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 .
New objections/ rejections in response to Applicant arguments or amendments:
Claim Objections
The amendment to the claims filed on 07/19/2026 does not comply with the requirements of 37 CFR 1.121(c) because changes in the two new claims filed on 07/19/2026 are not properly identified. Specifically, claims 16-24 have been canceled. The two new filed claims are both identified as claim 25. Amendments to the claims filed on or after 05-20-2005 must comply with 37 CFR 1.121(c) which states:
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
Any further claim amendments must comply with 37 CFR 1.121(c) or they may not be entered
For the sake of compact prosecution, the second claim identified as claim 25 has been interpreted as claim 26.
STATUS OF CLAIMS
This action is in response to papers filed July 19, 2026. Claims 1-15 and 25 and 26 are currently pending, claims 25 and 26 are newly added, claims 9, 10, 12, 13 14 have been amended and claims 16-24 have been canceled pursuant to the amendments filed on July 19, 2023.
Applicants’ previous election of Group II directed to an expression cassette, e.g. claims 9-14 was previously acknowledged. Therefore, claims 1-8 and 15-24 (claims 16-24 now canceled) were previously withdrawn from further consideration, pursuant to 37 CFR l. l 42(b), as being drawn to a non-elected invention, there being no allowable generic or linking claim. The restriction requirement was previously made FINAL.
Therefore, claims 9-14, and newly added claims 25 and 26 are under examination to which the following grounds of rejection are applicable.
Priority
This application is claiming benefit under 35 U.S.C. 119(e) of prior-filed provisional application 63/365,328 filing date May 25th, 2022.
Thus, the earliest possible priority for the instant application is May 25th, 2022.
Response to Arguments
Withdrawn objections/ Rejections in view of the Amendments filed July 19, 2026
Claim objection
In view of Applicants’ amendment of claim 12, the objection to claim 12 has been withdrawn.
Maintained Rejections in Response to Applicants’ Arguments or Amendments
Claim Rejections - 35 USC § 112
Claims 9-14 remain rejected and claim 25 is newly rejected under 35 U.S.C. l 12(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. This rejection has been modified necessitated by amendment of the claims in the response filed 7/19/2026.
Claim 9 remains indefinite in the recitation of "a complete gastrointestinal organoid". The term ”complete” is not defined by the claim. The specification does not provide any closed definition as to what is meant by "complete". The metes and bounds of the claims are unclear particularly since "complete" would vary depending on homology to the contractile human GIO in vivo and culture conditions, endodermal differentiation and others. As such, the metes and bounds of the claims cannot be determined.
Regarding claims 12, 13, 14 and 25, are unclear in their recitation of “the beginning of Step a)” as it is unclear what “the beginning” of step a) entails, and there is not a definitive reference point for “the beginning of step a)”. As such, the metes and bounds of this claim are unclear.
Regarding newly added claim 26, it depends on a cancelled claim 24. Applicants are required to cancel the claim(s) or amend the claim(s) to place the claim(s) in proper dependent form, or rewrite the claim(s) in independent form. Therefore, the metes and bounds of claim 26 is indefinite.
For the purpose of a compacted prosecution, claim 26 has been interpreted as dependent on claim 25.
Claims 10 and 11 are rejected insofar that they are dependent on claim 9.
Response to Arguments as they pertain to the Rejection of claim 9 over 35 USC § 112
Beginning on the Remarks filed July 19, 2026, Applicants essentially argue the following:
Applicant submits that the specification does indeed describe the term "complete" in a manner that would be understood by one skilled in the art. Specifically, the Applicants direct the Office to paragraphs 0002, 0014, 0056 and 0057 of the instant Specification for clarity.
In response, these arguments are considered but are not persuasive for the following reasons:
Regarding 1), although the Specification utilizes the term “complete” and describes various cell types and functional characteristics associated with gastrointestinal organoids, it does not specify which characteristics are required for an organoid to be denoted as “complete”. Further, Applicants’ discussion of prior art elucidates this uncertainty by emphasizing what characteristics regard an organoid to be “complete”, claim 9 does not disclose specific characteristics that define an organoid to be of such. For example, paragraph 0008 discusses that the complete organoid comprises smooth muscle cells, an enteric nervous system, etc. Moreover paragraphs 0009 and 0010 discuss other cell types that are within the organoid, as well as markers associated with the complete gastrointestinal organoid. These characteristics of a discussed within the Specification are not reflected in the instant claims as “complete”.
Claim Rejections - 35 USC § 103
Claims 9-10, 12-14, remain rejected and newly added claims 25 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over McCracken et al. (Published: 2011. Nat Protoc. PMC 2014 January 20; 6(12): 1920-1928.; pp. 1-19. Cited in IDS filed 01/26/26). This rejection has been modified necessitated by amendment of the claims in the response filed 7/19/2026.
