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 .
Priority
Applicants’ claim for the benefit of a prior-filed application parent provisional application 63238486 filed on 08/30/2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) was filed before the mailing date of the non-final first action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Election/Restrictions
Applicant's election with traverse of Group I, which encompass claims ( 1-10, and 12-13) in the reply filed on 08/04/2026 is acknowledged. The traversal is on the ground that the prior art applied by the Office, for example Kim et al, does not disclose or render obvious the special technical feature ( i.e. Alveolar organoid ( AlvO) consisting of at least 40% type I alveolar epithelial (AT1l) cells and type II alveolar epithelial (AT2) cells). Specifically, Applicants argue that Kim does not disclose the special technical feature because Kim's protocol is pluripotent stem cell-based; which uses different culture methods and differentiation conditions to generate alveolar organoids. As such, Pluripotent stem cell-derived organoids recapitulate embryonic development, yet their intrinsic fetal-like properties limit their utility for modeling post-birth diseases such as respiratory infections. This is not found persuasive because even if the assertion was accepted, it would not overcome the unity of invention objection. Because the Office relies on ( Yamamoto in view of Lim and Abdelwahab), rather than Kim, to establish that the alleged special technical feature does not provide contribution over the prior arts. ( See the rejection below).
Claims 15-18, 20-21, and 23-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 08/ 04/2026.
The requirement is still deemed proper and is therefore made FINAL. Accordingly, claims 1-10, and 12-13 are currently under examination.
Claim Interpretation
It should be noted that the optional recitations in the claims are not given
patentable weight as they are not required by the subject claim.
Claim Objections
Claim 6 is objected to because of the following informalities: the claim recites the abbreviation “DD medium” which is not defined in the claims. In claim 1, Applicants recite “distal differentiation medium” without introducing the abbreviation “DD medium”. Accordingly, the subsequent reference to “DD medium” in claim 6 lacks proper antecedent basis and renders the scope of the claim unclear. Applicant is required to amend claim 1 to introduce the abbreviation, or otherwise clarify the meaning of DD medium in claim 6. Appropriate correction is required.
Claim 12 is objected to because of the following informalities: in step (a)-2nd line the claim recites “ for at least 2 four weeks”. This phrase is unclear and appears to contain typographical error. It is not clear whether the intended limitation is “ 2 weeks”, “ 4 weeks” ,or “2-4 weeks”. Appropriate correction is needed.
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 1, 3-5, 7, 12, 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.
The claims recite the phrase "for example" which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The claims also recite the phrase "such as" which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The claims further recite the term "Preferably" which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. The metes and bound of the claims are unclear.
Claim 7 is indefinite because it makes reference to table 1 for the components of the expansion medium . As stated in MPEP 2173.05(s): “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).” In the instant case, the components of expansion medium can be incorporated into the claims.
Claim Rejections - 35 USC § 103
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 1-10, and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Yamamoto et al ( Nature Methods, 2017), in view of Lim et al ( BioRxiv Preprint, 2021), Abdelwahab et al ( Respiratory Research,2019), Tindel et al ( eLife, 2021), and Sandor et al ( Frontiers, 2021).
