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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Drawings
The application contains at least one color drawing or color photograph. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
It is noted that a Petition for color drawings was filed by the Applicants on 09/1/2023, which was dismissed by the Office in the Petition Decision of 2/14/2024 specifically indicating that no color drawings are submitted or are found.
Specification
The disclosure is objected to because of reference to colored referenced points within the drawings, [0019]. The specification must be amended to clearly reference the same figures without use of color identifiers, and to be in accordance with the changes in the drawings. Correction is required. See MPEP § 608.01(b).
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/31/2025, 11/02/2023 and 09/28/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of Claims
Claims 1-2, 6, 11-12, 15-16, 19, 20-21, 26, 28-30, 37, 40, 45-48, 51, 53-54 and 56 are pending and under examination. Claims 3-5, 7-10, 13, 17-18, 22-25, 27, 31-36, 38-39, 41-44, 49-50, 52, 55, and 57-62 are cancelled.
Claim Interpretation
Optional embodiments such as those recited in claim16 or 19 are not given patentable weight as these embodiments are not required by the claim.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 56 is rejected under 35 U.S.C. 101 because it is directed to a judicial exception without significantly more.
The claims have been analyzed for eligibility in accordance with their broadest reasonable interpretation.
Regarding claim 56: The claim is directed to a composition of an embryo.
The claim is directed to a method, which is a statutory category of invention (Step 1: YES).
The claim is then analyzed to determine whether it is directed to any judicial exception. The claims are directed to a synthetic embryo. When compared to the closest naturally occurring counterpart, mammalian embryo, to determine if it is markedly different from said closest naturally occurring counterpart, there is no marked difference between the claimed synthetic embryo and the product of nature. Thus, the claim (does) recite a product of nature judicial exception (Step 2A, Prong 1: YES).
The claim does not integrate the product into a practical application because the claim is to the embryo, per se, not a method of use. (Step 2A prong 2: NO). Therefore, the claim is directed to a product of nature judicial exception.
The claim does not recite any elements in addition to the judicial exception mammalian embryo, so there are no additional elements that add significantly more to the judicial exception (Step 2B: NO).
The claim is patent ineligible.
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.
Claim 40 is 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.
The claim requires the inner layer to be SOX2 positive epiblast, middle layer to be GATA3 positive hypoblasts-like and outer layer to be GATA6 positive trophoblast-like cells. However, it is not clear from the specification and drawings if the Applicants had possession of the claimed invention.
Figures 2B and 10B show the inner layer to be epiblasts, while the middle and the outer layers seem to be a mixture of both hypoblast-like and trophoblast-like cells. It is noted that [0027] of the specification pointed out “the presence of an inner domain surrounded by two concentric domains.” However, the presence of these markers and cell types are not conclusively shown at the interfaces claimed. The maximum projection images of the hypoblast-like layer between epiblast-like and trophoblast-like layers do not clearly demonstrate the claimed positioning. As such it is not clear that Applicants were in possession of the claimed subject matter.
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 12, 14, 30, 37 and 40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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 30 and 37 contains the trademark/trade name KnockOut Serum Replacement, or 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 cell-culture medium and medium supplement, accordingly, the identification/description is indefinite.
Claims 12, 14, 40 require various embodiments like epiblast-like domain or trophoblast-like cells, or inner epiblast-like domain or peri- implantation-like pluripotent hESCs. The metes and bounds of such claims are unclear as it is not clear from the specification as to what constitutes a cell “like” the claimed cells.
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.
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 1-2, 6, 15-16, 19, 21, 26, 28-30, 37, 45-48, 51, 53-54 and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Sozen et al (Nat Cell Biol. 2018 Oct; hereinafter "Sozen;" See IDS filed 09/28/2023) in view of Kubaczka et al (Cell Stem Cell. 2015 Nov 5; hereinafter "Kubaczka;" See PTO-892) and Shimosato et al (BMC Dev Biol. 2007 Jul 3; hereinafter "Shimosato;" See PTO-892); further as evidenced by Dupont et al (Sci Adv. 2023 Jan 18; hereinafter "Dupont;" See PTO-892).