Regarding claim 9 and 25, McCracken teaches a method for preparing a gastrointestinal organoid (Abstract, "We describe a protocol to generate 3-dimensional human intestinal tissue (called organoids) in vitro from human pluripotent stem cells") comprising: culturing human induced pluripotent stem cells (HiPSCs) in a first culture media to produce 3- dimensional gut spheroid cells (page 1920 col 2 para 2 "In addition, using patient specific induced pluripotent stem cells (iPSCs) will allow in vitro disease modeling to study the etiology and molecular mechanisms of disease processes"; page 1920 col 1 para l "In support of this, we recently published a method that demonstrates that high levels of FGF4 and WNT3A act in synergy to pattern human PSC-derived definitive endoderm into mid/ hindgut endoderm and promote a gut tube-like morphogenesis, resulting in the formation of 3-dimensional, mid/hindgut-like spheroids"); reading on step a) of claim 9 and new claim 25.
McCracken teaches treating said 3-dimensional spheroid cells with Activin A and generating gut spheroids (page 1922 col 2 para 2 "Combine RPMI 1640, 2%dFBS (vol/vol) Lglutamine (final concentration 2 mM), Pen/Strep (final concentration pen 100 Units/mL; strep 100 ug/mL), Activin A (final concentration l00ng/mL). Endoderm differentiation media is best if made fresh each day, but can be stored at 4°C for 1-3 days"); reading on step b) of claim 9 and partially on step b) of claim 25.
McCracken teaches treating said gut spheroid cells with Wnt3A and fibroblast growth factor 4 (page 1920 col 1 para 3 bridging into col 2 para 1, "Generation of human intestinal tissue from hPSCs takes approximately one month: 3 days of exposure to ActivinA for definitive endoderm (DE) induction, 4 days of exposure to FGF4/ WNT3A to generate mid/hindgut spheroids").
McCracken teaches seeding said large gut spheroid cells on a domeshaped gel-matrix in an intestinal media containing Rspondin, noggin and EGF (page 1922 para 2, "Thaw bottle of matrigel on ice or at 4 °C. Once matrigel has thawed, add B27 supplement (final concentration Ix), Rspondinl (final concentration 500ng/mL), Noggin (final concentration I 00ng/mL) and EGF (final concentration 100ng/mL ). ") reading on claim 25.
McCracken teaches culturing said domed-shaped gel matrix comprising large gut spheroid cells to provide a complete gastrointestinal organoid (Abstract page 1920, "The 3D spheroids are further cultured in matrigel along with pro-intestinal growth factors, and proliferate and expand over 1-3 months to give rise to intestinal tissue, complete with intestinal mesenchyme and epithelium consisting of all of the major intestinal cell types.") reading on claim 25.
Note that passage of colonies into the 6-well dish into a Matrigel-coated 24-well dish at a 1:6 ratio reads on a dome-shaped gel-matrix as illustrated in Figure 1A.
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However, McCracken does not explicitly teach that the large gut spheroid cells have a diameter of 200 micrometers.
It would have been obvious for one of ordinary skill in the art to optimize experimental conditions based influential considerations in the design of the instant invention such as concentrations of cell culture components, concentration of growth factors or Activin A treatments, temperature of three-dimensional cell culture, number of cell passages etc. to predictably create large gut spheroids with a diameter of about 200 micrometers. Thus, the prior art differs from the claimed invention only with respect to the diameter of the large gut spheroids.
The Court has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955). (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421.
MPEP 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount.
However, McCracken does not explicitly teach that the steps b) through e) are performed at specific days throughout this cultivation method, as required by claim 25. Moreover, McCracken discloses that genetic manipulation, addition or removal of growth factors or chemical agonist/antagonists can be used to achieve different experimental outcomes.
Therefore, it would have been obvious to a person with ordinary skill in the art to optimize the timing of administration of Activin A, FGF4 and WNT3A, as McCracken discloses that the addition of growth factors can be modified based on desired experimental outcomes. Thus, McCracken establishes that the addition of these growth factors was recognized as a variable affecting progression and development of the organoid cultivation method. The recitation of treatment beginning at days 3, 6, etc. represents optimization of known process conditions rather than a patentably distinct differentiation mechanism.
Regarding claim 10, McCracken renders obvious the method for producing gastrointestinal organoids according to claim 1. Moreover, McCracken teaches seeding said large gut spheroid cells on a dome-shaped gel matrix in wells of a multi-well plate (page 1925 bridging into page 11 "Use as little media as possible to transfer spheroids into Matrigel. The Matrigel should form a "bead" in the center of the well"; CRITICAL Step: A 24-well nunclon delta surface plate can alternatively be used in place of a 4-well plate.)