Regarding claim 1, Yamamoto et al disclose two approaches for generating alveolar organoids from human iPSC-derived progenitor cells; a fibroblast-dependent method and a fibroblast-free method. In the fibroblast-dependent approach, Yamamoto et al generate Alveolar organoids (AO) from iPSCs-derived progenitor cells. The resulting AOs contain SFTPC+ cells corresponding to AT2 cells, and report that these cells are capable of differentiating into alveolar epithelial type I (AT1). Specifically, Yamamoto et al identify a population of SFTPC-, PDPN+, AQP5+ AT1-like cells in the fibroblast dependent alveolar organoids. ( See abstract, Fig.1, and Supplementary Fig.7e). Thus, Yamamoto et al teach the generation of alveolar organoids (AO) comprising a cell population containing SFTPC+ AT2 cells, and AQP5+ AT1-like cells. In another embodiment, Yamamoto et al separately disclose a fibroblast-free approach for generating alveolar organoids. In this method, Yamamoto et al teach the generation of AO by culturing hiPSC-derived CPMhigh progenitor cells in alveolarization medium comprising dexamethasone, 8-bromo-cAMP, and IBMX, and CHIR99021 (i.e. Wnt agonist). ( See section “ Fibroblast-free induction of SFTPC+ cells” on page 3, and the components of the alveolarization medium on page 28”. Yamamoto et al, however, characterize the resulting organoids with respect to the presence of AT2 epithelial cells only. Accordingly, Yamamoto et al also teach the use of dexamethasone, 8-bromo-cAMP, and IBMX, and CHIR99021 (i.e. Wnt agonist) in the fibroblast-free condition.
It is submitted, however, that Yamamoto et al generate alveolar organoids using iPSCs-derived stem cells, while instant claim recites AO generated from lung organoid-derived stem cells.
Lim et al supplement Yamamoto et al by teaching fetal lung-derived organoid system and the differentiation of the lung-derived organoids toward alveolar fate. Specifically, the method of Lim et al involves culturing human fetal distal tip epithelial cells at the canalicular stage and cultures them into Lin+ lung organoids. Those organoids are then placed into a differentiation medium comprising of dexamethasone, 8-bromo-cAMP, and IBMX, and CHIR99021 and differentiate into AT2-like/alveolar organoids (i.e. Wnt agonist). ( See section “ Cultured canalicular stage tip cells differentiate readily into alveolar type 2 cells” on page 8). Accordingly, Lim et al experimentally demonstrate that Alveolar organoids can be generated from lungs organoids. Most importantly, Lim et al expressly state that the canalicular-stage tip cells are in a “distinct differentiation-ready state” and demonstrate their differentiation toward AT2 cells expressing SFTPC. As such, providing an ordinary skill in the art with the motivation for selecting a developmentally advanced lung-derived starting population over a PSC-derived starting population. Therefore, an ordinary skill in the art seeking to generate alveolar organoids would have a reason to use Lim’s lung-derived organoid populations in the Yamamoto fibroblast-free system with a reasonable expectation of obtaining Alveolar organoids comprising AT1 and AT2 cells.
Lim et al, however, did not comprehensively characterize AT1 differentiation in their organoid system.
Abdelwahab et al further supplement Lim by teaching that Wnt signaling regulates the differentiation of AT2 toward AT1. Specifically, Abdelwahab evaluate Wnt signaling in 3D human lung epithelial aggregates comprising small airway epithelial cells and lung fibroblast and examine expression of AT2- and AT1- associated markers. Abdelwahab et al report that Wnt ligands affect AT2-to-AT1 trans-differentiation and, in particular, Wnt 7a increases expression of the AT1-associated marker AQP5 at the mRNA and protein levels.( See abstract, Fig.3, and section “ 3D tissues and treatment with recombinant human Wnt” on page 3). Accordingly, Abdelwahab et al teach that activation of Wnt signaling can promote the acquisition of an AQP5+ AT1 phenotype form AT2 cells. Given the established role of Wnt singling in promoting AT2-AT1 trans differentiation, the alveolar differentiation system described by Lim et al may also have the potential to generate AT1 cells. Accordingly, the presence of AT2 population in a Wnt-dependent alveolar differentiation system provides a rational to investigate whether AT1 cells also arise in these organoids.
