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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/05/2026 has been entered.
1. Claims 1, 5, 6, 8, 11, 13, 14, 16, 17, 19 – 21, 23, 24, 26, 27, 29, 30, 34, 37, and 42 – 47 are pending.
2. Claims 1, 5, 6, 8, 11, 13, 14, 23, 24, 26, 27, 34, 37, and 42 – 47 are under consideration.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 03/05/2626, 03/27/2026, and 05/01/2023 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Maintained Claim Rejections
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.
4. Claim 37 remains rejected under 35 U.S.C. 101 because the claimed invention is directed to a naturally occurring aggregated organoid without significantly more. The claim recites aggregated organoid which is not shown to differ from that in nature. Although maintained, the rejection is revised in view of the amendment to claim 37.
Claim 37 is drawn to one or more aggregated organoids produced by claim 1 wherein the gut endoderm monolayer is differentiated from induced pluripotent stem cells (iPSCs).
The Office published Office's new guidance document entitled 2019 Revised Patent Subject Matter Eligibility Guidance, published January 7, 2019. Applicant is directed to the Federal Register, Volume 4, No. 4, pages 50-57 at page 74621.
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Step 1 of the USPTO' s eligibility analysis entails considering whether the claimed subject matter falls within the four statutory categories of patentable subject matter identified by 35 U.S.C. 101: Process, machine, manufacture, or composition of matter. The claims are directed to a composition of matter (step 1, Yes).
Step 2A of the 2019 Revised Patent Subject Matter Eligibility Guidance is a two-prong inquiry. In Step 2A Prong One, examiners evaluate whether the claim recites a judicial exception. The composition of matter (an aggregated organoids) is directed to a natural phenomenon (Step 2A, prong 1, Yes). Because claim 37 recites a nature-based product limitation (an aggregated organoids), the markedly different characteristics analysis is used to determine if the nature-based product limitation is a product of nature exception. Applicant’s specification teaches the field of invention relates generally to organoid compositions and methods of making the same involving the aggregation of precursor cells where the precursor cells are gut endoderm (page 1, 0002; page 2, 0004). Therefore, Applicant’s specification teaches an aggregated organoid comprises an aggregation of precursor cells. Applicant’s specification teaches human intestinal organoids are 3-dimensional gastrointestinal tissue containing all known intestinal epithelial cell types and exhibits properties of functional intestine tissue (page 1, 0003). Applicant’s specification teaches in hindgut, the simple cuboidal epithelium first develops into a pseudostratified columnar epithelium, then into villi containing a polarized epithelium and a proliferative zone at the base of the villi (page 26, 0106). Menard (Ménard, Daniel, et. al. Gastroenterology 88.3 (1985): 691-700; previously cited) teaches explant culture of human fetal small intestine comprising differentiated and undifferentiated cells (Figure 1; page 692, right col. paragraph 1; page 695, left col. paragraph 1; Figure 4). Menard teaches the cultured explant showed intestinal brush border enzymatic activity (Table 1; Figures 7 – 9). Menard teaches the overall architecture of the cultured explant was comparable to that of uncultured tissue where all epithelial cell types were observed including columnar epithelial cells and villi (page 698, left col. paragraph 2; Figure 1 – 2; page 694, right col. paragraph 1). The markedly different characteristics analysis is performed by comparing the nature-based product limitation in the claim to its naturally occurring counterpart to determine if it has markedly different characteristics from the counterpart. Here, the closest natural counterpart is naturally occurring aggregated organoids. When the claimed aggregated organoid is compared to this counterpart, the comparison indicates that there are no differences in structure, function or other characteristics. Further, the claimed aggregated organoid is not markedly different from the natural counterpart as a result of the method of claim 1 wherein the gut endoderm monolayer is differentiated from iPSCs because there is no evidence that the method imbues any markedly different characteristics compared to the natural counterpart. Therefore, the claimed aggregated organoid is a product of nature exception and recites a judicial exception.
In Step 2A Prong Two, examiners evaluate whether the claim recites additional elements that integrate the exception into a practical application of that exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. Besides the judicial exception, the claim recites the judicial exception is “produced by claim 1” and “wherein the gut endoderm monolayer is differentiated from induced pluripotent stem cells (iPSCs)”. An evaluation of whether this limitation is insignificant extra-solution activity is then performed. Note that because Step 2A Prong Two analysis excludes consideration of whether a limitation is well-understood, routine, conventional activity, this evaluation does not take into account whether or not the limitation is well-known. When so evaluated, this additional element is insignificant extra-solution activity because the steps of the method of claim 1 and gut endoderm are recited so generically. For example, claim 1 does not recite a method for obtaining definitive endoderm and Applicant’s specification teaches definitive endoderm represents the embryonic progenitor (pluripotent cells) of many major organs (page 33, 0124). Therefore, the claim reads on an aggregated organoid formed during development of an embryo (the explant taught by Menard) and fails to meaningfully limit the claim because it is at best the equivalent of merely adding the words “apply it” to the judicial exception. Further, MPEP 2113 (I) states that product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. Accordingly, the method does not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception (Step 2A, prong 2, No).
In Step 2B, the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements adds an inventive concept into the claim. As discussed with respect to Step 2A Prong Two, the claim recites “produced by claim 1” and “wherein the gut endoderm monolayer is differentiated from induced pluripotent stem cells (iPSCs)”, which is at best the equivalent of merely adding the words “apply it” to the judicial exception. Mere instructions to apply an exception cannot provide an inventive concept. At Step 2B, the evaluation of the insignificant extra-solution activity consideration takes into account whether or not the extra-solution activity is well-known. Here, recitation of an aggregated organoid produced by the method of claim 1 is recited at a high level of generality that it reads on the organ developed in an embryo where Applicant’s specification teaches in hindgut, the simple cuboidal epithelium first develops into a pseudostratified columnar epithelium, then into villi containing a polarized epithelium and a proliferative zone at the base of the villi (page 26, 0106). Thus, recitation of “produced by claim 1” does not amount to significantly more and does not provide an inventive concept (Step 2B: No).
Markedly different characteristics can be expressed as the product' s structure, function, and/or other properties. In accordance with this analysis, a product that is purified or isolated, for example, will be eligible when there is a resultant change in characteristics sufficient to show a marked difference from the product' s naturally occurring counterpart. If the claim recites a nature-based product limitation that does not exhibit markedly different characteristics, the claim is directed to a ‘‘product of nature” exception (a law of nature or naturally occurring phenomenon), and the claim will require further analysis to determine eligibility based on whether additional elements add significantly more to the exception.
