DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1, 18, 30, 37-38, 40, 44, 48, 51, 59-60, 63-64, and 107-113 are pending.
Claims 37, 44, 48, 59, and 63 are newly amended.
Claims 109-113 are newly added.
Claims 1, 18, 30, and 107-108 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/06/2025 and made FINAL.
Claims 37-38, 40, 44, 48, 51, 59-60, 63-64, and 109-113 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The prior rejections of claims 37, 40, 44-51, and 59 under 35 U.S.C. 103 as being unpatentable over Wells et al. (WO2019074793A1, published 04/18/2019, on IDS 03/22/2023) in view of Zhang et al. (Cell Stem Cell, 2018) and Kalabis et al. (Nature Protocols, 2012, on IDS 04/22/2025) is withdrawn in order to address the claims as amended.
The prior rejections of claims 38, 60, and 63 under 35 U.S.C. 103 as being unpatentable over Wells et al. (WO2019074793A1, published 04/18/2019, on IDS 03/22/2023) in view of Zhang et al. (Cell Stem Cell, 2018) and Kalabis et al. (Nature Protocols, 2012, on IDS 04/22/2025) as evidenced by Yan et al. (ThermoFisher, 2016) is withdrawn in order to address the claims as amended.
The prior rejection of claim 64 rejected under 35 U.S.C. 103 as being unpatentable over Wells et al. (WO2019074793A1, published 04/18/2019, on IDS 03/22/2023) in view of Zhang et al. (Cell Stem Cell, 2018) and Kalabis et al. (Nature Protocols, 2012, on IDS 04/22/2025), as applied to claim 37 above, and further in view of Wells et al. (US20170292116A1, 2017, on IDS 10/20/2023, hereafter “Wells 2”) is withdrawn in order to address the claims as amended.
Claim Rejections - 35 USC § 112(b)
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.
Claim 112 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.
Claim 112 contains the trademark/trade name Matrigel. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe Engelbreth-Holm-Swarm (EHS) mouse sarcoma matrix and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 113 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.
New claim 113 recites, “wherein the βIII-tubulin positive cells are not detectable in the esophageal raft culture as determined by an assay selected from immunostaining, flow cytometry, Western blotting, or nucleic acid quantification.”
The Application lacks disclosure for testing for βIII-tubulin by way of flow cytometry, Western blotting, or nucleic acid quantification.
In justification for disclosure of this feature, Applicant points to paragraph [0209] which states, “wherein the esophageal raft culture is effectively free of neuronal progenitor cells and/or βIII-tubulin+ neuronal cells,” but this paragraph does not mention specific assays for detecting βIII-tubulin positive cells.
Additionally, while Fig. 4B shows that βIII-tubulin can be measured by immunostaining, βIII-tubulin expression is never measured by flow cytometry, Western blotting, or nucleic acid quantification.
Furthermore, nothing in the specification implies these specific assays for measuring βIII-tubulin.
Therefore, the limitation of determining βIII-tubulin by flow cytometry, Western blotting, or nucleic acid quantification is considered new matter.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 37-38, 40, 44, 48, 51, 59-60, 63, 109-111, and 113 are rejected under 35 U.S.C. 103 as being unpatentable over Wells et al. (WO2019074793A1, published 04/18/2019, on IDS 03/22/2023, previously cited) in view of Zhang et al. (Cell Stem Cell, 2018, previously cited) and Kalabis et al. (Nature Protocols, 2012, on IDS 04/22/2025, previously cited) as evidenced by Yan et al. (ThermoFisher, 2016, previously cited).
In regards to claim 37, Wells teaches a method of producing (in culture) esophageal rafts (claims 23 and 24; paragraphs [0057, 0060, 0095]; Fig. 4), and thus a “method of producing an esophageal raft culture” (it is noted that “raft culture” is also called “organotypic culture” in the art).
In regards to step (a), Wells teaches that this method is performed by contacting anterior foregut cells with an EGF activator and a BMP inhibitor period of time sufficient to form a dorsal anterior foregut cells (claim 1).
In regards to steps (b), (c), and (d), Wells teaches esophageal rafts are produced by disassociating human esophageal organoids (produced in claim 1) to release esophageal progenitor cells as single cells (Claim 23; paragraph [0095]). Wells teaches that the method is performed on plate (paragraphs [00127, 0133]) and thus in a first tissue culture container.
