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 action is in response to the papers filed on June 26, 2026. Claims 1, 2, 5-7, 10-12, 16, 18, 22, 24-26, 28, 29, 31 and 32 are currently pending. Claims 1, 2, 5, 6, 7, 16, 18, 22, 24-26, and 28 have been amended. It is noted that 1 and 28 are independent claims.
The examiner acknowledges receiving an executed Declaration under 37 C.F.R. § 1.132 executed by Dr. Georgios Stroulios on June 3, 2026 (“Stroulios Decl. ”), and filed on 6/3/2026.
Therefore, claims 1, 2, 5-7, 10-12, 16, 18, 22, 24-26, 28, 29, 31 and 32 are under examination to which the following grounds of rejection are applicable.
Priority
The instant application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/CA2022/050943, filed June 14th, 2022.
Applicant’s claim for the benefit of prior-filed parent provisional applications 63/286,173 filed December 6, 2021 and 63/210,248 filed June 14, 2021, under 35 U.S.C 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is June 14, 2021.
Response to Arguments
Withdrawn Objections/Rejections in response to Applicants’ arguments and amendments:
Claim Rejections - 35 USC § 102
In view of Applicants, amendments filed June 26, 2026, the rejection of claims 1, 2, 5, 6, 10-12, 16, 18, 24, 26, 28, 29, 31, and 32 over Salahudeen (Cited in IDS Filed: 3/11/2024. Published: Nov 25 2020. Nature, 588(7839):670-675) has been withdrawn. Applicants’ arguments are moot in view of the withdrawn rejections. A response to any argument pertaining to a new or maintained rejection can be found below.
Claim Rejections - 35 USC § 103
In view of Applicants, amendments filed June 26, 2026, the rejection of claims 1, 2, 5, 6, 10-12, 16, 18, 24, 26, 28, 29, 31, and 32 over Salahudeen (Cited in IDS Filed: 3/11/2024. Published: Nov 25 2020. Nature, 588(7839):670-675) has been withdrawn.
In view of Applicants, amendments filed June 26, 2026, the rejection of claims 1, 22 and 25 over Salahudeen (Cited in IDS Filed: 3/11/2024. Published: Nov 25 2020. Nature, 588(7839):670-675) ) and in further view of Dye et al. (Published: 2015. In vitro generation of human pluripotent stem cell derived lung organoids. eLife, 4, e05098) has been withdrawn.
Applicants’ arguments are moot in view of the withdrawn rejections. A response to any argument pertaining to a new or maintained rejection can be found below.
Maintained Objections/Rejections in response to Applicants’ arguments and amendments:
Claim Rejections - 35 USC § 112(a)
Claims 1-2, 5, 6, 7, 10-12, 16, 18, 22, 24-26 and 28, 29, and 31-32 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for apical-out organoids comprising formed from 10 µM of DAPT and low concentrations of A77-01, a TGF-beta inhibitor , it does not reasonably provide enablement for all apical-out mediums with different concentrations of TGF-b inhibitor and DAPT. Moreover, the claims do not provide enablement for all inhibitors of signaling through a transforming growth factor, and 60% apical out polarity. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. This is a modified rejection necessitated by the amendments filed June 3, 2026.
The criteria for enablement set out In re Wans, MPEP 2162.01(a), considers the following factors:
Breadth of the Claims
The instant claims are directed to a method for forming apical-out organoids in a culture and an organoid medium for generating apical-out organoids comprising the step of contacting a population of epithelial cells comprising one or both of a notch signaling and inhibitor of signaling through a transforming growth factor, wherein the population of epithelial cells do not come into contact with an exogenously added extracellular matrix protein. Thus, the claims encompass all concentrations and/or combinations of an inhibitor of notch signaling and inhibitor through a transforming growth factor (TGF) that form apical-out organoids. As such, the breadth of the claims is great.
State of Prior Art
The prior art is silent on whether an inhibitor of TGF or an inhibitor of notch signaling alone could contribute to the development of apical out organoids.
Salahudeen et al. teaches distal lung apical-out organoids comprising TGF-beta inhibitor (A83-01 at 100 nM), recombinant human NOGGIN, DMEM/F12, B27, inter alia (pp. 676, col 1, para 3). Furthermore, Salahudeen discloses that apical out organoids can be achieved through the removal of extracellular matrix protein (Extended Data Fig. 10). Therefore, Salahudeen demonstrates that TGF-beta inhibition was known in pulmonary organoid culture, and that apical-out polarity is achieved through the removal of exogenously added extracellular matrix protein. Salahudeen does not establish that an inhibitor of TGF-beta alone leads to apical-out polarity.
