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 .
1. Claims 1 – 21 are pending.
Election/Restrictions
2. Applicant's election with traverse of Group I (claims 1 – 10) in the reply filed on 05/26/2026 is acknowledged. The traversal is on the ground(s) that (1) Applicant should not be required to incur the additional costs associated with the filing of multiple divisional applications in order to obtain protection for the claimed subject matter; and (2) it would not place undue burden on the Examiner to search the subject matter of all the claims (Groups I – III) together because a search directed to one Group would likely yield results applicable to other groups; and (3) Dye does not disclose infecting the culture composition with a respiratory pathogen as claimed and the technical feature of an ALO culture composition infected with a respiratory pathogen is a special technical feature that makes a contribution over the cited prior art. This is not found persuasive because this application is a national stage entry of 371 of PCT/US2022/032792 where “unity of invention” analysis is applied in a restriction requirement. Accordingly, Groups I – III share the special technical feature of a culture composition comprising human lung proximal airway epithelial cells and distal airway epithelial cells, and not “infected with a respiratory pathogen” because Group III (claims 17 – 21) do not recite that the culture composition is infected with a respiratory pathogen. This technical feature (a culture composition comprising human lung proximal airway epithelial cells and distal airway epithelial cells) is not a special technical feature as it does not make a contribution over the prior art in view of Dye as stated in the Restriction Requirement mailed 03/26/2026. .
The requirement is still deemed proper and is therefore made FINAL.
3. Claims 11 – 21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 05/26/2026.
Priority
4. This application is a U.S. National Phase Application of PCT Application No. PCT/US2022/032792, filed on June 9, 2022, which claims priority to US Provisional Application Serial No. 63/208,522 filed June 9, 2021.
Information Disclosure Statement
5. The information disclosure statement (IDS) submitted on 11/21/2023 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
6. The drawings submitted on 11/21/2023 are acknowledged.
Specification
7. The use of the term Knockout, HistoGel, Matrigel, Glutamax, B27, TrypLE, Pneumacult, TRIzol. Sybr, qScript, QuantStudio, TaqMan, Triton, ProLong, Cyto-Fast, Alexa Fluor, Guava easyCyte, TruSeq, NovaSeq, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
8. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
9. It is noted that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
10. Claim 7 is objected to because of the following informalities: in line 2, “the lung model” should read “the culture composition” because claim 6 recites that the lung model is a result of infecting and claim 7 recites analyzing before infecting. Therefore, the lung model recited in claim 7 does not exist until infection of the culture composition, and as such the culture composition would be analyzed prior to infecting. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
11. Claim 8 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 8 recites “the proximal airway epithelial cells permit viral infection”. However, Applicant defines human lung proximal airway epithelial cells as permitting viral infection at para. 00104 of the Specification. Therefore, claim 8 fails to further limit 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.
12. Claim 9 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 9 recites “wherein the distal alveolar cell differentiation permits viral propagation” and claim 5 (from which claim 9 depends) recites distal alveolar cells and alveolar type-1 (AT1( pneumocytes). However, Applicant defines distal alveolar cells as permitting viral propagation at para. 00106 of the Specification. Therefore, claim 9 fails to further limit claim 5. 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 Interpretation
13. For the purpose of applying prior art, “human lung proximal airway epithelial cells” of claim 1 is interpreted to include proximal ciliated cells based on Applicant’s specification at para. 00104 and para. 00135; “distal airway epithelial cells” is interpreted to include AT1 and AT2 cells based on Applicant’s specification at para. 00106 and 00135 – 00136.
14. For the purpose of applying prior art, claim 2 is interpreted as the culture composition is a 2D monolayer based on Applicant’s Example 4 in the specification beginning at para. 00153. Recitation of “derived from” and “stem-cell derived” are interpreted as product-by-process limitations that do not impose a particular structure on a monolayer of the culture composition of claim 1 that differs from dissociation of adult lung organoids into a monolayer, and because no active method steps are recited in claim 2.
15. For the purpose of applying prior art, “proximal ciliated cells” of claim 3 is interpreted as FOXJ1+ and/or Ac-Tub cells based on Applicant’s specification at para. 00133 and 00136.