The difference with the instant claim steps (b), (c), and (d) and the method of Wells is that instead of disassociating esophageal progenitor cells from organoids, in the instant claims, dorsal anterior foregut cells are dissociated as single cells (step (b)), then cultured in a first culture container to differentiate these cells into esophageal progenitor cells (step (c)), which are then disassociated again into single cells (step (d)), without an organoid.
However, in both cases, the result is identical – both the method of Wells and the instant steps (b) through (d) result in disassociated single esophageal progenitor cells.
According to MPEP 2144.04(IV), in regards to changes in sequences, selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946)). See also Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Indeed, as taught by Wells, they had previously identified that SOX2 expression promotes esophageal specification in dorsal anterior foregut (paragraph [0057]) and as demonstrated in Fig. 1F, prior to organoids formation) anterior foregut cells express SOX2, organoid formation does not appear critical to formation of esophageal progenitor cells.
Additionally, a person of ordinary skill in the art would have been motivated to forgo an organoid step in order to save time and simplify steps and use of reagents.
Furthermore, because Wells teaches that disassociated single esophageal progenitor cells themselves can be isolated, expanded in monolayer culture, and then re-differentiated into a stratified squamous epithelium (paragraph [0095]), because Wells teaches that dorsal anterior foregut cells develop before organoid formation, and because Zhang teaches that esophageal progenitor cells can be directly obtained from anterior foregut cells (Figure 1, p517), it could have been done with predictable results and a reasonable expectation of success.
In regards to step (e), Wells teaches that esophageal rafts are produced in transwells (paragraph [00145]). It is noted that it is well-known in the art that transwells are inserts upon which cells are cultured and which are positioned within a well-plate (thus, a second tissue container) and which are permeable to growth medium but not cells.
Wells teaches that rafts are initially cultured before being exposed to an exposed to a liquid-air interface (paragraph [0131]).
While Wells is silent on whether the rafts are submerged in media, a person of ordinary skill in the art would have recognized that because rafts are ultimately exposed to a liquid-air interface, it suggests that the rafts are in fact submerged prior to this step (it is noted that a “liquid air interface” is a well-known technique wherein cells in a transwell are exposed to air while media only passes through the permeable transwell insert membrane and partially covering cells).
Additionally, a person of ordinary skill in the art would have been motivated to complete submerge cells in growth medium to ensure that all cells have adequate access to nutrients within the growth media. Furthermore, because Kalabis teaches that esophageal organotypic culture (i.e., raft culture) is preformed by fully submerging single cells in media on transwell inserts for raft culture (Figure 1, p20) and because Wells teaches that it is known in the art that raft cultures are performed per the method of Kalabis (paragraph [00109]), it could have been done with predictable results and a reasonable expectation of success.
In regards to step (f), as above, Wells teaches that raft culture is performed in transwells in media (paragraphs [0073, 00133, and 00145]). Wells also teaches that rafts were exposed to a liquid-air interface to generate a stratified epithelium (paragraph [00133]).
It is well-known in the art that a liquid-air interface results in the partial submersion medium (i.e., with little or no aqueous medium in the insert member, see instant paragraph [0297]) of esophageal progenitor cells within a transwell (see also Experimental design, p3; Figure 1, p20 of Kalabis which illustrates this technique).
In regards to claim 38, Wells teaches that the anterior foregut can be contacted with CultureOne Supplement (paragraph [00131]), which as evidenced by Yan, is a commercial product well-known in the art used to eliminate neural progenitor cells (Introduction, p1).
In regards to claim 40, Wells teaches that the transwells are coated with collagen (an ECM) (paragraphs [0077, 00145]).
In regards to claim 44, Wells teaches that anterior foregut cells can be contacted for at least about three days (paragraph [0070; Fig. 1A), which overlaps with the timing of at least 1 day.
In regards to claim 48, Wells teaches that the dorsal anterior foregut cells can be cultured with an EGF activator (claim 1; paragraph [0061]).
In regards to claim 51, Wells teaches that the anterior foregut cells can be derived from human induced pluripotent stem cells (claim 11; paragraphs [00125, 00127]).