Regarding claim 1, 15, 45-46, 48 and 56: Sozen taught that embryonic stem cells, trophoblast stem (TS) and extra-embryonic-endoderm (XEN) can spontaneously self-assemble into structures that are remarkably similar to natural mouse embryos and contain all three embryonic and extra-embryonic compartments (As required by claim 56). (See Sozen p. 979, col. 2, last para). Sozen taught that “These structures
develop further and break symmetry to undertake the specification
of nascent mesoderm and primordial germ cells (PGCs) at the posterior” (See Sozen p. 979, col. 1- col. 2), as required by claim 46. It is however noted that Sozen did not teach use of modified ESCs to generate structures similar to embryos. However, Shimosato taught that “XEN cells derived from blastocysts were recently reported to show very similar morphology to Gata4 or Gata6 induced PE cells derived from ES cells.” (See Shimosato p. 2, col. 2, para 3) Further Shimosato taught that “activation of Gata4 or Gata6 is sufficient to induce proper differentiation of XEN-like cells from ES cells.” (See Shimosato p. 8, col. 2, last para). Further Kubaczka taught that “transient expression of Tfap2c, Gata3, Eomes, and Ets2 is sufficient to reprogram mouse embryonic fibroblasts and post-natal tail-tip-derived fibroblasts into induced TSCs (iTSCs) and surmount the epigenetic barrier separating somatic from extra-embryonic lineages.” (See Kubaczka Abstract). Kubaczka further taught that induced cells display morphology and gene expression profiles closely resembling TSCs. (See Kubaczka, p.559 ,col. 2 para 2-3).
Given the teachings of the cited prior art, it would have been obvious to a person of ordinary skill in the art to modify ESCs to express GATA6 to generate primitive endoderm/XEN-like cells per Shimosato, and modify ESC to express TFAP2C to generate trophoblast stem-like cels per Kubaczka. The co-culture of the lineage specified populations with ESC under self-organizing conditions taught by Sozen would have lead the artisan to arrive at embryo-like structures. As such the modification of ESC to overexpress GATA6 and modification of ESC to overexpress TFAP2C constitutes a predictable substitution of lineage-specified cells in the Sozen system as required by claims 1 and 48. ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
It is also submitted that it is routine experimentation to adjust the relative number of each cell-type to obtain proper self-organization as required by claim 15. It is submitted that optimizing within a range represents routine optimization well within the purview of a person or ordinary skill in the art.
It is also submitted that Sozen taught the expression of Nanog and Tfap2C among other markers in gastrulating ETX embryos as required by claim 45. (See Sozen Fig. 7b).
Regarding claims 2 and 6: Kubaczka taught use of dox inducible expression of Tfap2c to arrive at induced TSCs (iTSCs) where the transgene expression was activated for 10 days. (See Kubaczka Figure 1).
Regarding claim 16: Sozen used AggreWell plate for formation of embryos. (See Sozen p. 990, col. 1, para 6).
Regarding claim 19, 28-30 and 37: Sozen taught culturing ES, XEN and TS cells for 6 days. (See Sozen p. 990, col. 1, para 7) in an MEF-conditioned ETX medium (C-ETX). The ETX medium reads on the post-implantation medium as required by claims 28-29. As evidenced by Dupont, the ETX medium comprises DMEM (Gibco, 41966-029), 15% FBS, 100 μM NEAA, 1 mM sodium pyruvate, 2 mM l-alanyl-l-glutamine, penicillin-streptomycin (100 U/ml), and 0.1 mM β-mercaptoethanol. (See Dupont p. 13, col. 1, 3rd para).