Yonemura et al. ((2014). Differential Sensitivity of Epithelial Cells to Extracellular Matrix in Polarity Establishment. PLoS ONE, 9(11), e112922.) teaches apical-out polarity when culturing epithelial cells absent of any extracellular matrix protein (pp. 3 col 1, para 2). To form the apical out polarity, it was achieved through hanging-drop culture of DMEM containing 10% fetal bovine serum and 300 cells, without any TGF-beta inhibitor or inhibitor of notch signaling (pp. 3 col 1, para 2). Additionally, Yonemura discusses that apical-basal polarity can be reversed though the change of its environment (pp.8 col 2, para 1). Therefore, the prior art establishes that neither an inhibitor of TGF-beta or an inhibitor of notch signaling develops apical-out organoids, wherein 60% or more of the apical out organoids face away from a core thereof. Rather, the prior art demonstrates that apical-basal orientation is dependent upon additional culture parameters.
Amount of Guidance Provided
The specification provides insufficient direction and guidance to enable a person of ordinary skill in the art to practice the full scope of the claimed invention. The instant application discloses embodiments of an organoid media for generating apical-out organoids, wherein the media comprises a basal medium, and one or more of an inhibitors of TGF-beta, an inhibitor of notch signaling, and an agent that disrupts cytoskeletal structure (para 0007). Moreover, the disclosure provides various examples of inhibitors of TGF such as A83-01, A77-01, SB 431542, LY364947, and LDN 214117 (para 0055). The disclosure also provides examples of inhibitors of notch signaling such as DBZ, DAPT, Compound E, Compound W, SAHM1, and FLI 06, and DAPT (para 0053). The disclosure also discusses embodiments of different concentrations of inhibitors of notch signaling (para 0054) and inhibitors of TGF (para 0056). Despite this, however, the working examples only disclose one embodiment of organoid medium comprising DAPT and A83-01 showing a significantly different organoid amount that when using DAPT alone (Figure 5). Furthermore, the Specification discloses that specific concentrations of DAPT and A77-01 displayed a significant difference in organoid populations when culturing organoids in a medium containing A77-01 alone (inhibitor of TGF) (Figure 4). Additionally, the Specification suggests that a concentration of 2.5 μM to 10 μM for the inhibitor of notch signaling, and a concentration between 0.5 μM and 1.5 μM for the inhibitor of signaling through a TGF worked reasonably well for efficient generation of ciliated cell percentage (para 0090). Therefore, the Specification demonstrates only a particular combination of DAPT and A83-01 and DAPT with A77-01, whereas the claims encompass substantially broader embodiments involving the inhibition of each pathway independently.
Presence or Absence of Working Examples
The Specification does not reasonably enable the full scope of the claimed invention without undue experimentation. Although the Specification demonstrates the generation of apical-out organoids with a particular Notch inhibitor, DAPT, in in combination with the inhibitor of TGF signaling, A83-01 or A77-01, the claims are substantially broader and encompass embodiments in which any species of Notch signaling or TGF signaling could be used, and that each of these inhibitors can be used independently of each other to generate apical out organoids.
Essentially, apical-out organoids were formed form three different donors (para 0087), wherein two donor samples utilized apical-out media formulated with different concentrations of an inhibitor of notch signaling (DAPT) and an inhibitor of TGFbeta signaling (A77-01) (para 0090 and Figure 4). Moreover, a fifth donor revealed that when pulmonary lineage cells were cultured in the presence of an inhibitor of notch signaling (DAPT) and an inhibitor of TGFbeta signaling (A83-01), there was a significant increase in the population of organoids (Figure 5).
As such, the Specification does not establish that the inhibition of either pathway alone will successfully result in the formation of apical out organoids. Accordingly, the disclosure of these particular embodiments does not reasonably enable the full scope of the claimed invention without undue experimentation.
Quantity of Experimentation
The quantity of experimentation necessary to practice the full scope of the claimed invention would be substantial. Although the Specification demonstrates generation of apical-out organoids using specific combinations and concentrations of DAPT and A83-01, the claims encompass substantially broader embodiments in which either Notch signaling or TGF signaling is inhibited independently, at any concentration. To practice the full scope of the claims, a person of ordinary skill in the art would have to identify individual Notch and TGF signaling inhibitors would work well independently, which work well in combination, and which concentrations of these inhibitors can produce an apical-out phenotype.