Regarding claim 12, McCracken renders obvious the method for producing gastrointestinal organoids according to claim 1. Moreover, McCracken teaches the treatment with Activin A is initiated at Day 3 from the beginning said culturing of 3D spheroid, derived from the human induced pluripotent stem cells (HiPSCs) (page 1920 col 1 para 2 into page 1920 para 1 col 2, "Generation of human intestinal tissue from hPSCs takes approximately one month: 3 days of exposure to ActivinA for definitive endoderm (DE) induction").
Regarding claim 13, McCracken renders obvious the method for producing gastrointestinal organoids according to claim 1. Moreover, McCracken teaches Wnt3A and FGF4 are added to the spheroids at Day 6 from the beginning said culturing of 3D spheroid from the human induced pluripotent stem cells (HiPSCs), (page 1920 col 1 para 2 into page 1920 para 1 col 2, "Generation of human intestinal tissue from hPSCs takes approximately one month: 3 days of exposure to ActivinA for definitive endoderm (DE) induction, 4 days of exposure to FGF4/ WNT3A to generate mid/hindgut spheroids, and 14-28 days to allow spheroids to expand into intestinal tissue")
Regarding claim 14, McCracken renders obvious the method for producing Page 11 gastrointestinal organoids according to claim 1. Moreover, McCracken teaches said Rspondin, noggin, and EGF are added to the spheroids at Day 11 from the beginning of said culturing derived from a 3D spheroid of the human induced pluripotent stem cells (HiPSCs) (page 1922 col 1 para 2, "Thaw the bottle of matrigel on ice or at 4°C. Once matrigel has thawed, add B27 supplement (final concentration 1 x), Rspondinl (final concentration 500ng/mL), Noggin (final concentration l00ng/mL) and EGF (final concentration l00ng/mL). "; page 1922 col 1 para 5, "Combine Advanced DMEM:Fl2, B27 supplement (1 x final dilution= 2mLs per 50mL media), L-glutamine (final concentration 2 mM), Pen/Strep (final concentration pen 100 Units/mL; strep 100 ug/mL), HEPES buffer (final concentration 15mM), Rspondinl (final concentration 500ng/mL), Noggin (final concentration l00ng/mL), EGF (final concentration 100 ng/mL). Intestine growth media is best if made fresh, but can be stored at 4°C for up to one week"; page 1925, "Place spheroids into ice-cold "Intestinal Matrigel" from Step 22 and pipette sample up and down several times to mix. Total volume will be up to 75uL (50uL Matrigel + 25uL media+ spheroids").
***
Claim(s) 9, 11, and newly added claims 25 and 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over McCracken et al. (Published: 2011. Cited in IDS filed 01/26/26) and in further view of Costa et al. (Published: 2019. Frontiers in bioengineering and biotechnology, 7, 144.) This rejection has been modified necessitated by amendment of the claims in the response filed 7/19/2026
With regards to claims 1 and 25, the teachings of McCracken render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 1.
However, McCracken fails to teach the spheroids cultured in an electroconductive multiwell plate, as required by claim 11 and 26.
Costa teaches that an electroconductive multi-well plate that "assess[ es] the integrity and tightness of the epithelial cell monolayer in in vitro cultures" (page 7 col 1 para 3) Costa discusses that this is done though "TEER [trans-epithelial electrical resistance] measuring system is the Epithelial VoltOhmMeter EVOM (World Precision Instruments) that comes with chopstick-shaped electrodes for measuring the TEER in transwells" (page 7 col 1 para 3). Furthermore, Costa teaches that "The higher the value of TEER, the more compact and integral is the barrier, indicating well developed tight cell-cell junctions which inhibit paracellular current flow" (page 7 col 1 para 3).
It would have been obvious to substitute the multi-well plate of McCracken with the electroconductive plate of Costa to assess the integrity and tightness of the epithelial cell monolayer for the gut spheroids and organoids as it is a crucial component for intestinal epithelium. Such substitution would aid the in the determination of tight cell-cell junctions in the intestinal epithelium. A skilled artisan would have had a reasonable expectation of success as controlling tight cell-cell junctions in epithelial cells using an electroconductive multi-well plate was known in the art at before the effective filing date the claimed invention.
Response to Arguments as they apply to the rejection of the claims under 35 U.S.C 103 over McCracken et al.
Beginning on page 7 of the remarks filed on July 19 2026, Applicants’ essentially argue the following:
The difference in the nature of the cells at the beginning of the treatment method. The method of the present invention as defined in claim 9 defines that step a) produces 3- dimensional gut spheroid cells, and the subsequent steps treat those spheroid cells with Activin A, Wnt3A, etc. ultimately resulting in a complete GIO. On the other hand, McCracken starts with an adherent pluripotent stem cell monolayer culture, differentiates those cells into definitive endoderm, and then generates intestinal organoids that model developing fetal intestine.