In regards to claim 59, Wells teaches that human induced pluripotent stem cells are contacted with Activin A to differentiate into definitive endoderm (claim 11; paragraph [00205]).
Wells also teaches that definitive endoderm was contacted with Wnt3a (a specific Wnt activator) to induced differentiation to anterior foregut (paragraph [00205]).
In regards to claim 60, as above, Wells teaches that the anterior foregut can be contacted with CultureOne Supplement (paragraph [00131]), which as evidenced by Yan, is a commercial product well-known in the art used to eliminate neural progenitor cells (Introduction, p1).
In regards to claim 63, as CultureOne Supplement is known to eliminate neural progenitor cells, the culture of Wells would be expected to have the property of being “substantially free” of neural progenitor cells.
In regards to claim 109, it is noted that the claims do not require monolayer expansion, and therefore, this claim has been interpreted as optional (see MPEP 2111.04).
In regards to claims 110-111, while Wells is silent as to the timings of the start of step f) relative to the start of esophageal differentiation, a person of ordinary skill in the art could have arrived at timings of 25 days or 20 days by routine optimization and the disclosure does not point to a criticality in this timing (see MPEP 2144.05(II)(A), Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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 the instant case, because Zhang teaches that esophageal differentiation takes 19 days (which, if cells cell are taken at the end, is less than 25 or 20 days)), a person of ordinary skill in the art could have arrived at timing of 25 days or 20 days by routine optimization with predictable results and a reasonable expectation of success).
In regards to claim 113, in regards to whether βIII-tubulin cells are not detectable in the esophageal raft culture as determined by an assay selected from immunostaining, etc., Applicant should note that this is a natural property of the resulting cells in the raft culture, and the claim does not specifically require steps of performing an assay. In the instant case, since the method of Wells, as modified by Zhang and Kalabis performs the same steps, the resultant rafts are considered to not have detectable βIII-tubulin cells as determined by an assay selected from immunostaining, etc., absent evidence to the contrary. Moreover, it is well-known in the art that βIII-tubulin is a microtubule protein and a marker for neural cells, and therefore, a method that produces esophageal cells would not expected to express this marker absent specific neural differentiation.
Therefore, the combined teachings Wells, Zhang, and Kalabis renders unpatentable the invention as claimed.
Claim 64 is rejected under 35 U.S.C. 103 as being unpatentable over Wells et al. (WO2019074793A1, published 04/18/2019, on IDS 03/22/2023, previously cited) in view of Zhang et al. (Cell Stem Cell, 2018, previously cited) and Kalabis et al. (Nature Protocols, 2012, on IDS 04/22/2025, previously cited) as applied to claim 37 above, and further in view of Wells et al. (US20170292116A1, 2017, on IDS 10/20/2023, hereafter “Wells 2”, previously cited).
In regards to claim 64, while Wells does not explicitly teach combining disassociated esophageal progenitor cells with enteric neural crest cells to obtain an innervated esophageal raft culture, Wells teaches that morphologically, the esophagus comprises squamous epithelium and the enteric nervous system (paragraph [0002]). Therefore, a person of ordinary skill in the art would have been motivated to form an innervated esophageal raft culture to better mimic an in vivo esophageal tissue sample.
They would be further motivated to produce an innervated esophageal raft culture in order to, as taught by Wells 2, test motility, epithelial permeability and fluid exchange in a human model of the enteric nervous system (paragraph [0034]) since current methods rely on non-human animal models which do not always translate well into human studies (paragraph [0005]).
They would have been motivated to combine disassociated esophageal progenitor cells with enteric neural crest cells (and thus, comprising enteric neural crest cells) because Wells 2 teaches that innervated enteric organs can be made by contacting cells with neural crest cells (claim 6; paragraph [0036-0037]).
While Wells 2 specially combines neural crest cells with intestinal organoids (claim 6), it is noted that both intestine and the esophagus alike are gastrointestinal tissues derived from definitive endoderm and innervated by the enteric nervous system.
Therefore, because the esophagus is a closely related tissue and because Wells 2 teaches that neural crest cells can be contacted with cells to create three dimensional tissues (paragraph [0043]), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings Wells, Zhang, Kalabis, and Wells 2 renders unpatentable the invention as claimed.