Limitations that were found not to be enough to qualify as ‘‘significantly more” when recited in a claim with a judicial exception include: Adding the words ‘‘apply it” (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer; simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, e.g., a claim to an abstract idea requiring no more than a generic computer to perform generic computer functions that are well-understood, routine and conventional activities previously known to the industry; adding insignificant extrasolution activity to the judicial exception, e.g., mere data gathering in conjunction with a law of nature or abstract idea; or generally linking the use of the judicial exception to a particular technological environment or field of use.
In the instant case, the limitations of the claim does not impose limits on the claim scope such that they are not markedly different in structure from a naturally occurring product.
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.
5. Claim(s) 1, 6, 8, 11, 13, 14, 23, 24, 26, 27, and 37 remain rejected under 35 U.S.C. 103 as being unpatentable over McCracken (WO-2015183920-A2; previously cited), hereinafter McCracken which is cited on the IDS filed 05/04/2022 as evidenced by Spence (Spence JR, et. al. Nature. 2011 Feb 3;470(7332):105-9; previously cited), hereinafter Spence which is cited on the IDS filed 05/04/2022, in view of Ungrin (Ungrin MD, et. al. Biotechnol Bioeng. 2012 Apr;109(4):853-66; previously cited), hereinafter Ungrin as evidenced by Nostro (Nostro MC et. al. Development. 2011 Mar;138(5):861-71; previously cited), hereinafter Nostro. Although maintained, the rejection is revised in view of the amendment to claim 1.
Regarding claim 1, McCracken teaches a method comprising differentiating definitive endoderm to form foregut endoderm and foregut spheroids (“differentiating definitive endoderm to a gut endoderm monolayer and gut spheroids”) (page 22, 0087; page 40, 00148 – 00151; page 41, 00152 – 00153;page 49, 00177; Figure 1; Figure 19). McCracken teaches the foregut spheroids are floating and the endoderm is adherent (“wherein the gut endoderm monolayer is adherent and the gut spheroids are detached and suspended in a growth medium”) (page 41, 00153; Figure 2). McCracken teaches transfer of the spheroids to another culture system (“separating the adherent gut endoderm from the gut spheroids”) (page 41, 00155; Figure 2). McCracken teaches gut endoderm is differentiated from iPSCs (page 39, para. 0145 – 0149). McCracken does not teach “dissociating the adherent gut endoderm monolayer”, “aggregating the single cell suspension”, or “culturing the one or more gut endoderm aggregates” of claim 1.
Regarding claim 13, McCracken teaches foregut endoderm layer and foregut spheroids (page 41, 00152 – 00153).
Regarding claim 14, McCracken teaches contacting the definitive endoderm with Wnt3A (“Wnt signaling pathway activators”), CHIR99021 (“Wnt signaling pathway activators”), FGF4 (“FGF signaling pathway activators”), and Noggin (“BMP signaling pathway inhibitors”)(page 41, 00153).
Regarding claims 23 and 24, McCracken teaches the foregut spheroids contained a mesenchyme component similar to mid-hindgut spheroids (claim 23) (page 59, 00193). McCracken teaches CDX2 is a hindgut marker (page 35, 00124). McCracken teaches WNT3A and FGF4 induced CDX2 expression and this treatment induces hindgut differentiation of definitive endoderm as evidenced by Spence (page 108, left col. paragraph 4) (claim 24) (page 35, 00123; page 40, 00151; page 41, 00153; page 49 – 50, 00177; Figure 1c; page 49, 00177; Figures 1 and 19; page 53, 00182). McCracken teaches Wnt, FGF and BMP cooperate to promote a mid-hindgut fate (page 53, 00182; Figure 6A; page 16, 0059, 0064).
Regarding claim 26, McCracken teaches the organoids are Cdx2 positive organoid from a precursor cell where a precursor cell may be a hindgut cell (Figure 1; page 16, 0064; page 13, 0047). McCracken teaches KLF5, SOX9, GATA4 and GATA6 can be used to represent gastric development (page 35, 00124; page 58, 00191; Figure 9). The specification discloses that one or more of CDX2, KLF5, or SOX9 can be used to represent intestinal development (page 30, 0118). The specification discloses that one or more of GATA4 or GATA6 protein expression can be used to represent intestinal development. Therefore, McCracken teaches intestinal organoids.
Regarding claims 27, McCracken teaches an exemplary protocol for intestinal organoid formation with media comprising EGF, Wnt, FGF4, and Noggin (Figure 2a).
Regarding claim 37, McCracken teaches gastric organoids are produced by the method shown in Figure 2 where the gut endoderm is differentiated from pluripotent stem cells that are iPSCs (page 39, para. 0145 – 0147).
McCracken does not teach “dissociating the adherent gut endoderm monolayer”, “aggregating the single cell suspension”, or “culturing the one or more gut endoderm aggregates” of claim 1 or claims 6, 8, and 11. However, McCracken teaches the foregut forms the liver (page 23, 0090; page 54, 00184). McCracken teaches the method of development of organoids is astonishingly similar to in vivo stomach organogenesis (page 57, 00190). McCracken teaches the human gastric organoids may be used as an in vitro system to identify new mechanisms of human stomach development, physiology, as a model of the response to H. pylori, and for drug discovery (page 12, 0043). McCracken teaches what is needed in the art are methods and systems for accurately controlling the destination of a precursor cell (a definitive endoderm cell, posterior endoderm cell, and a hindgut cell) in order to create the specific type of tissue (page 2, 0005; page 16, 0059). McCracken teaches there is a need for robust in vitro systems for elucidating the mechanism underlying human stomach development and disease and for the identification of novel treatments useful for human treatment of such disease (page 2, 0004).