The present invention produces a complete GIO, not possible by the McCracken method. The present specification further explains that motile gut generation requires coordinated development of smooth muscle cells (SMC), the enteric nervous system (ENS), and interstitial cells of Caj al (ICC), and that the gut spheroid-derived organoids of the present invention develop these features and exhibit contractile behavior. The McCracken method is simply not capable of producing such a complete GIO, as even admitted by McCracken.
In summary, it is important that McCracken expressly acknowledges that its intestinal organoids lack several important components of the native intestine, such as the enteric nervous system (ENS), vasculature, lymphatic system, and immune system. McCracken expressly states that the resulting organoids lack important intestinal components, including the enteric nervous system (ENS) and vasculature.
As discussed in the Office Action, the Examiner cites Costa merely with relation to an electroconductive multi-well plate. But even that teaching in Costa does not teach or suggest all of the other deficiencies of McCracken as discussed above.
Applicants’ arguments have been fully considered but they are found not persuasive for the following reasons:
Regarding 1), while McCracken’s protocol describes the administration of Activin A prior to the formation of spheroids, McCracken teaches the same overall gastrointestinal differentiation pathway using Activin A, WNT3A and FGF4. McCracken discloses that the addition of Activin A contributes to definitive endoderm (DE) function (pp. 1920, col 1, para 3 bridging into col 2 para 1). Moreover, McCracken teaches that during each step of the differentiation protocol, growth factors (e.g. Activin A) may be added or removed for desired experimental outcomes (pp. 1920, col 2, para 1). Thus, McCracken does not teach that the endoderm-inducing function of Activin A is dependent upon maintaining the cells in a monolayer culture. Furthermore, it was known at the time of the invention that Activin A could be applied after the formation of three-dimensional spheroid or aggregates for purposes of directing endodermal differentiation, as evidenced by Kakni et al (Published: April 25, 2022. Front Bioeng Biotechnol.). Kakni formed pluripotent stem cells into three-dimensional embryoid bodies, then treats them with Activin A for three days to establish definitive endoderm spheroids (pp. 2 col 2 para 2; pp. 4 col 2 para 1). Therefore, it was known at the time of the invention that the step of adding Activin A could be applied to both three- and two-dimensional cell cultures, and this is a parameter that could be routinely optimized based on desired experimental outcomes.
Regarding 2) and 3), Applicants’ arguments rely on functional and structural characteristics that are not expressly required by instant claim 9. Claim 9 recites culturing the large gut spheroid cell to provide a “complete gastrointestinal organoid”, but does not require contractile activity, an enteric nervous system, interstitial cells of Cajal, which is not commensurate with the scope of the claim. Furthermore, McCracken states that the expansion of these spheroids over 1-3 months give rise to intestinal tissue, complete with intestinal mesenchyme and epithelial comprising all the major intestinal cell types in vitro (pp. 1920, Abstract). Moreover, the term “complete” does not establish that all of the functional characteristics identified in Applicants’ remarks are necessarily required by the claim. To the extent Applicants contends that the term “complete gastrointestinal organoid” requires the particular characteristics, such an interpretation underscores a lack of clarity around the word “complete” as it is unclear what are the metes and bounds of an organoid that is “complete”. Applicant also emphasizes that there are “inferior characteristics” disclosed in the organoids produced by McCracken, however McCracken nevertheless discloses a method of developing a three-dimensional intestinal tissue containing an intestinal mesenchyme and epithelial comprising the major intestinal cell types (pp. 1920, Abstract; pp. 1921, col 1 para 1). Further, although McCracken states various limitations of the intestinal organoids (i.e. lacking enteric nervous system, lymphatic and immune systems), these are not characteristics required by the claims.
Regarding 4), Costa is not relied upon for all the limitations of claim 9; rather, Costa is relied upon for the use of an electroconductive multi-well plate. Costa teaches that there is a need to assess the integrity of the tightness of the epithelium (pp. 7, col 1 para 3). Costa teaches that the trans-epithelial electrical resistance (TEER) is a measuring system for such needs. Further, Costa teaches use of an Epithelial VoltOhmMeter (EVOM) for electrically measuring TEER in cell-culture transwells (pp. 7 col 1 para 3). Therefore, a person with ordinary skill in the art would have been motivated to incorporate the electrical sensing system of Costa into the multi-well intestinal culture system of McCracken to provide a quantitative means of monitoring the integrity and tightness of the epithelium, as Costa teaches an electroconductive Transwell culture setup to measure the electrical resistance of the epithelial monolayer.
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Katriel B Kasayan whose telephone number is (571)272-1402. The examiner can normally be reached 10-4p.
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/KATRIEL BARCELLANO KASAYAN/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