Claim 112 is rejected under 35 U.S.C. 103 as being unpatentable over Wells et al. (WO2019074793A1, published 04/18/2019, on IDS 03/22/2023, previously cited) in view of Zhang et al. (Cell Stem Cell, 2018, previously cited) and Kalabis et al. (Nature Protocols, 2012, on IDS 04/22/2025, previously cited) as applied to claims 37 and 40 above, and further in view of Beckstead et al. (Biomaterials, 2005).
In regards to claims 112, as above, Wells teaches that the transwells are coated with collagen (an ECM) (paragraphs [0077, 00145]). While in embodiments, Wells uses rat tail collagen or Matrigel, Wells also generically teaches that “collagen” may be used (claim 23, paragraph [0074), and therefore, does not necessarily require a rat tail collagen matrix or Matrigel.
A person of ordinary skill in the art would have been motivated to use a collagen that is not rat tail collagen or Matrigel because Beckstead teaches that collagen IV is a major component of the esophageal membrane, and that mouse collagen IV promotes increased adhesion (p6210-6220). Furthermore, because Beckstead teaches that esophageal cells can be cultured with a matrix that is not rat tail collagen or Matrigel (Fig. 2, p6221), and because Wells broadly teaches that collagen can be used, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings Wells, Zhang, Kalabis, and Beckstead renders unpatentable the invention as claimed
Response to Arguments
Applicant argues that Wells in view of Zhang and Kalabis does not render the invention unpatentable as claimed Remarks, p7-9). Specifically, Applicant argues that the claims as amended do not use an organoid (Remarks, p8).
Additionally, Applicant argues that Wells teaches that disassociated and passaged organoids failed to stratify upon re-culture, that passaging efficiency diminished over time, and was unable to induce differentiation or stratification in passaged organoids (Remarks, p8; citing paragraph [0095] and Figs 12G-12R of Wells). Therefore, Applicant concludes that this undercuts any reasonable expectation of success to forgo the organoid stage of Wells and still obtain a stratified esophageal raft under the monolayer-based conditions recited in claim 37 (Remarks, p8). Applicant, thus also concludes that Wells teaches away from forgoing the organoid stage (Remarks, p8).
Applicant’s arguments filed 02/17/2026 have been fully considered but are not found persuasive.
In regards to organoids, as discussed above, while Wells obtains esophageal progenitor cells from organoids, in both cases, the result is identical – both the method of Wells and the instant steps (b) through (d) result in disassociated single esophageal progenitor cells.
According to MPEP 2144.04(IV), in regards to changes in sequences, selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946)). See also Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Indeed, as taught by Wells, they had previously identified that SOX2 expression promotes esophageal specification in dorsal anterior foregut (paragraph [0057]) and as demonstrated in Fig. 1F, prior to organoids formation) anterior foregut cells express SOX2, organoid formation does not appear critical to formation of esophageal progenitor cells.
Additionally, a person of ordinary skill in the art would have been motivated to forgo an organoid step in order to save time and simplify steps and use of reagents.
In the instant case, because Wells teaches that disassociated single esophageal progenitor cells themselves can be isolated, expanded in monolayer culture, and then re-differentiated into a stratified squamous epithelium (paragraph [0095]), and teaches that dorsal anterior foregut cells express SOX2, which promotes esophageal specification, and because Zhang teaches that esophageal progenitor cells can be directly obtained from anterior foregut cells (and without forming organoids which requires culturing these cells in Matrigel (Figure 1, p517; p523, right column, middle paragraph), it could have been done with predictable results and a reasonable expectation of success.
In regards to the properties of organoids in reference to paragraph [0095] of Wells, it is noted the claims do not require culturing cells over a certain number of passages, do not require monolayers, and do not require stratification.
Therefore, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., culturing cells over a number of passages, the use of monolayers, or stratification of the raft culture) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In regards to Applicant’s argument that Wells teaches away from not using an organoid, a prior art teaching does not constitute a teaching away if the does not criticize, discredit, or otherwise discourage the solution claimed solution. In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) (“a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.”) (see MPEP 2145(X)(D)(1)). In the instant case, Wells does not discredit the use of single cells while bypassing an organoid state. Furthermore, if anything, because the fact that Wells teaches that organoids failed to stratify upon re-culture, that passaging efficiency diminished over time, and was unable to induce differentiation or stratification in passaged organoids, a person of ordinary skill in the art would have looked to bypass the organoid state to avoid these limitations. And again, because as above, Zhang teaches that esophageal progenitor cells can be directly obtained from anterior foregut cells (Figure 1, p517), it could have been done with predictable results and a reasonable expectation of success.