Regarding “dissociating the gut endoderm monolayer”, “aggregating” and “culturing” of claim 1 and claims 6, 8 and 11, Ungrin teaches a method of producing definitive endoderm aggregates comprising dissociating cells with trypsin (claim 6) and passing through a filter to remove any clumps (“dissociating” and “to a single cell suspension” of claim 1) (page 854, right col. paragraph 2; Figure 1; page 856, right col. paragraph 2). Ungrin teaches cells are added to a microwell of an Aggrewell plate to achieve a homogenous suspension across the well and the plate was centrifuged (“centrifuging the single cell suspension in a ‘v’ or ‘u’-bottomed microwell culture plate” of claim 8) and incubated to form aggregates (“aggregating” of claim 1) (page 854, right col. paragraph 2). Ungrin teaches differentiation of definitive endoderm aggregates to pancreatic and hepatic lineages and that the aggregate cells could yield functional derivatives that may be useful for pre-clinical evaluation (“culturing” and “to produce the one or more aggregated organoids” of claim 1) (page 861, left col. paragraph 1; Figure 5). Ungrin teaches differentiation to the pancreatic fate was performed according to the protocol of Nostro which teaches culturing with gelatin (claim 11) (Nostro: page 862, left col. paragraph 2) (Ungrin: page 855, left col. last paragraph). Ungrin teaches aggregation has been reported to enhance formation of physiologically relevant structures from hepatocytes (page 864, right col. paragraph 3). Ungrin teaches the importance of consistency and size control in aggregate formation is a significant potential advantage in subsequent steps in the progression towards implantable liver organoids as aggregation has been reported to enhance the formation of physiologically relevant structures from hepatocytes (page 864, right col. paragraph 3). Ungrin teaches to facilitate the rapid incorporation of additional future process and culture improvements, the methods are easily replicated, improved, and extended upon without requiring unconventional technical capabilities (page 865, left col. paragraph 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of McCracken regarding a method of differentiating definitive endoderm to a gut endoderm monolayer and gut spheroids with the teachings of Ungrin regarding a method of producing endoderm aggregates to arrive at the claimed method of producing one or more aggregated organoids from gut endoderm aggregates. One would have been motivated to combine the teachings of McCracken and Ungrin to produce organoids to study the organ development and disease as McCracken teaches there is a need for robust in vitro systems for elucidating the mechanism underlying human stomach development and disease and for the identification of novel treatments useful for human treatment of such diseases. One would have a reasonable expectation of success in combining the teachings as McCracken teaches the method of development of organoids is astonishingly similar to in vivo stomach organogenesis and Ungrin teaches producing liver organoids from endoderm aggregates.
6. Claim(s) 1 and 5 remain rejected under 35 U.S.C. 103 as being unpatentable over McCracken (WO-2015183920-A2; previously cited), hereinafter McCracken which is cited on the IDS filed 05/04/2022 as evidenced by Spence (Spence JR, et. al. Nature. 2011 Feb 3;470(7332):105-9; previously cited), hereinafter Spence which is cited on the IDS filed 05/04/2022, in view of Ungrin (Ungrin MD, et. al. Biotechnol Bioeng. 2012 Apr;109(4):853-66; previously cited), hereinafter Ungrin in view of Breslin (Breslin, S., et. al. Receptor Tyrosine Kinases: Methods and Protocols (2015): 161-168; previously cited), hereinafter Breslin.
McCracken in view of Ungrin make obvious the limitations of claim 1 as set forth above. McCracken teaches transfer of the spheroids to another culture system (page 41, 00155; Figure 2). McCracken does not teach aspirating the growth medium and suspended gut spheroids from the gut endoderm layer.
Breslin teaches harvesting spheroids from culture dishes by aspiration (page 166, 3.4, step 2; Figure 2). Breslin teaches cells grown as spheroids tend to replicate the in vivo situation more reliably than monolayer cells thus the use of spheroids may be more clinically relevant than monolayer cultures (Abstract). Breslin teaches signaling in cells grown in 3D appears to replicate the in vivo situation more accurately than 2D (page 163, paragraph 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of McCracken regarding a method of differentiating definitive endoderm to a gut endoderm monolayer and gut spheroids with the teachings of Ungrin regarding a method of producing endoderm aggregates with the teachings of Breslin regarding aspirating spheroids in culture to arrive at the claimed method wherein the separating step comprises aspirating the growth medium and suspended gut spheroids from the gut endoderm monolayer. One would have been motivated to combine the teachings of McCracken, Ungrin, and Breslin to produce intestinal organoids to study intestinal develop and disease as McCracken teaches there is a need for robust in vitro systems for elucidating the mechanism underlying human stomach development and disease and for the identification of novel treatments useful for human treatment of such diseases. One would have a reasonable expectation of success in combining the teachings as McCracken teaches the method of development of organoids is astonishingly similar to in vivo stomach organogenesis Ungrin teaches producing liver organoids from endoderm aggregates.
7. Claim(s) 1 and 34 remain rejected under 35 U.S.C. 103 as being unpatentable over McCracken (WO-2015183920-A2; previously cited), hereinafter McCracken which is cited on the IDS filed 05/04/2022 as evidenced by Spence (Spence JR, et. al. Nature. 2011 Feb 3;470(7332):105-9; previously cited), hereinafter Spence which is cited on the IDS filed 05/04/2022, in view of Ungrin (Ungrin MD, et. al. Biotechnol Bioeng. 2012 Apr;109(4):853-66; previously cited), hereinafter Ungrin in view of Zhang (Zhang RR, et. al. Stem Cell Reports. 2018 Mar 13;10(3):780-793; previously cited), hereinafter Zhang which is cited on the IDS filed 05/04/2022.
McCracken in view of Ungrin make obvious the limitations of claim 1 as set forth above. McCracken and Ungrin do not teach claim 34. However, McCracken teaches the foregut forms liver (page 23, 0090; page 54, 00184). Ungrin teaches aggregation has been reported to enhance formation of physiologically relevant structures from hepatocytes (page 864, right col. paragraph 3).
Zhang teaches generation of posterior gut endoderm cells (PGECs) by differentiating definitive endoderm in a medium comprising FGF2 (Figure 1A). Zhang teaches differentiation of PGECs into liver organoids and transplantation of the liver organoids into an acute liver failure mouse where the organoids significantly rescued mouse survival (page 787, right col. paragraph 1; page 791, left col. paragraph 2; page 792, left col. paragraph 1). Zhang teaches PGECs area desirable approach to generate specific endodermal lineage cells because of their rigorous proliferative potential in vitro and the absence of teratoma formation in vivo (page 789, right col. paragraph 2). Zhang teaches the PGECs showed stable differentiation propensity into multiple endodermal lineages and could be robustly amplified suggesting PGECs may be a promising source for endoderm-derived organoids in studying human development, modeling disease, and therapy (Abstract).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of McCracken regarding a method of differentiating definitive endoderm to a gut endoderm monolayer and gut spheroids with the teachings of Ungrin regarding a method of producing endoderm aggregates with the teachings of Zhang regarding organoid transplantation to arrive at the claimed method where aggregated organoids are transplanted into a recipient subject. One would have been motivated to combine the teachings of McCracken, Ungrin, and Zhang to produce therapeutic organoids as McCracken teaches there is a need for robust in vitro systems for elucidating the mechanism underlying human stomach development and disease and for the identification of novel treatments useful for human treatment of such diseases. One would have a reasonable expectation of success in combining the teachings as Ungrin teaches aggregation has been reported to enhance formation of physiologically relevant hepatocyte structures and Zhang teaches the organoids significantly rescued mouse survival in a model of liver failure.
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.
8. Claims 1, 13, and 14 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 25 of co-pending Application No. 16611998 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims 1, 13, and 14 anticipate/render obvious the reference claims.
