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 .
Detailed Action
This application is in response to papers filed January 23rd, 2026. A response to the restriction requirement filed on January 23rd, 2026 is acknowledged. Claims 1-24 are currently pending as per claims filed on August 16, 2023. Applicants’ election of Group II, directed to a method for making a gastrointestinal organoid, e.g., claims 9-14 is acknowledged.
Applicant timely responded to the election requirement in the Paper filed January 23, 2026. Because Applicant did not distinctly and specifically point out the supposed errors in the examiner’s action, and further, did not specifically traverse the election requirement, the election was treated as an election without traverse (MPEP § 818.03(a)).
Claims 1-8, 15-24 are withdrawn from further consideration, pursuant to 37 CFR 1.142(b), as being drawn to a non-elected invention, there being no allowable generic or linking claim. The restriction requirement is deemed proper, maintained and made FINAL.
Therefore, claims 9-14 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.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on December 11 2023, February 28 2024, September 24 2025, were filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Objection Specification
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim objection
Claim 12 is objected to because of the recitation of “Day 3 from the beginning said culturing of 3D spheroid” as the claim appears to be missing “of” in from of the phrase “said culturing of 3D spheroid”. Appropriate correction is requested.
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.
Claims 9-14 are 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.
Claim 9 is indefinite in its recitation of “3-dimensional spheroid cells” in line 4. There is not proper antecedent bases for the recitation of “3-dimensional spheroid cells” in line 4. The claim requires “3-dimensional gut spheroid cells” in line 2.
Claim 9 is indefinite in its recitation of “said gut spheroid cells” in line 5. There is not proper antecedent bases for “said gut spheroid cells” in line 5. The claim recites “generating gut spheroids” in line 4.
Claim 9 is indefinite in the recitation of “greater than about” in line 6 for the following reason. “About” encompasses values above and below a reference point whereas “greater than” encompasses only values above the reference point. Therefore, the combination of both terms (greater than about) is confusing because one term (about) is including values below the reference point whereas the other term is excluding values below (greater) the reference point.
Claim 9 is 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 conditions. As such, the metes and bounds of the claims cannot be determined.
Claim 10 is indefinite in the recitation of “further comprising seeding said large gut spheroid cells” as seeding said large gut spheroid cells was already recited in claim 9. It is unclear if is this step is in addition of step d) in claim 9 or the claimed dome-shaped gel matrix of claim 9, step d) is located in the wells of a multi-well plate. As such the metes and bounds of the claim are indefinite.
Claim 12 is indefinite in its recitation of the phrase “initiated at Day 3 from the beginning said culturing of 3D spheroid, derived from the human induced pluripotent stem cells”. It is unclear if the treatment is initiated after the Day 3 of culturing HiPSCs (step a) of claim 9) or Day 3 of culturing the produced produce 3- dimensional gut spheroid cells of claim 9, step a). As such the metes and bounds of the claim are indefinite.
Claim 13 is indefinite in its recitation of the phrase “added the spheroids at Day 6 from the beginning said culturing of 3D spheroid from the human induced pluripotent stem cells (HiPSCs)”. It is unclear if the treatment is initiated after the Day 6 of culturing HiPSCs or Day 6 of culturing a mature three-dimensional spheroid.
Claim 13 is indefinite in its recitation of the phrase “added the spheroids at Day 6 from the beginning said culturing of 3D spheroid from the human induced pluripotent stem cells (HiPSCs).”. It is unclear if the treatment is initiated after the Day 11 of culturing HiPSCs or Day 11 of culturing a mature three-dimensional spheroid.
Claim 13 is indefinite in the recitation of “the spheroids”, “the beginning said culturing of 3D spheroid”. There is not proper antecedent bases for “the spheroids”, “the beginning said culturing of 3D spheroid” in the claim.
Claim 14 is indefinite in the recitation of “the spheroids at Day 11” and “the beginning of said culturing derived from a 3D spheroid”. There is not proper antecedent bases for the recitation of “the spheroids at Day 11” and “the beginning of said culturing derived from a 3D spheroid”.
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.
Claims 9-10, and 12-14 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) .
Regarding claim 1, 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 1“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”); 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) L-glutamine (final concentration 2 mM), Pen/Strep (final concentration pen 100 Units/mL; strep 100 ug/mL), Activin A (final concentration 100ng/mL). Endoderm differentiation media is best if made fresh each day, but can be stored at 4°C for 1–3 days”); 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”); seeding said large gut spheroid cells on a dome-shaped 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 1×), Rspondin1 (final concentration 500ng/mL), Noggin (final concentration 100ng/mL) and EGF (final concentration 100ng/mL).") and 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
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mesenchyme and epithelium consisting of all of the major intestinal cell types.”). 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.
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.
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 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×), Rspondin1 (final concentration 500ng/mL), Noggin (final concentration 100ng/mL) and EGF (final concentration 100ng/mL). “; page 1922 col 1 para 5, “Combine Advanced DMEM:F12, B27 supplement (1× 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), Rspondin1 (final concentration 500ng/mL), Noggin (final concentration 100ng/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”).
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Claim(s) 11 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.)
With regards to claim 1, 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 multi-well plate.
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.
Conclusion
No claims are allowed.
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