16. For the purpose of applying prior art, “wherein at least a portion of the distal alveolar cells are differentiated to alveolar type-1 (AT1) pneumocytes” of claim 5 is interpreted as descriptive of the distal alveolar cells containing AT1 pneumocytes and not an active method step of differentiating distal airway epithelial cells. For the purpose of applying prior art, “alveolar type-1 (AT1) pneumocytes” of claim 5 are interpreted as AQP5+ cells based on Applicant’s specification at para. 00133 and 00150.
17. For the purpose of applying prior art, “analyzing” of claim 7 is interpreted as measuring for the presence of ACE2 and TMPRSS2in the culture composition by any method.
18. For the purpose of applying prior art, “permit viral infection” of claim 8 is interpreted as the culture composition comprises proximal airway epithelial cells based on Applicant’s definition of proximal airway epithelial cells as permitting viral infection at para. 00104 of the Specification.
19. For the purpose of applying prior art, “permit viral propagation” of claim 9 is interpreted as the culture composition comprises distal alveolar cells that are AT1 pneumocytes based on Applicant’s definition of distal alveolar cells as permitting viral propagation at para. 00106 of the Specification.
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.
20. Claim(s) 1 – 5, 8, and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tan (Tan, Qi, et al. Biomaterials 113 (2017): 118-132.), hereinafter Tan in view of Zhou (Zhou, Jie, et al. Proceedings of the National Academy of Sciences 115.26 (2018): 6822-6827.), hereinafter Zhou.
Regarding claims 1, 3, 4, 5, 8, and 9, Tan teaches providing a culture composition comprising human lung proximal airway epithelial cells that are ciliated and express FOXJ1 and acetylated-alpha tubulin (“human lung proximal airway epithelial cells” of claim 1 and 8; “proximal ciliated cells” of claim 3) and distal airway epithelial cells that are AT1 pneumocytes that express AQP5 (“distal airway cells” of claim 1; “distal alveolar cells” of claims 4 and 9; “AT1” of claim 5) (page 119, left col. para. 3 – 4; page 120, left col. last para. and right col. para. 2; Figure 1A; page 123, left col. para. 3 and right col. para. 2; Figure 3F – I; page 129, left col. last para. and right col. last para.; page 131, left col. para. 1). Tan does not teach “infecting the culture composition with a respiratory pathogen of claim 1.
Tan does not teach “infecting the culture composition with a respiratory pathogen of claim 1 or monolayer of claim 2. However, Tan teaches a potential benefit of the de novo generation of complex three-dimensional lung-like tissues in culture is disease modeling (page 118, right col.). Tan teaches the human airway organoids is a novel tool for studying disease-relevant cellular and molecular function (page 119, left col. para. 3). Tan teaches an immediate opportunity for use of airway organoids is apparent in the realm of disease-modeling (page 130, right col. para. 3). Tan teaches the airway organoids have the potential to become a valuable tool for assessing tissue-, cell-, and molecular-level responses, and for evaluating novel therapies and patient-specific interventions (page 130, right col. para. 3). Tan teaches the airway organoids represent a new and potentially powerful tool within which to study physiologic and pathologic cell-cell interactions (page 131, left col. para. 1).
Regarding “infecting the culture composition with a respiratory pathogen of claim 1 and monolayer of claim 2, Zhou teaches transforming 3D airway organoids into a 2D monolayer (claim 2) and infecting the monolayer with influenza virus (claim 1) (page 6824, right col. para. 2 – 3; page 6825, left col. para. 1; Figure 5). Zhou teaches the 3D organoids can be infected with influenza viruses where the virus propagates (page 6824, left col. para. 2 – 3 and right col. para. 1; Figure 4). Zhou teaches a limitation of 3D organoids for studying microbial infections is the inaccessibility of the apical surface to pathogens since most organoids are oriented inwards, while receptors for most respiratory viruses are distributed in the apical surface (page 6824, right col. para. 2). Zhou teaches an intact epithelial barrier was formed across the 2D monolayers and were positive for acetylated tubulin (page 6824, right col. para. 2; Figure 5). Zhou teaches there is no robust in vitro model for assessing the infectivity of emerging viruses in humans (Abstract). Zhou teaches despite the tremendous progress made in virology and epidemiology, which subtype