Instant claim 1 recites a method of producing one or more aggregated organoids, comprising: differentiating definitive endoderm to a gut endoderm monolayer and gut spheroids,
wherein the gut endoderm monolayer is adherent and the gut spheroids are detached and
suspended in a growth medium; separating the gut endoderm monolayer from the gut spheroids;
dissociating the gut endoderm monolayer to a single cell suspension of gut endoderm cells;
aggregating the single cell suspension of gut endoderm cells into one or more gut endoderm aggregates; and culturing the one or more gut endoderm aggregates to produce the one or more aggregated organoids. Instant claim 13 recites the method of claim 1, wherein the gut endoderm monolayer is a foregut endoderm monolayer and the gut spheroids are foregut spheroids. Instant claim 14 recites the method of claim 13, wherein differentiating the definitive endoderm to the foregut endoderm monolayer and the foregut spheroids comprises contacting the definitive endoderm with one or more FGF signaling pathway activators, one or more Wnt signaling pathway activators, or one or more BMP signaling pathway inhibitors, or any combination thereof.
Reference claim 1 recites a method of inducing formation of a liver organoid from
pluripotent stem cells (PSCs), comprising the steps of a) contacting definitive endoderm (DE) derived from said PSCs with an FGF pathway activator and a Wnt signaling pathway activator for a first period of time until posterior foregut spheroids are obtained; b) incubating said posterior foregut spheroids of step a in the presence of retinoic acid (RA) for a second period of time until said liver organoid is obtained. Reference claim 25 recites the method of claim 1, wherein said Wnt signaling pathway activator is selected from a small molecule or protein Wnt signaling pathway activator.
Instant claims 1, 13, and 14 anticipate reference claims 1 and 25 because the instant claims are generic to (broader than) the reference claims of the co-pending application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
13. Claims 1 and 11 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 19 of co-pending Application No. 16755193 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims anticipate/render obvious the reference claims.
Instant claim 1 recites a method of producing one or more aggregated organoids, comprising: differentiating definitive endoderm to a gut endoderm monolayer and gut spheroids,
wherein the gut endoderm monolayer is adherent and the gut spheroids are detached and
suspended in a growth medium; separating the gut endoderm monolayer from the gut spheroids;
dissociating the gut endoderm monolayer to a single cell suspension of gut endoderm cells;
aggregating the single cell suspension of gut endoderm cells into one or more gut endoderm aggregates; and culturing the one or more gut endoderm aggregates to produce the one or more aggregated organoids. Instant claim 11 recites the method of claim 1, wherein the culturing step comprises contacting the one or more gut endoderm aggregates with an extracellular matrix, or mimetic or derivative thereof.
Reference claim 1 recites a method of making an esophageal organoid (EO), comprising
a. contacting a definitive endoderm with a BMP signaling pathway inhibitor, a Wnt signaling
pathway activator, an FGF signaling pathway activator, and retinoic acid (RA), for a first period
of time to form an anterior foregut culture, wherein said anterior foregut culture expresses SOX2
andHNF1B;
b. contacting said anterior foregut culture with a BMP signaling pathway inhibitor, and an
EGF signaling pathway activator for a second period of time sufficient to form a dorsal anterior
foregut (dAFG) spheroid, wherein said dAFG spheroid expresses SOX2 and TP63 but does not
express PDX1, PAX9, or NKX2.1;
c. culturing said dAFG spheroid for a third period of time sufficient to allow formation of an
esophageal organoid (EO), wherein said culturing is carried out in the presence of EGF signaling
pathway activator, and wherein the EO comprises a luminal structure.
Reference claim 19 recites the method of claim 1, further comprising contacting the anterior foregut culture of step a) or the spheroid of step b) with a matrix selected from collagen, basement membrane matrix, and a combination thereof.
Instant claims 1, 11, and 19 anticipate reference claims 1 and 19 because the instant claims are generic to (broader than) the reference claims of the copending application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
9. Claims 1 and 37 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 15 of copending Application No. 17595493 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims anticipate/render obvious the reference claims.
Instant claim 1 recites a method of producing one or more aggregated organoids, comprising: differentiating definitive endoderm to a gut endoderm monolayer and gut spheroids,
wherein the gut endoderm monolayer is adherent and the gut spheroids are detached and
suspended in a growth medium; separating the gut endoderm monolayer from the gut spheroids;
dissociating the gut endoderm monolayer to a single cell suspension of gut endoderm cells;
aggregating the single cell suspension of gut endoderm cells into one or more gut endoderm aggregates; and culturing the one or more gut endoderm aggregates to produce the one or more aggregated organoids. Instant claim 37 recites an aggregated organoid produced by claim 1.
Reference claim 1 recites a method of producing a liver organoid that produces hematopoietic stem cells (HSCs), comprising: culturing a foregut spheroid under conditions sufficient to differentiate the foregut spheroid into a liver organoid, wherein culturing the foregut spheroid comprises contacting
the foregut spheroids with a Notch activator or ligand; wherein the liver organoid comprises a CD34+ hemogenic endothelium population that differentiate into hematopoietic stem cells; and
wherein the foregut spheroid comprises mesenchyme. Reference claim 15 recites a liver organoid produced by the method of claim 1.
Instant claims 1 and 37 anticipate reference claims 1 and 15 because the instant claims are generic to (broader than) the reference claims of the copending application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
10. Claims 1, 13, 14, 34, and 37 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 19, 20, 21, 35, 36, 45, and 51 of co-pending Application No. 18573954 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims anticipate/render obvious the reference claims.
Instant claim 1 recites a method of producing one or more aggregated organoids, comprising: differentiating definitive endoderm to a gut endoderm monolayer and gut spheroids,
wherein the gut endoderm monolayer is adherent and the gut spheroids are detached and
suspended in a growth medium; separating the gut endoderm monolayer from the gut spheroids;
dissociating the gut endoderm monolayer to a single cell suspension of gut endoderm cells;
aggregating the single cell suspension of gut endoderm cells into one or more gut endoderm aggregates; and culturing the one or more gut endoderm aggregates to produce the one or more aggregated organoids. Instant claim 13 recites the method of claim 1, wherein the gut endoderm monolayer is a foregut endoderm monolayer and the gut spheroids are foregut spheroids. Instant claim 14 recites the method of claim 13, wherein differentiating the definitive endoderm to the foregut endoderm monolayer and the foregut spheroids comprises contacting the definitive endoderm with one or more FGF signaling pathway activators, one or more Wnt signaling pathway activators, or one or more BMP signaling pathway inhibitors, or any combination thereof. Instant claim 34 recites the method of claim lany one of the preceding claims, further comprising transplanting the one or more aggregated organoids to a recipient subject. Instant claim 37 recites an aggregated organoid produced by claim 1.