Conclusion
In light of the unpredictability surrounding the claimed subject matter in the art and lack of adequate guidance in the Specification, one wishing to practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Although the Specification provides working examples for the specific combination of DAPT and A83-01 and DAPT and A77-01, the claims encompass substantially broader embodiments in which either Notch signaling or TGF signaling is inhibited independently. Accordingly, the disclosure of a limited number of working embodiments does not enable a person of ordinary skill in the art to practice the full scope of the claimed invention without undue experimentation.
Response to Applicant arguments as they apply to the rejection of the claims under 35 U.S.C. 112(a), Scope of Enablement
Beginning on page 12 of the remarks filed June 03, 2026, Applicants essentially argue the following:
Given that the data in Figure 1 establishes the applicability of the claimed methods and media for generating apical-out organoids starting from 4 different epithelial cell populations, Claims 1 and 28, as amended, and the claims dependent thereupon, are fully supported by the specification and comply with the written description requirements of 35 USC §112(a).
In response to these arguments, they are fully considered but deemed not persuasive for the following reasons:
Regarding 1) the Examiner acknowledges the amendments filed June 3, 2026 and agrees that the amendment to specify a population of “epithelial” cells is enabled for within the Specification. However, the basis of the rejection now focuses on whether the claims are enabled for every species of inhibitor of Notch signaling or TGF signaling, and whether these inhibitors can generate apical-out organoids alone. The Specification only appears to be enabling for the generation of apical-out organoids with a particular Notch inhibitor, DAPT, in in combination with the inhibitor of TGF signaling, A83-01 or A77-01. The claims are substantially broader and encompass embodiments in which any species of Notch signaling or TGF signaling could be used, and that each of these inhibitors can be used independently of each other to generate apical out organoids. Accordingly, the disclosure of a limited number of working embodiments does not enable a person of ordinary skill in the art to practice the full scope of the claimed invention without undue experimentation.
New Grounds Objections/Rejections necessitated by Applicants’ amendments to the claims in the response filed August 18, 2025.
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.
Claim 7 is newly 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 7, it is indefinite in its recitation of the term single cells or cells, as it lacks proper antecedent basis. Claim 7 and claim 1 only recite “epithelial cells”.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 5, 6, 10-12, 16, 18, 24, and 26 is/are newly rejected under 35 U.S.C. 103 as being unpatentable over Yonemura ((2014). Differential Sensitivity of Epithelial Cells to Extracellular Matrix in Polarity Establishment. PLoS ONE, 9(11), e112922.) in view of Salahudeen (Cited in IDS Filed: 3/11/2024. Published: Nov 25 2020. Nature, 588(7839):670-675), e112922.). This is a new rejection necessitated by the amendments filed on June 26, 2026.
Regarding claim 1, Yonemura discusses the sensitivity of epithelial cells in 3D spheroid culture when cultured with and without the presence of an extracellular matrix (pp. 1, Abstract). Moreover, Yonemura discusses that when epithelial cells are embedded in ECM gels to form spheroid aggregates, the apical membranes are formed within the inner surface while the basal membrane faces the outer membrane, forming a lumen (pp. 1, col 2, para 2). However, when epithelial cells are cultured in suspension without coming into contact with an extracellular matrix, apical membranes are formed on the outer surface of the spheroid, while the basolateral membranes are faced inwards (pp. 1, col 2, para 2; Figure 1.). Yonemura also teaches that when culturing 3 epithelial cell lines (Madin-Darby Canine Kidney II cells (MDCKII), EpH4 cells, R2/7 α-Cate cells) in the absence of extracellular matrix proteins, all epithelial spheroids displayed 100% apical-out (tight junction (TJ) outside) epithelial spheroids (Figure 6, attached). Yonemura cultures epithelial cells in hanging drop culture in the absence of extracellular matrix to understand the role of the extracellular matrix in epithelial polarity, especially across different epithelial cell lines (pp. 9, col 1 para 2).
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However, Yonemura fails to teach a culture with an inhibitor of TGF-beta or Notch signaling.
Salahudeen teaches the cultivation of distal-lung apical-out organoids that the apical-out organoids were maintained in an organoid growth medium for up to 30 days to characterize apical-out polarity, ciliogenesis, and differentiation (pp. 678 or page 3 of Methods, left col, para 4). Furthermore, Salahudeen expresses that the lung organoid medium comprising DMEM, and TGF-beta inhibitor, A83-01, inter alia, was used in all experiments except for data shown in Extended Data Fig. 4f (pp. 676 or page 1 of Methods, left col para 3). Furthermore, Salahudeen discusses that after infection of SARS-CoV-2, lung apical out organoids were cultured in the medium (pp. 678, col 2 para 1).