or strain of influenza A viruses will cause the next outbreak remains unpredictable (page 6822, left col.). Zhou teaches a biologically relevant, reproducible, and readily available in vitro model remains urgently needed for studying the biology and pathology of the human respiratory tract (page 6823, left col. para. 1). Zhou teaches the 2D model showed differences in viral titer between H7N9/Ah and H7N2 and between the highly human-infective H1N1pdm and a swine H1N1 isolate (page 6824, right col. last para.; page 6825, left col. para. 1 and right col. para. 1; Figure 5B). Zhou teaches the ability of the 2D model to differentiate the avian H7 subtype virus and swine H1 subtype virus from the counterpart human-infective viruses suggests that these models could be used to assess the cross-species transmission potential of emerging influenza viruses in humans (page 6826, left col. para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Tan regarding a culture composition comprising human lung proximal airway epithelial cells and distal airway epithelial cells that can be used for disease modeling with the teachings of Zhou regarding dissociating 3D airway organoids into 2D and infecting the cells with influenza virus to assessing the infectivity of emerging viruses in humans to arrive at the claimed method of modeling a biological process in a human lung, the method comprising:
providing a culture composition comprising human lung proximal airway epithelial cells and distal airway epithelial cells; and infecting the culture composition with a respiratory pathogen. One would have been motivated to combine the teachings of Tan and Zhou in an in vitro method of modeling virus infectivity in human lungs as Tan teaches a potential benefit of the de novo generation of complex three-dimensional lung-like tissues in culture is disease modeling and Zhou teaches there is no robust in vitro model for assessing the infectivity of emerging viruses in humans and Zhou teaches despite the tremendous progress made in virology and epidemiology, which subtype or strain of influenza A viruses will cause the next outbreak remains unpredictable and Zhou teaches a biologically relevant, reproducible, and readily available in vitro model remains urgently needed for studying the biology and pathology of the human respiratory tract. One would have a reasonable expectation of success in combining the teachings as both Tan and Zhou teach the airway organoids comprise ciliated cells and Zhou teaches the airway organoids can be infected with influenza virus where the virus propagates and the 2D cells from the organoids can be also be infected with influenza virus where the virus propagates and each model can distinguish between viral strains based on viral titer output.
21. Claim(s) 6 and 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tan (Tan, Qi, et al. Biomaterials 113 (2017): 118-132.), hereinafter Tan in view of Zhou (Zhou, Jie, et al. Proceedings of the National Academy of Sciences 115.26 (2018): 6822-6827.), hereinafter Zhou as applied to claims 1 – 5, 8, and 9 above, and further in view of Blanco-Melo (Blanco-Melo, Daniel, et al. BioRxiv (2020): 2020-03.), hereinafter Blanco-Melo.
Tan in view of Zhou do not teach infecting the culture composition with SARS-CoV-2 of claim 6. Regarding claim 7, Zhou teaches analyzing the culture composition for TMPRSS2 expression by RT-qPCR (page 6824, left col. para. 1; Figure 3A; page 6827, left col. para. 3) but does not teach analyzing for ACE2. However, Tan teaches the airway organoids were prepared from NHBE cells and both proximal and distal markers were found in the organoids (page 119, left col. para. 4; page 123, right col. para. 2; page 129, right col. last para.; page 131, left col. para. 1). Tan teaches unsorted NHBE cells maintain the potential to express hallmarks of both proximal and distal epithelial lineages found in the adult lung (page 130, left col. para. 1).
Regarding “SARS-CoV-2” of claim 6, Blanco-Melo teaches infecting human proximal airway cells (NHBE) with SARS-CoV-2 (page 3, last para.; page 4, para. 1; Figure 2a; page 8, last para.). Blanco-Melo teaches infecting human distal alveolar cells (A549) with SARS-CoV-2 (page 3, para. 1; Figure 2a; page 8, last para.). Blanco-Melo teaches the infection of NHBE cells showed similar transcriptional response to that of A549 cells (page 4, para. 1).
Regarding claim 7, Blanco-Melo teaches analyzing the cells for ACE2 and TMPRSS2 as they are the putative receptor and protease, respectively, for SARS-CoV-2 entry (page 3, para. 1; page 6, para. 3).