Reference claim 1 recites a method for preparing a gastrointestinal organoid from the three primary germ layers, comprising: contacting gut endoderm spheroids with splanchnic mesoderm cells (SM) and enteric neural crest cells (ENCCs) to form a cell mixture; and culturing the cell mixture under conditions sufficient to differentiate the cell mixture into a gastrointestinal organoid comprising epithelium, mesenchyme, and a functional enteric nervous system (ENS). Reference claim 3 recites the method of claim 1, wherein the gut endoderm spheroids have been derived from definitive endoderm cells; and/or wherein the gut endoderm spheroids are spontaneously formed but endoderm spheroids that develop during differentiation of definitive endoderm cells into gut endoderm. Reference claim 19 recites the method of claim 1, wherein the gut endoderm spheroids are foregut endoderm spheroids. Reference claim 20 recites the method of claim 19, wherein the foregut endoderm spheroids are
posterior foregut endoderm spheroids, and the gastrointestinal organoid is a gastric organoid. Reference claim 21 recites the method of claim 20, wherein the posterior foregut endoderm
spheroids have been derived from definitive endoderm cells according to a method comprising
activating an FGF pathway, a BMP pathway inhibitor, and a Wnt pathway in the definitive endoderm cells for a first period and activating an FGF pathway, a BMP pathway inhibitor, and a Wnt pathway, in combination with retinoic acid, for a second period, thereby differentiating the definitive endoderm cells into the posterior foregut endoderm spheroids; and/or wherein the gastric organoid is an antral gastric organoid and the conditions sufficient to differentiate the cell mixture to the antral gastric organoid comprises inhibiting a BMP pathway and activating an EGF pathway, in combination with retinoic acid, in the cell mixture for a third period, and activating an EGF pathway activator for a fourth period; and/or wherein the gastric organoid is a fundic gastric organoid and the conditions sufficient to
differentiate the cell mixture to the fundic gastric organoid comprises inhibiting a BMP pathway
and activating Wnt pathway and an EGF pathway, in combination with retinoic acid, in the cell
mixture for a fifth period, and activating a Wnt pathway and an EGF pathway for a sixth period,
and/or wherein, in the fundic gastric organoid, a BMP pathway is further activated and a MEK
pathway is inhibited, to induce parietal cell differentiation. Reference claim 35 recites the method of claim 19, wherein the foregut endoderm spheroids are anterior foregut endoderm spheroids, and the gastrointestinal organoid is an esophageal organoid. Reference claim 36 recites the method of claim 35, wherein the anterior foregut endoderm spheroids have been derived from definitive endoderm cells according to a method comprising activating an FGF pathway and inhibiting a BMP pathway the definitive endoderm cells for a first period, thereby differentiating the definitive endoderm cells into the anterior foregut endoderm spheroids; and/or wherein the conditions sufficient to differentiate the cell mixture to the esophageal organoid comprises activating an FGF pathway and an EGF pathway and inhibiting a BMP pathway for a second period, and activating an EGF pathway for a third period. Reference claim 45 recites the method of claim 1, further comprising transplanting the gastrointestinal organoid into a mammal. Reference claim 51 recites a gastrointestinal organoid produced by the method of claim 1.
Instant claims 1, 13, 14, 34, and 37 anticipate reference claims 1, 3, 19, 20, 21, 35, 36, 45, and 51 because the instant claims are generic to (broader than) the reference claims of the co-pending application the reference claims are essentially a species of a method of producing gastric organoids and transplanting gastric organoid into a subject where instant claims 1, 13, 14, and 34 teach a method of producing gastric organoids and the produced gastric organoids which encompasses the method of reference claims 1, 3, 19, 20, 21, 35, 36 and 45 and the gastric organoid of reference claim 51.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Rejections Necessitated by Amendment and New Rejections
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.
11. Claim 45 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.
Claim 45 is drawn to the method of claim 1, wherein the gut endoderm monolayer is encapsulated prior to aggregation.
Claim 45 broadly recites “encapsulated”, however, the specification provides no implicit or explicit support for the context of the breadth of “encapsulated”. The specification has only provided support for “encapsulated” at page 41 where “a lid may be included with plate (12) and configured to cover wells (24) so as to be encapsulated rather than open”. Applicants are reminded that it is their burden to show where the specification supports any amendments to the claims. See 37 CFR 1.121 (b)(2)(iii), the MPEP 714.02, 3rd paragraph, last sentence and also the MPEP 2163.07, last sentence.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application. MPEP 2163.06 further notes “When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure [or point to case law supporting incorporation of such a limitation as in the instant case]” (emphasis added).
12. Claim 47 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.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
Claim 47 is drawn to the method of claim 46, wherein the 3D structure comprises an extracellular matrix, or a mimetic or derivative thereof. Thus, the claim is a genus claim that encompasses any compound or molecule that mimics or is derived from an extracellular matrix. However, the instant specification fails to describe the entire genus of compounds or molecules that mimic or are derived from an extracellular matrix. The genus for mimetics and derivatives of an extracellular matrix is highly variant, inclusive to numerous compounds. Thus, the genus of compounds or molecules that mimic or are derived from an extracellular matrix, which, when used as claimed, lacks a written description, and as such, there is no indication that Applicants had possession of the claimed invention.
From the specification, it is clear that Applicants have possession of Matrigel (para. 0178, 0196, 0198, 0203). However, the claims are not limited to Matrigel and Applicant’s specification discloses that examples of extracellular matrices or mimetics or derivative thereof to include cell-based feeder layers, polymers, proteins, polypeptides, nucleic acids, sugars, lipids, poly-lysine, poly-omithine, collagen, gelatin, fibronectin, vitronectin, laminin, elastin, tenascin, heparan sulfate, entactin, nidogen, osteopontin, basement membrane, Matrigel, hydrogel, PEI, VVGA, or hyaluronic acid (para. 0095). The claims only require a mimetic or derivative of an extracellular matrix. The specification fails to teach or describe any other extracellular matrix for culturing aggregates.
The specification lacks sufficient variety of species of extracellular matrix mimetics or derivatives to reflect this variance in the genus since the specification provides only culturing with Matrigel. The MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable that the claims are broad generics, with respect to all of the potential extracellular matrix mimetics and derivatives that may be used to form or culture gut endoderm aggregates. The possible variations of extracts are limitless with potentially thousands of compounds that may be used for formation or culturing with gut endoderm aggregates. The purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter claimed by them. A patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that the inventor invented the claimed invention. Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention."
In the instant case, the breadth of the genus of extracellular matrix mimetics or derivatives, lacks a written description. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only factor present in the specification is a reference to cinnamon powder. The skilled artisan cannot envision the detailed chemical composition of all of the compounds that are encompassed by the claims, and therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method.
Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the recited genus. Thus, the written description requirement has not been satisfied.
Applicant is reminded that Vas-Cath makes clear that the written description of 35 U.S.C. 112 is severable from its enablement provision [see p. 1115].
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.
13. Claim 42 is 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.
Regarding claim 42, it is unclear what is meant by “the total number of cells” in line 2. It is unclear if the total number of cells refers to definitive endoderm and gut endoderm or definitive endoderm and mesoderm or monolayer and spheroid.
Claim Interpretation
14. For the purpose of applying prior art, claim 13 is interpreted as foregut endoderm is formed by differentiating the definitive endoderm to the foregut endoderm monolayer and the foregut spheroids comprises contacting the definitive endoderm with one or more FGF signaling pathway activators, one or more Wnt signaling pathway activators, or one or more BMP signaling pathway inhibitors, or any combination thereof based on Applicant’s specification at page 35, para. 0128.
15. For the purpose of applying prior art, claim 14 is interpreted as hindgut endoderm is formed by contacting the definitive endoderm with one or more FGF signaling pathway activators, or one or more Wnt signaling pathway activators, or both based on Applicant’s specification at page 36, para. 0129.
16. For the purpose of applying prior art, the “wherein” clauses of claims 42 – 44 are not given patentable weight as it does not recite a method step.
17. For the purpose of applying prior art, “encapsulated” recited in claim 45 is given the broadest reasonable interpretation including covering the gut endoderm monolayer with a lid based on Applicant’s specification at page 41, para. 0139.
18. For the purpose of applying prior art, “cultured with a 3D structure” of claim 46 is given the broadest reasonable interpretation including culturing in a culture dish, which is a 3D structure.
New Claim Rejections - 35 USC § 103
19. Claim(s) 1, 6, 8, 11, 13, 14, 23, 24, 26, 27, 34, 37, and 42 – 47 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Zhang, Ran-Ran, et al. Stem Cell Reports 10.3 (2018): 780-793; previously cited), hereinafter Zhang which is cited on the IDS filed 05/04/2022 in view of Sendi (Sendi, Hossein, et al. PloS one 13.7 (2018): e0200847.), hereinafter Sendi.
Regarding claim 1 and 42 – 44, Zhang teaches a method of differentiating iPSCs to definitive endoderm (DE) followed by differentiating the DE to adherent gut endoderm monolayer (PGECs) (“differentiated definitive endoderm to a gut endoderm monolayer”, “wherein the gut endoderm monolayer is adherent” and “wherein the gut endoderm monolayer is differentiated from induced pluripotent stem cells (iPSCs)”) and detached gut spheroids (“gut spheroids” and “the gut spheroids are detached and suspended in a growth medium”) (page 781, right col. para. 2; Figure 1A and 3A; page 785, left col. last para. and right col. para. 1 – 2; page 791, left col. last para. and right col.; page 792, left col. para. 1 – 3). Zhang teaches the formation of a gut endoderm monolayer in Figure 1C and 3B and gut spheroids in Figure 3C and 3D. Zhang teaches dissociating the adherent gut endoderm monolayer to a single cell suspension of gut endoderm cells (page 785, left col. para. 1). Zhang teaches separating the spheroids from the cell sheets (“separating the adherent gut endoderm monolayer from the gut spheroids”) and culturing the spheroids to produce gut organoids (page 785, right col. para. 1 – 2). Zhang teaches culturing the PGECs to form liver bud organoids (Figure 5; page 787, left col. last para. and right col. para. 1). Zhang does not teach “aggregating the single cell suspension of gut endoderm cells into one or more gut endoderm aggregates”.
Regarding claim 6, Zhang teaches dissociating with Accutase (page 791, right col. last para.).
Regarding claim 11, Zhang teaches contacting the gut endoderm with Matrigel (page 785, right col. para. 2; page 791, right col. para. 2 – 3; page 792, left col. para. 1 – 3; Supplemental Experimental Procedures para. 2).
Regarding claims 13, 14, 23, and 24, Zhang teaches formation of gut endoderm monolayer and spheroids (claims 13 and 23) by culturing with FGF4 (“one or more FGF signaling pathway activators” of claims 14 and 24) and CHIR99021 (“one or more Wnt signaling pathway activators” of claim 14 and 24) (Figure 3A; page 785, left col. last para. and right col. para. 1 – 2; page 791, right col. last para.; page 792, left col. para. 1 – 3).
Regarding claim 26, Zhang teaches the organoids contained absorptive enterocytes and hindgut epithelial cells (page 785, right col. para. 2).
Regarding claim 27, Zhang teaches the spheroids with CHIR99021 to form the organoids with absorptive enterocytes and hindgut epithelial cells (“Wnt signaling pathway activator”) (page 785, right col. para. 2).
Regarding claim 34, Zhang teaches transplanting the liver bud organoids into an acute liver failure mouse model (page 787, left col. last para. and right col. para. 1; Figure 5).
Regarding claim 37, Zhang teaches in Figure 3C, 3D, and 5B organoids produced from differentiating DE to gut endoderm.
Regarding claim 45, Zhang teaches culturing the PGEC monolayer in 24-well culture plates (page 792, left col. para. 2).
Regarding claims 46 and 47, Zhang teaches the spheroids were cultured with Matrigel (page 792, left col. para. 2).
Zhang does not teach “aggregating the single cell suspension of gut endoderm cells into one or more gut endoderm aggregates” of claim 1 or “hanging drops” of “u-shape bottom microwell culture plate” of claim 8. However, Zhang teaches fresh and thawed gut endoderm could successfully differentiate into mature hepatocyte-like cells (page 787, left col. para. 1; Figure 4A). Zhang teaches that both fresh and thawed gut endoderm-derived hepatocyte-like cells secreted albumin (page 787, left col. para. 2). Zhang teaches PGECs could form liver bud organoids that when transplanted into an acute liver failure mouse model rescued mouse survival (page 787, left col. last para. and right col. para. 1; Figure 5). Zhang teaches the use of storable and robustly amplifying PGECs from feeder-free human iPSCs represents a rational cell source for future applications (page 791, left col. para. 1). Zhang teaches PGECs may be a promising cellular source for endoderm-derived organoids in studying human development, modeling disease, and ultimately therapy (Abstract). Zhang teaches although pluripotent stem cells show unlimited capacity for in vitro expansion, recent emerging evidence suggests that factors including genetic and epigenetic variations or chromosomal instabilities may change the properties of PSCs and their derivations, thus dampening their utility for future applications (page 780, left col.; page 789, right col. para. 2). Zhang teaches targeting developmental progenitors seems to be a reasonable strategy to obtain a large number of cells for subsequent applications purposes but establishing a stable source of developmental progenitors remains a challenge (page 780, left col.). Zhang teaches PGECs are found along almost the entire length of the gut and eventually develop the majority of the gastrointestinal tract (page 780, right col. para. 1). Zhang teaches the PGECs are a desirable approach to generate specific endodermal lineage cells because of their rigorous proliferative potential in vitro and the absence of teratoma formation in vivo (page 789, right col. para. 2). Zhang teaches PGECs may be a promising candidate for in vivo modeling and autologous therapy for human liver diseases and are an important tool to deliver the clinical or pharmaceutical promises of human iPSCs in medical applications (page 791, left col. para. 2 – 3).
