 is moot.
Claims 1, 7-15, 20 and 22-26 are examined in the instant application.
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.
Claim(s) 1, 7-14 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nahmias et al. (2006, cited on IDS filed on 6/2/2023) in view of and Gomez-Aristizabal et al. (2009, cited on IDS filed on 6/2/2023) and Li et al. (2006, Stem Cells, Vol. 24, pgs. 322-332).
Regarding claims 1 and 7, Nahmias et al. teach “A major goal of liver tissue engineering is to understand how the constituent cell types interact to achieve liver-specific structure and function. Here we show that hepatocytes migrate toward and adhere to endothelial vascular structures formed on Matrigel in vitro, and that hepatocyte recruitment is dependent on endothelium-derived hepatocyte growth factor. The hepatocyte-decorated endothelial vascular structures resemble in vivo sinusoids containing plate-like structures, bile canaliculi, and a lumen. The sinusoid-like structures retained cytochrome P450 expression and activity, in addition to stable albumin expression and secretion rate for over 2 months in vitro.” (Abstract lines 1-7).
Specifically, Nahmias teaches a method of preparing an organ bud (liver) comprising culturing a hepatocyte and dermal endothelial cells (a mesenchymal cell) to obtain a liver organ bud that exhibited liver specific functions (see Abstract, pg. 1628 – Materials and Methods and Fig. 8 reproduced below).
Regarding claim 9, Nahmias teaches that their method used vascular endothelial cells (HUVECs and MVECs, Materials and Methods).
Regarding claim 11, Nahmias teaches that their organ bud is at least 100 μm in size (see Figs. 8 and 11).
Regarding claim 12, Nahmias does not teach CD133, CD271 or nestin expression.
Regarding claim 13, Nahmias does not teach scaffolding.
Regarding claim 14, Nahmias teaches that co-cultures developed over 2 days (Fig. 2).
Nahmias continues to teach that advances in stem cell biology will make their co-culture system suitable for the study of human liver fibrosis, cirrhosis, ischemia/reperfusion injury and toxicity (pg. 1637 col. 1 parag. 1).
Nahmias does not teach:
using and undifferentiated organ cell (claim 1) and mesenchymal stem cells (claim 10).
(i) Regarding using mesenchymal stem cells in the creation of an organ bud and claims 8 and 10, Gomez-Aristizabal et al. teach that mesenchymal stem cells provide support for hepatocyte cultures by maintaining hepatocyte functionality as well as improving hepatocyte survival and proliferation in vitro (see Abstract and pgs. 1504-1505). Gomez-Arisitzabal continues to teach that all organs in the body comprise a supportive component and that BM-MSCs can differentiate into bone, cartilage and fat cells (pg. 1504 col. 1).
Regarding an undifferentiated organ cell in claims 1 and 22, Li et al. teach that “Liver progenitor cells have drawn a great deal of attention both for their therapeutic potential and for their usefulness in exploring the molecular events surrounding liver development and regeneration.” (Abstract lines 1-4). Specifically, Li teaches that oval cells (a type of hepatic progenitor) derived from liver-associated gene modified mice are a powerful approach to explore the mechanism of liver development and regeneration (pg. 330 col. 1 parag. 2).
Regarding claim 20, there is no teaching in the art of using metanephric mesenchymal precursor cells as claimed.
Thus, at the time of filing the ordinary artisan would have found it prima facie obvious to combine the teachings of Nahmias regrading a method of preparing a liver organ bud from an undifferentiated organ cell with the teachings of Gomez-Aristizabal regarding the role of MSCs and their support of hepatocytes and with the teachings of Li regarding the role of hepatic progenitors to generate liver tissue to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to make such as combination since Gomez-Aristizabal teaches that MSCs support hepatocyte function, survival and proliferation and thus the ordinary artisan would have been motivated to use MSCs in the method of Nahmias to improve the generation of a liver organ bud. Further motivation is provided by Li regarding the role of hepatic progenitors in liver generation.
There would have been a reasonable expectation of success that the MSCs of Gomez-Aristizabal and the hepatic progenitor cells of Li could work in the method of Nahmias since Gomez-Aristizabal teaches that MSCs function support the growth and survival of hepatocytes.
Thus, the cited art provides the requisite teachings and motivation to make and use the invention as claimed.
Response to Arguments
Applicant’s Arguments
Applicants argue in amendment that in view of the amendments to the claims, the art of record no longer teaches the claimed invention.
Examiner’s Response
While Applicant’s arguments have been fully considered they are not found persuasive. As set forth above, the 103 rejection of record has been amended to incorporate the teachings of Li which would motivate the ordinary artisan to prepare an organ bud with hepatic progenitor cells as claimed.
Thus, for the reasons above and of record the rejection is maintained.
Claim(s) 15 and 24-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nahmias et al. (2006, cited on IDS filed on 6/2/2023) in view of and Gomez-Aristizabal et al. (2009, cited on IDS filed on 6/2/2023) and Li et al. (2006, Stem Cells, Vol. 24, pgs. 322-332) as applied to claims 1, 7-14 and 20 above, and further in view of Johansson et al. (2008, Diabetes, Vol. 57, pgs. 2393-2401-cited on IDS filed on 6/2/2023) and Teta et al. (2007, Developmental Cell, Vol. 12, pgs. 817-826).
