CTFR 18/005,167 CTFR 99566 DETAILED ACTION This action is in reply to papers filed 03/08/2026. Claims 1-4, 6-7, and 9-13 are pending and examined herein. Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Election/Restrictions Applicant elected without traverse of Group I, drawn to claims 1-13 in the reply filed on 09/26/2025. Claims 14-15 are withdrawn from consideration as being drawn to a non-elected invention. Withdrawn Objection(s) and Rejection(s) The objection to the disclosure is withdrawn in light of submission of 1) a Sequence Listing and 2) substitute specifications containing sequence identifiers and numeric identifiers for tables on pages 56-58. The objection to claim 1 regarding minor informalities is withdrawn in light of the amendment to the claim. The rejection of claims 1-4, 6-7, and 9-13 under 35 U.S.C. 112(a) as failing to comply with the written description requirement is withdrawn in light of the amendment to the claim to recite “epidermal growth factor and a BMP agonist” in lieu of “factors.” The rejection of claim 1 under 35 U.S.C. 112(b) is withdrawn in light of the amendment to the claim to recite “lung parenchyma tissue” instead of “peripheral lung tissue.” The rejection of claim 2 under 35 U.S.C. 112(b) is withdrawn in light of Applicant’s arguments. Applicant’s arguments regarding this rejection are addressed below. The rejection of claims 1, 3-4, and 9-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sachs (The EMBO Journal, 2019, 38: e100300) is withdrawn in light of amendment to claim 1 to recite “wherein the culture medium does not contain RSPONDIN 1 (RSPO1).” The rejection of claims 6-7 under 35 U.S.C. 103 over Sachs (The EMBO Journal, 2019, 38: e100300), in view of Lamers (Science, May 2020, 369(6499): 50-54), as evidenced by Corning (Guidelines for Use, Product: Corning Matrigel Basement Membrane Matrix Growth Factor Reduced), is withdrawn in light of amendment to claim 1 to recite “wherein the culture medium does not contain RSPONDIN 1 (RSPO1).” The rejection of claim 2 under 35 U.S.C. 103 over Sachs (The EMBO Journal, 2019, 38: e100300), in view of Co (Cell Reports, 2019, 26(9): 2509-2520), is withdrawn in light of amendment to claim 1 to recite “wherein the culture medium does not contain RSPONDIN 1 (RSPO1).” The rejection of claim 2 under 35 U.S.C. 103 over Sachs (The EMBO Journal, 2019, 38: e100300) is withdrawn in light of amendment to claim 1 to recite “wherein the culture medium does not contain RSPONDIN 1 (RSPO1).” The rejection of claim 13 under 35 U.S.C. 103 over Sachs (The EMBO Journal, 2019, 38: e100300), in view of Co (Cell Reports, 2019, 26(9): 2509-2520) and Elbadawi (The Lancet, 2020, 8: e55-56; published May 21, 2020), is withdrawn in light of amendment to claim 1 to recite “wherein the culture medium does not contain RSPONDIN 1 (RSPO1).” The cancellation of claims 5 and 8 renders any rejections thereof moot. Claim Objections Claim 1 is objected to because of the following informalities: Claim 2, which depends from claim 1, recites the limitation “the lumen of the organoid” (line 4). Although a lung organoid comprises a lumen, the phrase “lung organoid” is not recited in the body of claim 1, but only in the preamble (line 1). Claim 1 does not explicitly recite that performing the steps therein results in a lung organoid, but only that it results in organoids (line 7). For the sake of clarity, it is recommended that claim 1 be amended to recite “to form the organoids” or “to form lung organoids” at line 7. Claim Rejections - 35 USC § 112(d) 07-36 AIA The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. 07-36-01 AIA Claim 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 7 is drawn to the method of claim 1, wherein the medium further comprises an inhibitor of TGF-b. However, claim 1 recites the limitation of “culturing the cells in culture medium comprising extracellular matrix and an effective concentration of epidermal growth factor and a BMP antagonist” (lines 5-6). BMPs (Bone Morphogenetic Proteins) are a member of the TGF-ß superfamily (see, e.g., Poniatowski, Mediators of Inflammation, 2015: 137823 at page 2, Figure 1). Therefore, claim 7 broadens the limitation set forth in claim 1 . Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Claim Rejections - 35 USC § 112(a) 07-30-01 AIA 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. 07-31-03 AIA Claim s 1-4, 6-7, and 9-13 are 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 culturing lung organoids, wherein the lung organoid media comprises an effective concentration of Noggin and a TGF-beta inhibitor, and wherein the cells in the extracellular matrix are plated in droplets , does not reasonably provide enablement for culturing lung organoids, wherein the lung organoid media does not comprise Noggin and a TGF-beta inhibitor, and wherein the cells in the extracellular matrix are not plated in droplets . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to carry out the invention commensurate in scope with these claims. Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " ( Wands , 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." ( Wands , 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below. The nature of the invention : The nature of the invention is a method of culturing human distal lung organoids, comprising obtaining a human peripheral lung parenchyma tissue sample; dissociating the peripheral lung tissue into single cells; culturing the cells in culture medium comprising extracellular matrix and an effective concentration of epidermal growth factor and a BMP antagonist, for a period of time sufficient to form organoids; wherein the culture medium does not contain RSPONDIN 1 (RSPO1). The breadth of the claims : Claims 1-4, 6-7, and 9-13 encompass a method of culturing single cells obtained from a human peripheral lung parenchyma tissue sample in a culture medium to form organoids, wherein the culture medium comprises an extracellular matrix and an effective concentration of epidermal growth factor and a BMP antagonist, and wherein the culture medium does not contain RSPONDIN 1. Claim 6 narrows the BMP antagonist to a Noggin protein. Claim 7 narrows the scope of claim 1 to require the medium to comprise an inhibitor of TGF-b. The state of the prior art : Sachs ( The EMBO Journal, 2019, 38: e100300) teaches a method for establishing long-term expanding human airway organoids from broncho-alveolar resections (reads on lung parenchyma ) (Abstract). Sachs teaches medium for culturing human airway organoids, wherein the medium comprises RSPO1 (Wnt/ß-catenin activator), FGF7 (FGFR2ß activator), FGF10 (FGFR2ß activator), 100ng/mL of Noggin (TGFß antagonist), 500nM of A83-01 (TGFß antagonist), Y- 27632 (ROCK antagonist), SB202190 (p38 MAPK antagonist), and B27 supplement (insulin signaling activator), and further comprising other factors including B27 supplement, N-Acetylcysteine, Nicotinamide, GlutaMax, Hepes, Penicillin/Streptomycin, Primocin, and DMEM/F12 (Table EV1). Lung cell pellets were resuspended in Cultrex growth factor reduced BME type 2 (Trevigen‐3533‐010‐02), and 40 μl drops of BME‐cell suspension were allowed to solidify on pre‐warmed 24‐well suspension culture plates. Following gelation, 400 μl of AO medium was added to each well (Methods and Protocols, Organoid Culture). Lamers ( Science, May 2020, 369(6499): 50-54) teaches a method for culturing human lung organoids. Lamers teaches isolating human bronchial airway stem cells according to the protocol adapted from Sachs (Supplementary Materials, p 2, para 3). Following dissociation of lung tissue into single cells, lung cell pellets were resuspended in growth factor reduced Matrigel (Corning) and plated in ~30 μL droplets in a 48 well tissue culture plate. Once the Matrigel droplets solidified, 250uL of medium was added to each well, and cultured under standard conditions to obtain organoids (Supplementary Materials, p 3, para 1). The level of one of ordinary skill : One of ordinary skill in the art is a research scientist holding a postgraduate degree or equivalent experience. The level of predictability in the art : The prior art, as set forth above in Sachs and Lamers, teaches that Noggin and a TGF-b inhibitor (A83-01) are essential components in a medium for culturing lung organoids, and that the plating of resuspended cells in an extracellular matrix in drops or droplets is necessary to obtain lung organoids. Therefore, there was a high level of unpredictability regarding the culturing of organoids in a medium without FGF7 (FGFR2ß activator), FGF10 (FGFR2ß activator), Noggin (TGFß antagonist), A83-01 (TGFß antagonist), Y- 27632 (ROCK antagonist), SB202190 (p38 MAPK antagonist), or B27 supplement (insulin signaling activator). Furthermore, there was a high level of unpredictability regarding the culturing of lung organoids without the physical constraint of plating resuspended cells in an extracellular matrix in drops or droplets. Working examples and the amount of guidance: The instant specification discloses culturing of lung organoids, wherein the lung organoid media comprises Advanced DMEM/F12 (lnvitrogen) supplemented with 10 mM nicotinamide, n-acetyl cysteine, 1 X B27 supplement minus vitamin A, recombinant human NOGGIN (100 ng/ml, R&D Systems), recombinant human EGF (50 ng/ml, R&D Systems), and TGF-beta inhibitor A83-01 (100nM, Tocris), and the cells in a