Regarding “aggregating the single cell suspension of gut endoderm cells into one or more gut endoderm aggregates” of claim 1 and “hanging drops” of “u-shape bottom microwell culture plate” of claim 8, Sendi teaches a method of forming liver organoids by aggregating primary human hepatocytes using gravitational aggregation in either InSphero hanging drop plates or ultralow adhesion U bottomed plates (page 3, para. 2). Sendi teaches 2D cultures of primary hepatocytes only partially mimic the microenvironment of the liver because they lack other major hepatic cells and cellular microarchitecture (page 2, para. 1). Sendi teaches the organoids showed excellent viability for at least 28 days (page 5, para. 2 – 3; Figure 1). Sendi teaches liver organoids generated by stirring in bioreactors or gravitational aggregation in hanging drop cultures or ultralow attachment surfaces constitute models that allow high-throughput screenings and studying different liver diseases in 3D liver models in vitro (page 2, para. 1). Sendi teaches chronic liver diseases of diverse etiologies are among leading causes of mortality and morbidity around the world (page 2, para. 2). Sendi teaches the use of the liver organoids to understand the role of miR-122 inhibition and suggests that miR-122 mimics could play a useful role in reversing liver inflammation, steatofibrosis, and insulin resistance seen in NAFLD patients (page 14, para. 5).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Zhang regarding a method of differentiating iPSCs to DE and then to gut endoderm monolayer and gut spheroids, where the gut endoderm monolayer is storable and where the gut endoderm monolayer can be thawed and form organoids with the teachings of Sendi regarding a method of forming liver organoids with gravitational aggregation where the organoids remained viable for at least 28 days to arrive at the claimed method of producing one or more aggregated organoids, comprising: differentiating definitive endoderm to a gut endoderm monolayer and gut spheroids, wherein the gut endoderm monolayer is adherent and the gut spheroids are detached and suspended in a growth medium; separating the adherent gut endoderm monolayer from the gut spheroids; dissociating the adherent gut endoderm monolayer to a single cell suspension of gut endoderm cells; aggregating the single cell suspension of gut endoderm cells into one or more gut endoderm aggregates; and culturing the one or more gut endoderm aggregates to produce the one or more aggregated organoids; and wherein the gut endoderm monolayer is differentiated from induced pluripotent stem cells (iPSCs). One would have been motivated to combine the teachings of Zhang and Sendi in a method of producing liver organoids from stored gut endoderm monolayer cells instead of iPSCs for modeling liver disease as Zhang teaches although pluripotent stem cells show unlimited capacity for in vitro expansion, recent emerging evidence suggests that factors including genetic and epigenetic variations or chromosomal instabilities may change the properties of PSCs and their derivations, thus dampening their utility for future applications and Zhang teaches targeting developmental progenitors seems to be a reasonable strategy to obtain a large number of cells for subsequent applications purposes but establishing a stable source of developmental progenitors remains a challenge and Zhang teaches PGECs may be a promising candidate for in vivo modeling and autologous therapy for human liver diseases and are an important tool to deliver the clinical or pharmaceutical promises of human iPSCs in medical applications and Sendi teaches liver organoids generated by stirring in bioreactors or gravitational aggregation in hanging drop cultures or ultralow attachment surfaces constitute models that allow high-throughput screenings and studying different liver diseases in 3D liver models in vitro. One would have a reasonable expectation of success in combining the teachings as Zhang teaches fresh and thawed gut endoderm could successfully differentiate into mature hepatocyte-like cells and Zhang teaches that both fresh and thawed gut endoderm-derived hepatocyte-like cells secreted albumin and Zhang teaches PGECs could form liver bud organoids that when transplanted into an acute liver failure mouse model rescued mouse survival and Zhang teaches the PGECs are a desirable approach to generate specific endodermal lineage cells because of their rigorous proliferative potential in vitro and the absence of teratoma formation in vivo and Sendi teaches the organoids showed excellent viability for at least 28 days.
20. Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Zhang, Ran-Ran, et al. Stem Cell Reports 10.3 (2018): 780-793; previously cited), hereinafter Zhang which is cited on the IDS filed 05/04/2022 in view of Sendi (Sendi, Hossein, et al. PloS one 13.7 (2018): e0200847.), hereinafter Sendi as applied to claims 1, 6, 8, 11, 13, 14, 23, 24, 26, 27, 34, 37, and 42 – 47 above, and further in view of Haass (Haass, Nikolas. (2017). Re: How to seperate spheroids from single cells after spheroid formation?. Retrieved from: https://www.researchgate.net/post/How_to_seperate_spheroids_from_single_cells_after_spheroid_formation/5881c10b96b7e4cf296662a4/citation/download. Accessed on 05/26/2026), hereinafter Haass.
Zhang teaches spheroids formed from the monolayer and the spheroids were separated and embedded to form organoids (page 785, right col. para. 1 – 2). Zhang does not teach aspirating the growth medium and suspended gut spheroids of from the gut endoderm monolayer of claim 5.