Blanco-Melo teaches one of the greatest threats to humanity is the emergence of a pandemic virus and those with the greatest potential for such an event include influenza viruses and coronaviruses (page 1, para. 1). Blanco-Melo teaches SARS-CoV-2 is the causative agent of the ongoing COVID-19 pandemic and it is important to understand the host response to this virus as this may guide the efforts in development towards novel therapeutics (page 1, para. 1). Blanco-Melo teaches the current pandemic of COVID-19 represents an acute and rapidly developing global health crisis (page 2, para. 2). Blanco-Melo teaches the physiological basis for the morbidity of SARS-CoV-2 in older populations is believed to be the selective death of Type II pneumocytes that results in both loss of air exchange and fluid leakage into the lungs (page 6, last para.).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Tan regarding a culture composition comprising human lung proximal airway epithelial cells and distal airway epithelial cells that can be used for disease modeling with the teachings of Zhou regarding dissociating 3D airway organoids into 2D and infecting the cells with influenza virus to assessing the infectivity of emerging viruses in humans with the teachings of Blanco-Melo regarding infecting proximal and distal airway epithelial cells with SARS-CoV-2 to arrive at the claimed method wherein the respiratory pathogen is SARS-CoV-2, such that infecting the culture composition creates a lung model of COVID-19 disease. One would have been motivated to combine the teachings of Tan, Zhou, and Blanco-Melo in an in vitro method of modeling COVID-19 in human lungs as Tan teaches a potential benefit of the de novo generation of complex three-dimensional lung-like tissues in culture is disease modeling and Zhou teaches there is no robust in vitro model for assessing the infectivity of emerging viruses in humans and Zhou teaches a biologically relevant, reproducible, and readily available in vitro model remains urgently needed for studying the biology and pathology of the human respiratory tract and Blanco-Melo teaches one of the greatest threats to humanity is the emergence of a pandemic virus and those with the greatest potential for such an event include influenza viruses and coronaviruses and Blanco-Melo teaches SARS-CoV-2 is the causative agent of the ongoing COVID-19 pandemic and it is important to understand the host response to this virus as this may guide the efforts in development towards novel therapeutics. One would have a reasonable expectation of success in combining the teachings as Tan teaches the airway organoids are derived from NHBE that can be used to model disease and comprise both distal and proximal airway cells and Zhou teaches the airway organoids can be infected with influenza virus where the virus propagates and Blanco-Melo teaches NHBE and distal airway cells can be infected with SARS-CoV-2.
22. Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tan (Tan, Qi, et al. Biomaterials 113 (2017): 118-132.), hereinafter Tan in view of Zhou (Zhou, Jie, et al. Proceedings of the National Academy of Sciences 115.26 (2018): 6822-6827.), hereinafter Zhou as applied to claims 1 – 5, 8, and 9 above, and further in view of Nikolic (Nikolić, Marko Z., et al. elife 6 (2017): e26575.), hereinafter Nikolic in view of VanNussen (VanDussen, Kelli L., et. al. Stem cell research 37 (2019): 101430.), hereinafter VanNussen.
Tan in view of Zhou do not teach culturing the airway organoids in a conditioned media from L-WRN cells which express Wnt3, R-spondin and Noggin of claim 10. Tan teaches the airway organoids are prepared from adult lung cells (page 119, left col. para. 4) and Zhou teaches the airway organoids are prepared from adult stem cells (page 6823, left col. para. 2; page 6826, left col. last para.).
Regarding “R-spondin” and “Noggin”, Nikolic teaches a method of culturing human lung epithelial tips in the presence of Noggin and R-spondin to form organoids (page 9, para. 1). Nikolic does not teach “Wnt3” but does teach culturing with the Wnt signaling pathway activator CHIR99021 in addition to Noggin and R-spondin (page 9, para. 1; Figure 4; page 20, para. 2; page 11, para. 3). Nikolic teaches activation of EGF, FGF and Wnt signaling and inhibition of BMP and TGFβ are sufficient to grow human epithelial tips as long-term, self-renewing organoids with an initial colony forming efficiency of 100% (page 9, para. 1). Nikolic teaches the human tip organoids can be directed to differentiate towards alveolar or bronchiolar fate in vitro (page 2, last para.; page 14, para. 3 – 5; page 16, para. 1). Nikolic teaches these findings provide a useful guide to allow scientists to coax human cells growing in a laboratory to become lung cells (page 3, para. 5). Nikolic teaches further improvements to this process will make the lungs-in-a-dish more true to the real organs, meaning that they could be used to better understand lung disease and identify new medicines (page 3, para. 5). Nikolic teaches improved in vitro models of human disease are needed to complement available mouse models (page 2, para. 7). Nikolic teaches human organoids are typically derived from adult stem cells limiting their use for studying pediatric disease and disease progression (page 2, para. 7). Nikolic teaches the ability to in vitro self-renew and differentiate bona fide human lung tip progenitors could provide a genetic system for pediatric disease modeling (page 2, para. 7). Nikolic does not teach “conditioned media from L-WRN cells”. One would have been motivated to combine the teachings of Tan, Zhou, and Nikolic and substitute the adult cells for preparing airway organoids of Tan and Zhou with the lung tip cells of Nikolic to model pediatric disease as Nikolic teaches human organoids are typically derived from adult stem cells limiting their use for studying pediatric disease and disease progression and Nikolic teaches the ability to in vitro self-renew and differentiate bona fide human lung tip progenitors could provide a genetic system for pediatric disease modeling.