It would have been obvious for a person to culture the apical-out epithelial spheroids Yonemura in a medium comprising TGF-beta inhibitor, as taught by Salahudeen, as Salahudeen demonstrates that an A83-01-containing lung orgnaoid medium is suitable for maintaining apical-out organoids under suspension culture. Further, a person with ordinary skill in the art would have been motivated to culture the apical-out spheroids disclosed by Yonemura, in a culture comprising TGF-beta inhibitor, A83-01, as Salahudeen demonstrates that such culture conditions support the characterization of apical-out polarity, ciliogenesis and differentiation (pp. 678, right col para 1).
Regarding claim 2, the combined teachings of Yonemura and Salahudeen render obvious the claimed methodology. Moreover, Salahudeen teaches that the population of epithelial cells are pulmonary lineage cells, specifically that organoids were derived from single adult human alveolar epithelial type 2 cells (pp. 670, Abstract).
Regarding claim 5, the combined teachings of Yonemura and Salahudeen render obvious the claimed methodology. Moreover, Salahudeen characterizes different subtypes of distal airway cells, such as epithelial cells (pp. 673, col 1, para 2). Moreover, Salahudeen teaches that when establishing apical-out suspension of distal lung organoids, the organoids reorganized into apical-out epithelial spheroids (pp. 673, col 2, para 2).
Regarding claim 5, the combined teachings of Yonemura and Salahudeen render obvious the claimed methodology. Moreover, Yonemura teaches that the population of epithelial cells were aggregated in a hanging drop culture (pp. 9, col 1, para 1).
Regarding claim 7, the combined teachings of Yonemura and Salahudeen render obvious the claimed methodology. Moreover, Yonemura teaches that hanging drop culture, in the absence of extracellular matrix component, consisted of epithelial spheroids contained 300 cells (pp. 3, col 1, para 2).
Regarding claim 6, the combined teachings of Yonemura and Salahudeen render obvious the claimed methodology. Moreover, Salahudeen teaches that the organoids were cultured in lung organoid medium comprising DMEM supplemented with nicotinamide, N-acetyl cysteine, B27 without vitamin A, recombinant human NOGGIN, recombinant human EGF, and TGF0B inhibitor, A83-01 at a concentration of 100 nM (pp. 676, col 1, para 2).
Regarding claims 10, the combined teachings of Yonemura and Salahudeen render obvious the claimed methodology. Moreover, Salahudeen teaches that distal lung organoids were cultured in a chemically defined medium comprising DMEM supplemented with nicotinamide, N-acetyl cysteine, B27 without vitamin A, recombinant human NOGGIN, recombinant human EGf, and TGF0B inhibitor, A83-01 at a concentration of 100 nM (pp. 676, col 1, para 2). Salahudeen does not teach adding serum to the lung organoid medium when cultivating distal lung organoids. As such, the organoid medium does not comprise serum, absent any evidence to the contrary.
Regarding claim 11, the combined teachings of Yonemura and Salahudeen render obvious the claimed methodology. Moreover, Salahudeen teaches that the organoid comprises a TGF-B inhibitor, A83-01 at a concentration of 100 nM (pp. 676, col 1, para 2).
Regarding claim 12, the combined teachings of Yonemura and Salahudeen render obvious the claimed methodology. Moreover, Salahudeen teaches that the organoid comprises a TGF-B inhibitor, A83-01 at a concentration of 100 nM (pp. 676, col 1, para 2).
Regarding claim 18, the combined teachings of Yonemura and Salahudeen render obvious the claimed methodology. Moreover, Salahudeen teaches that 25% of cells of the apical-out organoids are ciliated (pp. 671 col 2 para 2 bridging into page 671; Figure 2, attached)
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Regarding claim 24, the combined teachings of Yonemura and Salahudeen render obvious the claimed methodology. Moreover, Salahudeen teaches that mixed distal lung organoids express angiotensin-convertin enzyme 2 (ACE2) (Figure 10a, see attached.)
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Regarding claim 26, the combined teachings of Yonemura and Salahudeen render obvious the claimed methodology. Moreover, Salahudeen teaches that influenza virus H1N1 avidly infected distal lung organoids (pp. 676, col 1, para 4). Moreover, SARS-CoV-2 infected apical out mixed distal organoids (pp. 673, col 2, para 2).