Regarding claim 26, Nahmias teaches that culturing is performed for at least six hours (pg. 1629 col. 1 parag. 3).
Nahmias, Gomez-Aristizabal and Li are relied upon above in teaching a method of preparing an organ bud.
Nahmias, Gomez-Aristizabal and Li do not teach:
an isolated cell population of β cells.
(i) Regarding pancreatic β cells in claim 15, Johansson et al. teach a method of co-culturing a vascular endothelial cell, a pancreatic islet comprising pancreatic β cells and mesenchymal stem cell (MSC) in a medium for culturing both endothelial vascular cells and pancreatic islet cells (see Abstract and pgs. 2393-2394).
Johansson continues to teach that “the islets of Langerhans are micro-organs, with
afferent and efferent blood vessels connecting the capillary network of the islets to the circulation system” (pg. 2393 col. 1 parag. 5 lines 1-4), and “This capacity of MSCs may be of particular importance in facilitating EC migration into dense micro-organs such as islets. In addition, MSCs most likely contributed growth factors and extracellular matrix production that serve to encourage the stabilization and maturation of the EC sprouts (9). This effect of MSCs was evidenced by the increased sprout formation by EC-MSC islets in fibrin gels, where close interactions between EC sprouts and MSCs occurred to a high degree.” (pg. 2398 col. 2 parag. 1 lines 14-22).
Importantly, Johansson teaches that “Insulin release by EC-MSC islets showed preserved
dynamics during high-glucose stimulation after 1 and 3–4 days compared with control islets” (Fig. 3B–C).” (pg. 2397 col. 1 parag. 1 lines 1-3).
Regarding claim 24, Johansson teaches that their organ bud was at least 100 μm in size (pg. 2397 col. 1 last parag.).
Regarding claim 25, no scaffolding was used in Johansson.
Thus, Johansson teaches the ordinary artisan that endothelial cells, MSCs and pancreatic islets comprising β cells work together to form a functional micro-organ which produces insulin in response to glucose stimulation.
It would have been obvious to use an isolated population of pancreatic β cells in view of the teachings of Teta et al. who teaches that “specialized progenitors do not contribute to adult β cells, not even during acute β cell regeneration. Instead, β cells are the products of uniform self-renewal, slowed by a replication refractory period that prevents β cells from immediately redividing.” (see Abstract).
Thus, at the time of filing the ordinary artisan would have found it prima facie obvious to combine the teachings of Nahmias, Gomez-Aristizabal and Li regrading a method of preparing a liver organ bud with the teachings of Johansson and Teta regarding using β cells to generate an organ bud to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to make such as combination since Johansson teaches that islets cells (comprising β cells), ECs and MSCs work together for form a functional micro-organ that will have improved vascularization following transplantation. There would have been a reasonable expectation of success that the β cells of Johansson and Teta would work in the method of Nahmias, Gomez-Aristizabal and Li regrading since Johansson teaches that islets cells (comprising β cells), ECs and MSCs work together for form a functional micro-organ.
Thus, the cited art provides the requisite teachings and motivation to make and use the invention as claimed.
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nahmias et al. (2006, cited on IDS filed on 6/2/2023) in view of and Gomez-Aristizabal et al. (2009, cited on IDS filed on 6/2/2023) and Li et al. (2006, Stem Cells, Vol. 24, pgs. 322-332) as applied to claims 1, 7-14 and 20 above, and further in view of Zaret et al. (2008, Science, Vol. 322(5907), pgs. 1490-1494).
Nahmias, Gomez-Aristizabal and Li are relied upon above in teaching a method of preparing an organ bud.
Nahmias, Gomez-Aristizabal and Li do not teach:
pancreatic progenitors.
(i) Regarding pancreatic progenitors in claim 23, Zaret et al. “Within the liver and pancreas buds, notch signaling components are important for creating the proper balance in the numbers of hepatocytes and cholangiocytes from hepatoblasts (46,47) and of endocrine and exocrine cells from pancreatic progenitor cells” (pg. 3 parag. 5).
Zaret continues to teach that pancreatic progenitors contribute to pancreas organogenesis (pg. 3 parags. 2-5 bridge pg. 4 parag. 1).
Thus, at the time of filing the ordinary artisan would have found it prima facie obvious to combine the teachings of Nahmias, Gomez-Aristizabal and Li regrading a method of preparing a liver organ bud with the teachings of Zaret regarding using pancreatic progenitor cells to generate an organ bud to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to make such as combination since Zareta teaches that pancreatic progenitors contribute to the pancreas organogenesis.
There would have been a reasonable expectation of success that the pancreatic progenitors of Zareta would work in the method of Nahmias, Gomez-Aristizabal and Li regrading since Zareta teaches that pancreatic progenitors have a role in pancreatic organogenesis.
Thus, the cited art provides the requisite teachings and motivation to make and use the invention as claimed.
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 DAVID A MONTANARI whose telephone number is (571)272-3108. The examiner can normally be reached M-Tr 8-6.
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DAVID A. MONTANARI
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632