Taken together, it would have been prima facie obvious at the time the invention was filed to modify the organoid differentiation system of Yamamoto and use the more developmentally advanced lung organoids of Lim et al as the starting material in the differentiation approach of Yamamoto. Because Yamamoto et al teach methods for producing AO using iPSC-derived lung organoids, including a fibroblast-independent method, and teach employing an alveolarization medium comprising the same components of the distal differentiation medium of instant claim. Lim et al teach an alternative route for AO in which a lung organoids, rather than iPSCs, is used as the starting material and is cultured under distal differentiation conditions to generate AOs. Lim et al also expressly state that canalicular-stage cells used to generate lung organoids are in a “distinct differentiation-ready state”. Thus, an ordinary skill in the art seeking to produce AOs according to the method of Yamamoto would have been motivated to use the more developmentally advanced lung organoids of Lim as the starting material for the fibroblast-independent differentiation approach of Yamamoto. Moreover, Lim’s teaching would have provided a reasonable expectation of success because Lim demonstrate that lung organoids can be directed toward an alveolar fate using the same medium of instant claims. Abdelwahab further teaches that Wnt signaling promotes trans differentiation of AT2 cells into AT1 phenotype and induces the expression of AQP5. Accordingly, in view of the combined teachings of Yamamoto, Lim, and Abdelwahab, an ordinary skill in the art would have had a reason to expect that applying the fibroblast independent alveolar differentiation method to the lungs organoids of Lim would result in an alveolar organoids comprising both SFTPC+ AT2 cells and AQP5+ AT1 cells. Furthermore, the recited requirement that the cell population comprise at least 40% AT1 and AT2 cells does not impart patentable weight where that percentage is an inherent result of performing the prior art process. In other words, the limitation is considered a functional outcome that would result from performing the active steps of the method. As discussed above, the combined teachings of the cited prior arts render obvious the method steps of instant claim, therefore, the numerical limitation of at least 40% is considered an inherent property of the prior-art product that would flow naturally from following the suggestion of the combined teachings of the prior art rather than a patentably distinguished feature.
Regarding claims 2-3, following the discussion of claim 1 above, the combined teachings of Yamamoto, Lim and Abdelwahab render obvious a method of producing AOs from lung organoids. However, none of the cited prior arts teach the use of a Wnt agonist wherein the Wnt agonist is Wnt3.
Tindle et al supplement the cited prior arts by teaching the use of Wnt3 in the context of human lung organoid culture. Specifically, Tindel et al provide an express teaching of using Wnt3 in connection with human lung organoid culture, and further characterize the resulting lung organoids as containing distal/alveolar epithelial populations, including AT2 cells and a significant population of AT1 cells identified as AQP5 expressing cells. Thus, Tindel et al provide an express teachings of using Wn3 in connection with human lung organoids culture. ( See section “ Creation of a lung organoid model, complete with both proximal and distal airway epithelia” on page 8).
On the other hand, the cited prior arts by Yamamoto, Lim and Abdelwahab experimentally demonstrate that Wnt-pathway activators can be used to promote alveolar fate. Therefore, an ordinary skill in the art seeking to produce AO according to the method of instant claim 1 would have had a reasonable expectation of success in selecting a Wnt agonist, such as Wnt3, as the Wnt activator in the differentiation medium. In view of the teachings of Lim Yamamoto, and Abdelwahab regarding the use of Wnt signaling to promote alveolar fate, and the known activity of Wnt3 as a Wnt activator, an ordinary skill in the art would have expected substitution of Wnt 3 for the Wnt agonist used in the differentiation methods of Yamamoto and Lim to promote alveolar fate, including the generation of AT1 and AT2. As per claim3, Tindel teach the use of Wnt3-conatining L-WRN conditioned medium in culturing human lung organoids, and describe the use of the conditioned medium at 50% of the lung-organoid expansion medium. ( See section “ Isolation and culture of human whole lung-derived organoids “ on page 32). Thus, the selection of a Wnt3-containg conditioned medium within the claimed range of instant claim would have been a routine optimization of the Wnt-containing culture conditions known in the art. Accordingly, the claimed concertation range would have been obvious as a result-effective variable.
As per the MPEP. "[W]here the general conditions of a claim are disclosed in the prior
art, it is not inventive to discover the optimum of workable ranges by routine experimentation.