***
Claim(s) 1, 22 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Yonemura ((2014). Differential Sensitivity of Epithelial Cells to Extracellular Matrix in Polarity Establishment. PLoS ONE, 9(11), e112922.) in view of Salahudeen (Cited in IDS Filed: 3/11/2024. Published: Nov 25 2020. Nature, 588(7839):670-675), e112922.) as applied to claims 1, 2, 5, 6, 10-12, 16, 18, 24, and 26, and in further view of Dye et al. (Published: 2015. In vitro generation of human pluripotent stem cell derived lung organoids. eLife, 4, e05098).
With regard to claim 1, the combined teachings of Salahudeen et al. and Yonemura render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 1.
However, Salahudeen and Yonemura do not teach wherein the organoids express one or more markers of ciliogenesis and the one or more markers of ciliogenesis comprise FOXJ1 and/or TUBB4B, as required in claim 22.
Dye teaches the culture of human lung organoids that comprise epithelial and mesenchymal compartments of the lung, and possess an airway-like epithelium with basal cells and ciliated cells (pp. 1, Abstract). Moreover, Dye teaches that human lung organoids displayed markers of ciliogenesis such as FOXJ1 and ACTTUB, after culturing the organoids for more than two months (pp. 10, para 1). Further, Dye discloses that when cultured in the correct stimulus or environment, lung organoids have the capability of expressing more FOXJ1+ cells and develop more mature ciliated cells (pp. 10, para 2).
Regarding claim 25, Dye teaches the organoids express markers of ciliogenesis comprising FOXJ1 (page 15 para 2) and that the organoids do not express MUC5AC (page 9 para 1, “Although the goblet cell marker MUC5AC mRNA expression was detected, protein expression was not detected by immunofluorescence (Figure 4A and data not shown).”).
It would have been obvious for someone with ordinary skill in the art to implement the teachings of Dye into the apical-out distal lung organoids of Saluhadeen with apical-out polarity in order to detect lack of expression of goblet cells within the apical-out organoid structure by lack of MUC5AC expression with a reasonable expectation of success. Further, it would have been obvious for someone with ordinary skill in the art to implement the expression of FOXJ1 in organoids taught by Dye into the apical-out organoids taught by Salahudeen in order to study basal cell differentiation as well as potential airway dynamics in lung tissue. Such incorporation of FOXJ1 would have been expected to achieve predictable results in resulting in apical-out lung organoids that would express FOXJ1, a marker of ciliogenesis. Additionally, a skilled artisan would have been motivated to incorporated ciliated cells to encourage the resemblance naturally occurring mesenchymal and lung epithelial cells of proximal airways.
***
Claim(s) 28-29 and 31-32 are newly rejected under 35 U.S.C. 103 as being unpatentable over Yonemura ((2014). Differential Sensitivity of Epithelial Cells to Extracellular Matrix in Polarity Establishment. PLoS ONE, 9(11), e112922.) in view of Salahudeen (Cited in IDS Filed: 3/11/2024. Published: Nov 25 2020. Nature, 588(7839):670-675), e112922.), as applied to claims 1, 2, 5, 6, 10-12, 16, 18, 24, and 26, in further view of Kong et al. (January 2021, Lung organoids, useful tools for investigating epithelial repair after lung injury. Stem Cell Res Ther 12, 95 (2021)). This is a new rejection necessitated by the amendments filed on June 26, 2026.
With regard to claim 1, the combined teachings of Salahudeen et al. and Yonemura render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 1. Moreover, Yonemura teaches when epithelial cells are cultured in suspension without coming into contact with an extracellular matrix, apical membranes are formed on the outer surface of the spheroid, while the basolateral membranes are faced inwards (pp. 1, col 2, para 2; Figure 1.)
Salahudeen discloses a method of forming apical-out organoids in a culture derived from (pp. 670, Abstract), said method comprising the isolation of distal airway cells from lung parenchyma, then culturing the distal airway cells in a medium comprising a TGF-B inhibitor, A83-01, inter alia (pp. 676, col 1, para 2). Further, Salahudeen teaches that the organoids were cultured in lung organoid medium comprising DMEM supplemented with nicotinamide, N-acetyl cysteine, B27 without vitamin A, recombinant human NOGGIN, recombinant human EGf, and TGF-B inhibitor, A83-01 at a concentration of 100 nM (pp. 676, col 1, para 2).