Regarding claim 21: Sozen used DMEM for culture of ES cells. (See Sozen p. 990, col. 1, para 3)
Regarding claim 26 and 54: Sozen taught that “[a]t the optimized cell density, the three cell types spontaneously underwent self-organization into multicellular aggregates within 24 h.” (See Sozen p. 980, col. 1, para 2).
Regarding claim 47: Sozen taught that 30% of the co-cultures developed into embryos. One of ordinary skill in the art would expect that applying known methods to human ESCs using transcription-factor driven lineage conversion would result in similar efficiencies for example between 5% to 30%.
Regarding claim 51: It is noted that Sozen taught the formation of embryos in a mouse model. However a person of ordinary skill in the art would have been motivated to try the mouse ETC strategy taught by Sozen in a human ESC to form a human embryo. It was known that the claimed transcription factors were conserved in human beings (See Kubaczka and Shimosato Abstract). As such a person of ordinary skill in the art would have found it obvious to try implementing the known mouse stem-cell embryo modeling strategies in human ESC, with a reasonable expectation of success.
Regarding claim 53: Sozen taught that “[a]fter 96 h, approximately 70% of multicellular aggregates contained all three cell types. Of these, 29.8% (n = 130/435) had single adjoining ES-derived embryonic and TS-derived extraembryonic compartments surrounded by a layer of XEN cells, and were strikingly similar in morphology to mouse embryos at 5–6 days after fertilization” (See Sozen p. 980, col. 1, para 2). As such one of ordinary skill in the art would have reasonable expectation to observe similar embryogenesis in human embryos when started from human ESCs.
Claims 11-12 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Sozen et al (Nat Cell Biol. 2018 Oct; hereinafter "Sozen;" See IDS filed 09/28/2023) in view of Kubaczka et al (Cell Stem Cell. 2015 Nov 5; hereinafter "Kubaczka;" See PTO-892) and Shimosato et al (BMC Dev Biol. 2007 Jul 3; hereinafter "Shimosato;" See PTO-892)l; further as evidenced by Dupont et al (Sci Adv. 2023 Jan 18; hereinafter "Dupont;" See PTO-892) further in view of Nichols (Cell Stem Cell. 2009 Jun 5; hereinafter "Nichols;" See PTO-892).
Regarding claims 11-12 and 14: The teachings of Sozen in view of Shimosato and Kubaczka are set forth above. The claimed references do not particularly recite the claimed states of ESCs. Nichols taught “Ground state naive pluripotency is established in the epiblast of the mature blastocyst and may be captured in vitro in the form of ESCs. Shortly after implantation, the epiblast transforms into a cup-shaped epithelium and becomes primed for lineage specification and commitment in response to stimuli from the extraembryonic tissues.“ As such a person of ordinary skill in the art was aware of the states of ESCs prior to the filing date of the instant application. It is submitted that selection of particular pluripotent state for use in embryo-like modeling is a routine design choice. It is submitted that Sozen’s embryo-like aggregation methods could be performed in any of the known pluripotent states. It is submitted that such selection would have been obvious absent unexpected results.
Regarding claim 20: Nichols taught that ESCs derived or previously cultured, can be propagated in serum free culture (See Nichols p. 488, col. 2, last para).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 56 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 60 of copending Application No. 18/485,192 (reference application).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending application requires a synthetic embryo. While it is noted that the method claimed in the applications are different, it is submitted that Claim 56 is drafted in product-by-process format (“a synthetic embryo obtained by the method of claim 1”). It is well established that product-by-process claims are examined based on the product itself, not on the recited process steps used to make the product. The patentability of a product-by-process claim is determined by the structure and characteristics of the claimed product, and the claim is not limited to products prepared by the recited process unless the product is structurally distinguishable from prior art products. Accordingly, the method limitations in claim 1 do not impart patentable weight to claim 56 if the claimed synthetic embryo is not structurally distinct from prior art embryo-like structures.
Conclusion
Claim 40 appears free of art, however, lacks written description.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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/JAGAMYA NMN VIJAYARAGHAVAN/ Examiner, Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633