matrix of Basement Membrane Extract II (Trevigen) were plated in 50 microliter droplets (para 203). The specification recites effective concentration of agents, which vary from 1 ng/mL to 10 μg/mL or more (para 71). The specification does not disclose culturing of lung organoids, wherein the lung organoid media comprises a BMP antagonist other than Noggin (as encompassed by claims 1-4, 7, and 9-13), in the absence of a TGF-beta inhibitor (as encompassed by claims 1-4, 6, and 9-13), or wherein the cells in the extracellular matrix were not plated in droplets (as encompassed by claims 1-4, 6-7, and 9-13). The quantity of experimentation necessary: Based on the content of the disclosure and the state of the prior art, undue experimentation is required to carry out the invention as claimed. As discussed above, the experimental examples disclosed in the specification are limited to embodiments of the invention wherein lung organoids are cultured in a medium comprising 100 ng/ml of NOGGIN (100 ng/ml, R&D Systems), 50 ng/ml of EGF, and TGF-beta inhibitor A83-01, and wherein cells in a matrix were plated in 50 microliter droplets (para 203). Given the content of the disclosure and the state of the prior art, additional experimentation is required to carry out the method of culturing lung organoids, wherein the lung organoid media comprises a BMP antagonist other than Noggin (as encompassed by claims 1-4, 7, and 9-13), in the absence of a TGF-beta inhibitor (as encompassed by claims 1-4, 6, and 9-13), or wherein the cells in the extracellular matrix were not plated in droplets (as encompassed by claims 1-4, 6-7, and 9-13). Therefore, in light of the breadth of the claims, the limited guidance in the specification with respect to the breadth, and the state of the art, undue experimentation is required to carry out the invention as broadly claimed. In conclusion, the evidence provided in the disclosure, in light of the teachings available in the art, does not enable one skilled in the art to make the claimed invention without undue or reasonable experimentation. Therefore, the method recited in claims 1-4, 6-7, and 9-13 are not enabled in its full breadth. Response to Arguments RE: Rejection of claim 2 under 35 U.S.C. 112 Applicant argues: MPEP § 2173.05(e) makes it clear that a claim cannot be held indefinite if an element that appears to have no antecedent basis is implicitly or inherently part of another component that is recited earlier in a claim. The MPEP provides a number of examples of situations in which this rule applies. Most relevantly, MPEP § 2173.05(e) states that, for example, "the outer surface of said sphere" would not require an antecedent recitation that the sphere recited earlier in the claim has an outer surface. Bose Corp. v. JBL, Inc ., 274 F.3d 1354, 1359, 61 USPQ2d 1216, 1218-19 (Fed. Cir 2001). In the present case, the organoid inherently contains an interior, i.e., lumen, and an exterior. As stated in the background, "Further, organoid cultures often grow as cystic structures with their apical surfaces directed inwards towards a central lumen." The above was well known in the art, as is stated in Sachs which states "Following opening of the CFTR channel by cAMP-inducing agents (e.g., forskolin), anions and fluid are transported to the organoid lumen resulting in rapid organoid swelling (Dekkers et al, 2013)" (pg.22nd column last paragraph). Accordingly, "the lumen" has implicit support from the recitation of organoid in claim 1. In response: Applicant’s arguments have been fully considered and are persuasive. The rejection of claim 2 under 35 U.S.C. 112(b) has been withdrawn. As asserted by Applicant and as evidenced by Zimmerman ( Differentiation, 1987, 36(1): 86-109) , a lung organoid comprises a lumen. Conclusion 07-40 AIA 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 Risa Takenaka whose telephone number is (571)272-0149. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /RISA TAKENAKA/Examiner, Art Unit 1632 /TITILAYO MOLOYE/Primary Examiner, Art Unit 1632 Application/Control Number: 18/005,167 Page 2 Art Unit: 1632 Application/Control Number: 18/005,167 Page 3 Art Unit: 1632 Application/Control Number: 18/005,167 Page 4 Art Unit: 1632 Application/Control Number: 18/005,167 Page 5 Art Unit: 1632 Application/Control Number: 18/005,167 Page 6 Art Unit: 1632 Application/Control Number: 18/005,167 Page 7 Art Unit: 1632 Application/Control Number: 18/005,167 Page 8 Art Unit: 1632 Application/Control Number: 18/005,167 Page 9 Art Unit: 1632 Application/Control Number: 18/005,167 Page 10 Art Unit: 1632 Application/Control Number: 18/005,167 Page 11 Art Unit: 1632
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