Regarding claims 29, Salahudeen teaches that distal lung organoids were cultured in a chemically defined medium comprising DMEM supplemented with nicotinamide, N-acetyl cysteine, B27 without vitamin A, recombinant human NOGGIN, recombinant human EGf, and TGF0B inhibitor, A83-01 at a concentration of 100 nM (pp. 676, col 1, para 2). Salahudeen does not teach adding serum to the lung organoid medium when cultivating distal lung organoids. As such, the organoid medium does not comprise serum, absent any evidence to the contrary.
Regarding claim 31, Salahudeen teaches that the organoid comprises a TGF-B inhibitor, A83-01 at a concentration of 100 nM (pp. 676, col 1, para 2).
Regarding claim 32, Salahudeen teaches that the organoid comprises a TGF-B inhibitor, A83-01 at a concentration of 100 nM (pp. 676, col 1, para 2).
However, Salahudeen does to expressly teach that the concentration of TGF-B inhibitor is between a concentration of 0.5 to 20µM.
Kong develops lung organoid model comprising lung epithelial progenitors to explore regulatory mechanisms of lung organoids (pp. 8, col 2 para 3). Moreover, TGF-B has been shown to disrupt organoid formation and overall decrease epithelial regeneration (pp. 9, col 1, para 1).
It would have been obvious to optimize the concentration of TGF-B inhibitor based on influential considerations of the design of the apical-out organoid of Salahudeen (i.e. organoid size, apical-out polarity percentage), as concentrations present a result-effective parameter a skilled artisan would routinely optimize. Moreover, a person with ordinary skill in the art would have increased the concentration the inhibitor of TGF-B taught by Salahudeen to arrive at the instant invention as Kong discloses that TGF-B affects organoid formation. In view of this negative attribute of TGF-B, an ordinary artisan would reasonably expect that an increased concentration of TGF-B in the organoid would maintain the overall organoid formation of Salahudeen with reasonable expectation of success.
Response to Applicant arguments as they apply to the rejection of the claims under 35 U.S.C. 103 as being unpatentable over Saluhudeen
Beginning on page 12 of the remarks filed June 26, 2026, Applicants essentially argue the following:
With regard to medium, Salahudeen is silent about a concentration of an inhibitor of notch signaling in an organoid medium and does not teach that a concentration of the inhibitor of signaling through a TGF ranges between about 0.5 μMand 20 μM.
Accordingly, the claimed [cell count] range is critical as it defines a condition to achieve uniform organoid dimensions, yielding unexpected and highly predictable morphological results across the recited range.
As Salahudeen's entire workflow depends on the addition and subsequent removal of an exogenous ECM, it fails to teach or suggest a method performed completely in the absence of an exogenously added ECM component, as required by Claim 1, as amended.
In response to these arguments, they are fully considered but deemed not persuasive for the following reasons:
Regarding 1), the Examiner agrees that Salahudeen fails to teach the claimed range for TGF-B inhibitor concentration. However, the concentration of TGF-B presents as a result effective variable a skilled artisan would routinely optimize. Moreover, a person with ordinary skill in the art would have increased the concentration the inhibitor of TGF-B taught by Salahudeen to arrive at the instant invention as Kong discloses that TGF-B affects organoid formation. In view of this negative attribute of TGF-B, an ordinary artisan would reasonably expect that an increased concentration of TGF-B in the organoid would maintain the overall organoid formation of Salahudeen with reasonable expectation of success.
Regarding 2) and 3), although Salahudeen does not teach explicitly that the population of epithelial cells, wherein the epithelial cells do not come in contact with an exogenously added extracellular matrix, Yonemura addresses these deficiencies. Yonemura also cultures epithelial cells in hanging drop culture in the absence of extracellular matrix to understand the role of the extracellular matrix in epithelial polarity, especially across different epithelial cell lines (pp. 9, col 1 para 2), and found that when not in contact with an extracellular matrix, all epithelial cell types displayed 100% apical-out polarity (Figure 6). Furthermore, the teaching of Yonemura discloses that the hanging-drop cultures utilized 300 cells, which is within the claimed range disclosed in instant claim 7 (pp. 3, col 1, para 2). Therefore, a skilled artisan would have reasonably expected that culturing the distal lung epithelial cells of Salahudeen in a hanging-drop culture absent of extracellular matrix component, would result in the establishment of apical-out organoids with some expectation of success.
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
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