In regards to Zhang, Applicant argues that Zhang does not teach replacing Wells organoid intermediate in a raft formation method and does not disclose the claimed two-container insert-membrane transwell sequence to generate a stratified esophageal from dAFG-derived progenitors (Remarks, p8).
Applicant’s arguments filed 02/17/2026 have been fully considered but are not found persuasive.
In particular, Zhang is not relied upon to teach the claimed two-container insert-membrane transwell sequence to generate a stratified esophageal from dAFG-derived progenitors. Rather this feature is taught by Wells, as discussed in detail above.
Furthermore, in regards to organoid intermediates, as discussed above, while Wells obtains esophageal progenitor cells from organoids, in both cases, the result is identical – both the method of Wells and the instant steps (b) through (d) result in disassociated single esophageal progenitor cells.
According to MPEP 2144.04(IV), in regards to changes in sequences, selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946)). See also Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Indeed, as taught by Wells, they had previously identified that SOX2 expression promotes esophageal specification in dorsal anterior foregut (paragraph [0057]) and as demonstrated in Fig. 1F, prior to organoids formation) anterior foregut cells express SOX2, organoid formation does not appear critical to formation of esophageal progenitor cells.
Additionally, a person of ordinary skill in the art would have been motivated to forgo an organoid step in order to save time and simplify steps and use of reagents.
In the instant case, because Wells teaches that disassociated single esophageal progenitor cells themselves can be isolated, expanded in monolayer culture, and then re-differentiated into a stratified squamous epithelium (paragraph [0095]), and teaches that dorsal anterior foregut cells express SOX2, which promotes esophageal specification, and because Zhang teaches that esophageal progenitor cells can be directly obtained from anterior foregut cells (and without forming organoids which requires culturing these cells in Matrigel (Figure 1, p517; p523, right column, middle paragraph), it could have been done with predictable results and a reasonable expectation of success.
In regards to Kalabis, Applicant argues that Kalabis teaches a different organotypic system, does not teach PSC-derived dAFG monolayers, progenitor expansion in the first container, or the two-container workflow (Remarks, p8). Specifically, Applicant also argues that the rejection does not provide an articulated reason to combine Kalabis with Wells with a rational underpinning to replace Well’s organoid with Applicant’s organoid-free monolayer process, particularly in view of Well’s teaching that passaged organoids fail to stratify (Remarks, p9).
Applicant’s arguments filed 02/17/2026 have been fully considered but are not found persuasive.
In regards to Kalabis, the reference is not relied upon to teach PSC-derived dAFG monolayers, progenitor expansion in the first container, the two-container workflow (these features are taught by Wells, as discussed in depth above), or using an organoid-free monolayer process.
Rather, as above, Kalabis is relied upon to demonstrate that esophageal raft culture is performed by fully submerging single cells in media on transwell inserts. Specifically, as above, a person of ordinary skill in the art would have been motivated to complete submerge cells in growth medium to ensure that all cells have adequate access to nutrients within the growth media. Furthermore, because Kalabis teaches that esophageal organotypic culture (i.e., raft culture) is preformed by fully submerging single cells in media on transwell inserts for raft culture (Figure 1, p20) and because Wells teaches that it is known in the art that raft cultures are performed per the method of Kalabis (paragraph [00109]), it could have been done with predictable results and a reasonable expectation of success.
Applicant argues that Yan and Wells 2 fail to remedy the deficiencies of Wells, Zhang, and Kalabis.
Applicant’s arguments filed 02/17/2026 have been fully considered but are not found persuasive because Wells, Zhang, and Kalabis are not deficient for the reasons discussed above.
Conclusion
No claims are 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 JOSEPH (PAUL) MIANO whose telephone number is (571)272-0341. The examiner can normally be reached Mon-Fri from 8:30am to 5:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Doug) Schultz can be reached at (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
Prosecution Insights