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
Applicant’s election without traverse of claims 1 – 3, 5 – 8, 10, 13, 16, 18, 20, 25, 29, 32, 34, 36, 46 and 49 – 50 in the reply filed on March 9, 2026, is acknowledged.
Claims 53 and 54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 9, 2026.
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.
Claims 1 – 3, 5 – 8, 13, 16, 18, 20, 25, 29, 32, 36, 46, 49 and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Sozen et al. (Self-assembly of embryonic and two extra-embryonic stem cell types into gastrulating embryo-like structures. Nat Cell Biol 20, 979–989 (2018); cited on IDS, hereinafter Sozen) in view of Zhang et al. (Computer Simulations of Cell Sorting Due to Differential Adhesion. PLOS ONE 6(10): e24999 (2011); cited on IDS, hereinafter Zhang) and Yue et al. (U.S. Patent Application Publication No. US20030044913; hereinafter Yue).
Regarding claims 1, 3, 18, 20 and 25, Sozen teaches a method of generating a synthetic embryo in vitro that comprises (Fig. 1a): contacting a plurality of ESCs, TSCs, and XEN cells in a pyramidal AggreWell to form a synthetic embryo. Sozen specifically discloses that the three cell types organize into multicellular aggregates within 24 h of the contacting step (p. 980, Results, Establishing conditions…) forming a structure comprising one TS-derived compartment, one ES-derived compartment, and partially covered by an outside XEN-derived monolayer (Fig. 1a). The efficiency at which this organization happens at 96 hours is disclosed but not for 12 hours post contact. However, this is an optimizable inherent feature of contacting the three different cell types, once they are engineered to express the cadherins. Although, Sozen discloses the use of the cadherins as expression markers (Fig. 4a, b, c) for epithelial-to-mesenchymal transition, the study does not explicitly teach the over expression of E-cadherin, P-cadherin, or K-cadherin. However, Zhang discloses a computer simulation (Abstract), the Glazier-Graner-Hogeweg model, to investigate how variations in the distribution of the number of cadherins per cell and in the choice of binding model affect cell sorting. Zhang further discloses that an aggregate with a continuous variation in the level of a single type of cadherin molecule sorts more slowly than one with two levels. The motivation to use Zhang’s computer model with Sozen’s protocol would be to generate a synthetic embryo that has enhanced cell-to-cell adhesion. Furthermore, Yue discloses expression vectors (Abstract) that encode for extracellular matrix and cell adhesion molecules (XMAD) for the purpose of genetically modifying cells (p. 98, claim 9). Furthermore, Yue discloses the cadherins (para. [0014]), such as E-, N-, and P-cadherins as part of the XMAD molecules and how they are important for embryonic development (para. [0013]). Yue further (Table 2) introduces SEQ ID NO. 21, which comprises the fragments that encode for the cadherins.
Claim 25 is reciting a limitation of the characteristics of the embryo, which is inherently produced by the method and flows from performing the method steps.
Regarding claim 29, Sozen discloses the specific cell number totals that suit the cell ranges for the cell types of claim 29 (p. 990, Methods, Preparing and plating…).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the computer model of Zhang as a simulation of a synthetic embryo and then utilize the expression XMAD constructs of Yue in order to overexpress the specific cadherin(s) in the designated cell types that comprise the synthetic embryo of Sozen. Doing so would increase the sorting rate based off the interfacial tension, which depends both on the maximum difference in number of cadherins per cell and on the binding model, according to Zhang.
Regarding claim 5, Sozen discloses the efficiency at which the multicellular aggregate structure develops into a synthetic embryo in Fig 1c after at least 3 days following the contacting step.
Regarding claims 6 and 7, Sozen discloses a synthetic embryo developing a cavity at day 5 (p. 990, Methods, Criteria for ETX embryo…).
Regarding claim 8, Sozen teaches a synthetic embryo laminin-containing basement membrane (p. 980, XEN cell layer, basal membrane…) developing at day 5.
Regarding claim 10, Sozen discloses Fig. 2a, which shows the size of the synthetic embryo at 72 hours following the contacting step.
Regarding claim 13, Sozen teaches the TS cell-markers, ES cell-markers and the XEN cell-markers disclosed in the instant application (p. 990, Methods, Criteria for ETX embryo inclusion and comparison to natural embryos).
Regarding claim 16, Sozen discloses the synthetic embryo resembling an egg cylinder structure at three days and the embryo resembling a post-implantation embryo structure after four or five days (Fig. 1).
Regarding claim 32, Sozen discloses the use of mouse wild-type ES cells (p. 990, Methods, Cell lines).
Regarding claim 36, Sozen discloses a first culture media step comprising a ROCK inhibitor and removing the ROCK inhibitor after 24 hours (p. 990, Methods, Preparing and plating cell…).
Regarding claims 2, 46, 49 and 50, Sozen discloses the media components and the schedule of media changes for the generation of the synthetic embryo that encompasses the limitations of claims 2, 46 and 49 – 50 (p. 990, Cell culture; Preparing and plating cell…).
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Sozen, Zhang, and Yue as evidenced by STEMCELL™ TECHNOLOGIES (Datasheet for AggreWell™400; hereinafter STEMCELL).
Regarding claim 34, Sozen discloses the use of a pyramidal AggreWell (Fig. 1a; p. 990, Methods, Preparing and plating…) but does not disclose the exact measurements of said AggreWell. However, the Aggrewell is only manufactured in the two sizes that are disclosed in instant claim 34 as evidenced by STEMCELL.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WALTER JACKSON III whose telephone number is (571)272-0247. The examiner can normally be reached M-F 9:00A - 5:00P.
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/WALTER JACKSON III/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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