Haas teaches using aspiration for separating spheroids from single cells after spheroid formation (page 1, para. 1 – 2; page 2, para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Zhang regarding a method of differentiating iPSCs to DE and then to gut endoderm monolayer and gut spheroids, where the spheroids are separated from the 2D cells with the teachings of Sendi regarding a method of forming liver organoids with gravitational aggregation where the organoids remained viable for at least 28 days with the teachings of Haass regarding a method of separating spheroids from cells by aspiration to arrive at the claimed method where the separating step comprises aspirating the growth medium and suspended gut spheroids from the gut endoderm. One would have been motivated to combine the teachings of Zhang and Sendi in a method of producing liver organoids from stored gut endoderm monolayer cells instead of iPSCs for modeling liver disease as Zhang teaches although pluripotent stem cells show unlimited capacity for in vitro expansion, recent emerging evidence suggests that factors including genetic and epigenetic variations or chromosomal instabilities may change the properties of PSCs and their derivations, thus dampening their utility for future applications and Zhang teaches targeting developmental progenitors seems to be a reasonable strategy to obtain a large number of cells for subsequent applications purposes but establishing a stable source of developmental progenitors remains a challenge and Zhang teaches PGECs may be a promising candidate for in vivo modeling and autologous therapy for human liver diseases and are an important tool to deliver the clinical or pharmaceutical promises of human iPSCs in medical applications and Sendi teaches liver organoids generated by stirring in bioreactors or gravitational aggregation in hanging drop cultures or ultralow attachment surfaces constitute models that allow high-throughput screenings and studying different liver diseases in 3D liver models in vitro. One would have a reasonable expectation of success in combining the teachings as Zhang teaches the spheroids were separated from the 2D cell culture and formed organoids and Zhang teaches fresh and thawed gut endoderm could successfully differentiate into mature hepatocyte-like cells and Zhang teaches that both fresh and thawed gut endoderm-derived hepatocyte-like cells secreted albumin and Zhang teaches PGECs could form liver bud organoids that when transplanted into an acute liver failure mouse model rescued mouse survival and Zhang teaches the PGECs are a desirable approach to generate specific endodermal lineage cells because of their rigorous proliferative potential in vitro and the absence of teratoma formation in vivo and Sendi teaches the organoids showed excellent viability for at least 28 days.
Double Patenting
21. Claims 1, 5, 6, 8, 11, 13, 14, 23, 24, 26, 27, 34, 37, and 42 – 47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 14 of U.S. Patent No. 10174289. Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by patent claim 1.
Patent claim 1 recites a method of inducing formation of a gastric tissue, comprising the steps of: a) contacting a culture containing a mammalian definitive endoderm cell with an FGF signaling pathway activator, a Wnt signaling pathway activator, and a BMP inhibitor for at least two days or for a period of time sufficient to form SOX2+foregut cells; b) contacting said SOX2+foregut cells of step (a) with retinoic acid for a period of time sufficient to form three-dimensional foregut spheroids, wherein said spheroids express SOX2, PDX1, HNF1β, and HNF6; c) contacting said three-dimensional foregut spheroids of step (b) with retinoic acid, EGF, and a BMP inhibitor for a period of time sufficient for formation of a gastric organoid, wherein said gastric organoid is characterized by expression of MUC5AC, gastrin, ghrelin, 5-HT, and ChrA and the presence of cell types selected from one or more of antral mucous cells and endocrine cells. Therefore patent claim 1 is in essence a species of the generic invention of instant claim 1. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
22. Claims 1, 5, 6, 8, 11, 13, 14, 23, 24, 26, 27, 34, 37, and 42 – 47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 14 of U.S. Patent No. 11053477. Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by patent claim 1.
Patent claim 1 recites a method of inducing formation of a gastric tissue, comprising the steps of: a) contacting a culture containing a mammalian definitive endoderm cell with an FGF signaling pathway activator, a Wnt signaling pathway activator, and a BMP inhibitor for a period of time sufficient to form SOX2+ foregut cells; b) contacting said SOX2+ foregut cells of step (a) with retinoic acid for a period of time sufficient to form three-dimensional foregut spheroids, wherein said three-dimensional foregut spheroids express SOX2, PDX1, HNF1beta, and HNF6; c) contacting said three-dimensional foregut spheroids of step (b) with retinoic acid, EGF and a BMP inhibitor for a period of time sufficient for formation of a gastric organoid, wherein said gastric organoid is characterized by expression of MUC5AC, gastrin, ghrelin, 5-HT, and ChrA and the presence of a cell type selected from an antral mucous cell, an endocrine cell, and a combination thereof. Therefore patent claim 1 is in essence a species of the generic invention of instant claim 1. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
Applicant’s Arguments/ Response to Arguments
23. Applicant Argues: Applicant traverses the rejection of claim 37 under 35 U.S.C. § 101 because the claim has been amended to recite that the organoids are derived from non-naturally occurring iPSCs and would possess structural and genetic changes from natural cells.
Response to Argument: This is not found persuasive because Applicant has not identified how the organoids derived from iPSCs would be structurally and genetically different which would result in a such organoids being functionally different from naturally occurring organoids derived from naturally occurring PSCs.
Applicant Argues: Applicant assert that McCracken has no teaching regarding retaining and subsequently culturing an adherent gut endoderm monolayer and McCracken teaches away from doing so.
Response to Argument: This is not found persuasive because McCracken teaches iPSCs plated as single cells to form definitive endoderm which is then differentiated to form adherent gut endoderm monolayer from which spheroids develop. Essentially, McCracken teaches that the gut endoderm spheroids separate from the adherent gut endoderm monolayer by forming spheroids (aggregation of gut endoderm cells). Therefore the aggregation of gut endoderm cells to form gut endoderm aggregates is highly predictable as McCracken teaches that gut endoderm cells aggregate to form gut endoderm spheroids as shown in Figure 2.
Applicant Argues: Applicant asserts that Ungrin has no teaching whatsoever regarding aggregating cells which are already differentiated and Ungrin teaches away from the presently claimed method.
Response to Argument: This is not found persuasive because Ungrin teaches a plate for cell aggregation. Further, as McCracken teaches gut endoderm aggregates on its own to form spheroids, it is predictable that gut endoderm aggregated by culturing in the plate of Ungrin would form gut endoderm aggregates because Ungrin teaches that dissociated undifferentiated cells can form aggregates in the AggreWell plate and be further differentiated into organoids.
Applicant Argues: Applicant asserts that the gut endoderm monolayer can be distinguished from gut spheroids produced according to previous methods by the relative abundance of mesoderm and/or mesenchyme lineages. Applicant asserts that the claimed method has advantageous technical effects including improved scalability due to increased yield and homogeneity of spheroids produced by aggregation compared to the spontaneous formation.
Response to Argument: This is not found persuasive because the remaining adherent gut endoderm after removal of the spheroids would be predicted to aggregate and form spheroids as taught by Figure 2 of McCracken. Further, it appears Applicant is reading limitations regarding the method of aggregating into claim 1. Claim 1 broadly recites “aggregating” and as shown in McCracken’s Figure 2, the gut endoderm aggregates spontaneously in the absence of any aggregation methods recited in claim 8. Should Applicant present arguments regarding dissociated adherent gut endoderm produces spheroids that differ functionally from those produced spontaneously by adherent gut endoderm, the rejection may be overcome upon further consideration.
Applicant argues: Applicant requests the requirement for filing a terminal disclaimer be held in abeyance.
Response to Arguments: MPEP 804 states a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional. Only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Accordingly, the s double patenting rejection is maintained.
Conclusion
No claims allowed.
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/ZANNA MARIA BEHARRY/Examiner, Art Unit 1632
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