The "discovery of an optimum value of a result effective variable in a known process is ordinarily
within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219
(C.C.P.A. 1980). See MPEP 2144.05
Regarding claims 4-5, Yamamoto et al teach an alveolarization medium comprising 100 um of IBMX, 50 um dexamethasone, 100 um 8-Br-cAMP, this overlaps with the concentrations ranges required by instant claims.
Regarding claims 6-7,following the discussion of claim 1 above, Yamamoto in view of Lim and Abdelwahab render obvious claim 1. Lim et al further teach obtaining human fetal lung tissue and isolating lung epithelial tip progenitor cells therefrom. Lim et al further teach culturing the isolated lung cells under self-renewing condition to generate three-dimensional lung organoids (i.e. LinPOS organoids). Thus, Lim et al teach obtaining lung cells from the lung tissue samples, and culturing the lung cells in an organoid formation phase to generate lung organoids, this reads on claim 6. Lim et al disclose culturing the lung cells in a self-renewal/expansion medium to generate the lung organoids, wherein the medium comprises of Noggin ( a BMP inhibitor), FGF10, FGF7, N-acetylcysteine, SB431542 ( an inhibitor of TGFB)
this reads on claim 7. ( see sections “In vitro culture of human fetal lung organoids” on page 19). Accordingly, instant claims would have been obvious over the combination of the cited prior arts.
Regarding claim 8, following the discussion of claim 6-7, above. Lim et al disclose culturing the lung cells in a self-renewal/expansion medium to generate the lung organoids, wherein the medium comprises of Noggin ( a BMP inhibitor), FGF10, FGF7, N-acetylcysteine, SB431542 ( an inhibitor of TGFB). However, the expansion medium taught by Lim et al does not contain R-spondin, or heregulin-beta-1. Sandor et al supplement Lim et al by teaching culturing human lung-derived organoids in a medium comprising R-spondin, Noggin ( A BMP inhibitor), A83-01 ( a TGFB inhibitor), FGF-10,FGF7, and heregulin beta-1. Sandros therefore teach an organoid culture medium comprising the components recited in instant claim. Sandor et al further disclose that human bronchiolar and lung adenocarcinoma organoids were generated by digesting lung tissue, embedding the resulting cells in Matrigel, and culturing the cells in the disclosed medium. ( See section “ Human Bronchiolar and LUAD Organoids” on page 3). Therefore, it would have been obvious to one with ordinary skill in the art to employ the expansion medium of Sandros et al in the lung-organoid formation/expansion phase in the method of Lim et al, because Sador et al demonstrate that this combination of components support the formation of lung organoids. An ordinary skill in the art would have a reasonable expectation of success when culturing the lung cells of Lim et al in the expansion medium of Sandor et al that the lung organoid would be formed. In other word, instant claim 8 is combining prior art elements according to known methods to yield predictable results. See MPEP 2143 (I)(A).
Regarding claims 9-10, and 12-13, following the discussion of claim 1 above, Yamamoto in view of Lim and Abdelwahab render obvious claim 1. Lim et al further teach the particular process of instant claims. Specifically, Lim et al teach culturing isolated human fetal lung tip epithelial cells embedded in Matrigel, an extracellular matrix, in self-renewal/expansion medium to generate three-dimensional lung organoids (i.e. Linpos organoids), this reads on step (a) of claim 12. Lim et al further teach changing the culture medium to a differentiation medium comprising DAPT, CHIR99021, dexamethasone,8-Br- cAMP, IBMX, and SB431542, wherein DAPT is Notch inhibitor. Lim et al demonstrate that medium change caused LinPOS organoids to differentiate toward an AT2 fate with increased expression of SFTPC and other AT2 markers, this reads on step (b) of claim 12. Lim et al further teach changing the medium every other day and teach the use of human cells, this reads on claim 13. ( see sections “In vitro culture of human fetal lung organoids” and “ Type 2 alveolar differentiation of LinPOS organoids” on pages 19-20) . Accordingly, instant claims would have been obvious over the combination of the cited prior arts.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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