Regarding “conditioned media from L-WRN cells” and “Wnt3”, VanDussen teaches L-WRN conditioned media is produced from an L cell line engineered to secrete Wnt3a, R spondin, and Noggin into a single conditioned media (CM) (Abstract; page 2, last para.). VanDussen teaches L-WRN CM is a specialized biological reagent used to culture epithelial cells from multiple endodermal tissues and is used to culture stem cells to produce human intestinal organoids (page 2, para. 1 and 3; page 3, left col. para. 2). VanDussen teaches CM derived from engineered cells often facilitates the cost-effective culture of a variety of stem cells (Abstract). VanDussen teaches growing emphasis on the importance of rigor and reproducibility in lab-based science requires development of best practices approaches, including quality control procedures for the assessment of CM batches to ensure reliable interpretation and reproducibility (Abstract; page 2, left col. para. 2). VanDussen teaches L-WRN CM is highly reproducible over time and between laboratories and teaches guidelines for L-WRN CM quality control testing, which will benefit experiment replication efforts in stem cell research (Abstract; page 2, right col. para. 2). VanDussen teaches implementation of robust quality control measures will reduce resource waste and improve the reproducibility of in vitro culture experiments across the scientific community (page 10, right col. para. 3). VanDussen teaches L-WRN CM will enable faithful reproduction of spheroid culture experiments over time and between laboratory groups (page 2, right col. para. 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Tan regarding a culture composition comprising human lung proximal airway epithelial cells and distal airway epithelial cells that can be used for disease modeling with the teachings of Zhou regarding dissociating 3D airway organoids into 2D and infecting the cells with influenza virus to assessing the infectivity of emerging viruses in humans with the teachings of Nikolic regarding a method of culturing human lung epithelial tips in the presence of Noggin and R-spondin, and the Wnt signaling pathway activator CHIR99021 to form with the teachings of VanDuessen regarding conditioned media from L-WRN cells express R-spondin, Wnt3, and Noggin to arrive at the claimed method wherein the culture is grown in a conditioned media from L-WRN cells which express Wnt3, R-spondin and Noggin. One would have been motivated to combine the teachings of Tan, Zhou, Nikolic, and VanDussen in an in vitro reproducible and cost-effective method of modeling human pediatric lung disease due to respiratory pathogens as Tan teaches a potential benefit of the de novo generation of complex three-dimensional lung-like tissues in culture is disease modeling and Zhou teaches there is no robust in vitro model for assessing the infectivity of emerging viruses in humans and Zhou teaches a biologically relevant, reproducible, and readily available in vitro model remains urgently needed for studying the biology and pathology of the human respiratory tract and Nikolic teaches human organoids are typically derived from adult stem cells limiting their use for studying pediatric disease and disease progression and Nikolic teaches the ability to in vitro self-renew and differentiate bona fide human lung tip progenitors could provide a genetic system for pediatric disease modeling and VanDussen teaches CM derived from engineered cells often facilitates the cost-effective culture of a variety of stem cells. One would have a reasonable expectation of success in combining the teachings as Nikolic teaches the human tip organoids can be directed to differentiate towards alveolar or bronchiolar fate in vitro and Zhou teaches the airway organoids can be infected with influenza virus where the virus propagates and Nikolic teaches activation of EGF, FGF and Wnt signaling and inhibition of BMP and TGFβ are sufficient to grow human epithelial tips as long-term, self-renewing organoids with an initial colony forming efficiency of 100% and VanDussen teaches L-WRN CM is a specialized biological reagent used to culture epithelial cells from multiple endodermal tissues and is used to culture stem cells to produce human intestinal organoids and VanDussen teaches L-WRN CM will enable faithful reproduction of spheroid culture experiments over time and between laboratory groups.
Conclusion
No claims allowed.
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/ZANNA MARIA BEHARRY/Examiner, Art Unit 1632
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