Patent Application 17353049 - COMPOSITIONS AND METHODS FOR AIRWAY TISSUE - Rejection

Patent Application 17353049 - COMPOSITIONS AND METHODS FOR AIRWAY TISSUE

Title: COMPOSITIONS AND METHODS FOR AIRWAY TISSUE REGENERATION

Application Information

• Invention Title: COMPOSITIONS AND METHODS FOR AIRWAY TISSUE REGENERATION
• Application Number: 17353049
• Submission Date: 2025-05-19T00:00:00.000Z
• Effective Filing Date: 2021-06-21T00:00:00.000Z
• Filing Date: 2021-06-21T00:00:00.000Z
• National Class: 424
• National Sub-Class: 093700
• Examiner Employee Number: 98210
• Art Unit: 1632
• Tech Center: 1600

Rejection Summary

• 102 Rejections: 0
• 103 Rejections: 3

Cited Patents

No patents were cited in this rejection.

Office Action Text

    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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection.  Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.  Applicant's submission filed on 03/06/2025 has been entered.
Claim Status
1. 	The Amendment filed 03/06/2025 has been entered.  Claims 1 – 3, 12 – 14, 17 – 19, and 42 remain pending.  Claims 4 and 61 have been canceled.  Claim 61 has been incorporated into claim 1. 
Election/Restrictions
2. 	Applicant’s election without traverse of Group I (claims 1 – 4, 9, 12 – 14, and 17 – 19) in the reply filed on 06/05/2024 is acknowledged.
3. 	Claims 20 – 24, 27 – 35, 39, and 42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/05/2024.  
Priority
4. 	This application is a continuation of International Application No. PCT/US2019/067486 filed December 19, 2019, which claims priority to U.S. Provisional Application No. 62/784,125, filed December 21, 2018.
Claims Under Consideration
5. 	Claims 1 – 3, 12 – 14, and 17 – 19 are under consideration.
Withdrawn Claim Rejections

6. 	The rejection of claims 1 – 3, 12 – 14, 17, and 18 under 35 U.S.C. 103 as being unpatentable over Ott (US-20170326273-A1, Filed 5/15/2017, Published 11/16/2017; previously cited), hereinafter Ott which is cited on the IDS filed 06/21/2021, in view of Schwank (Schwank, Gerald, et al. Cell stem cell 13.6 (2013): 653-658), hereinafter Schwank, which is cited on the IDS filed 06/05/2024 is withdrawn in view of Applicant’s amendment to claim 1.
7. 	The rejection of claim 61 under 35 U.S.C. 103 as being unpatentable over Ott (US-20170326273-A1, Filed 5/15/2017, Published 11/16/2017; previously cited), hereinafter Ott which is cited on the IDS filed 06/21/2021, in view of Schwank (Schwank, Gerald, et al. Cell stem cell 13.6 (2013): 653-658), hereinafter Schwank, which is cited on the IDS filed 06/05/2024 is rendered moot by Applicant’s cancellation of the claim.
8. 	The rejection of claim 4 under 35 U.S.C. 103 as being unpatentable over Ott (US-20170326273-A1, Filed 5/15/2017, Published 11/16/2017; previously cited), hereinafter Ott which is cited on the IDS filed 06/21/2021, in view of Schwank (Schwank, Gerald, et al. Cell stem cell 13.6 (2013): 653-658), hereinafter Schwank, which is cited on the IDS filed 06/05/2024 as applied to claims 1 – 3, 12 – 14, 17, 18, and 61  above, and further in view of Wang (Wang DY, et. al. Curr Allergy Asthma Rep. 2015 Jan;15(1):490; previously cited), hereinafter Wang, which is cited on the IDS filed 06/21/2021 is rendered moot by Applicant’s cancellation of the claim.
9. 	The rejection of claim 19 under 35 U.S.C. 103 as being unpatentable over Ott (US-20170326273-A1, Filed 5/15/2017, Published 11/16/2017; previously cited), hereinafter Ott which is cited on the IDS filed 06/21/2021, in view of Schwank (Schwank, Gerald, et al. Cell stem cell 13.6 (2013): 653-658), hereinafter Schwank, which is cited on the IDS filed 06/05/2024 as applied to claims 1 – 3, 12 – 14, 17, 18, and 61  above, and further in view of Gubbels (Gubbels, Samuel P., et al. Otolaryngology—Head and Neck Surgery 134.6 (2006): 1028-1035.), hereinafter Gubbels is withdrawn in view of Applicant’s amendment to the claims.

New Rejections 
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.


10. 	Claims 1, 3, 12, and 14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to naturally occurring gene edited sinus basal stem cells expressing Krt5 embedded in a bioscaffold without significantly more. The claim(s) recite(s) gene edited sinus basal stem cell expressing Krt5 embedded in a bioscaffold which are not shown to differ from that in nature. 
The Office published Office's new guidance document entitled 2019 Revised Patent Subject Matter Eligibility Guidance, published January 7, 2019. Applicant is directed to the Federal Register, Volume 4, No. 4, pages 50-57 at page 74621.

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	Step 1 of the USPTO' s eligibility analysis entails considering whether the claimed subject matter falls within the four statutory categories of patentable subject matter identified by 35 U.S.C. 101: Process, machine, manufacture, or composition of matter. The claims are directed to a composition of matter (step 1, Yes). 
	
	Step 2A of the 2019 Revised Patent Subject Matter Eligibility Guidance is a two-prong inquiry. In Step 2A Prong One, examiners evaluate whether the claim recites a judicial exception. The composition of matter (gene edited sinus basal stem cell expressing Krt5 embedded in a bioscaffold) is directed to a natural phenomenon (Step 2A, prong 1, Yes).  Because the claims recite a nature-based product limitation (gene edited sinus basal stem cell expressing Krt5 embedded in a bioscaffold), the markedly different characteristics analysis is used to determine if the nature-based product limitation is a product of nature exception.  The claims recite “gene edited”, which is defined as “an airway stem cell that is genetically edited or altered by nuclease-mediated genome editing” “such that a heterologous nucleic acid has been introduced” (page 10, 0063).  The broadest reasonable interpretation of this limitation includes naturally occurring gene editing processes that result in mutations to genes in sinus basal stem cells expressing Krt5.  For example, Faa (Faà V, et. al. J Mol Diagn. 2006 Sep;8(4):499-503) teaches cystic fibrosis patients where their CFTR gene has mutations comprising an insertion of 182 base pairs (Figure 2; page 501, right col. last paragraph; page 502, left col. paragraph 3).   Faa teaches a mechanism responsible for this mutation may involve endonuclease cleavage and integration of the inserted sequence (page 502, left col. paragraph 3).  Faa teaches patients with this naturally occurring CFTR mutant are affected by a classical form of cystic fibrosis (page 500, left col. paragraph 3).  Regarding gene edited sinus basal stem cell, Bravo (Bravo, Dawn T., et al. International Forum of Allergy & Rhinology. Vol. 3. No. 10. 2013) teaches in upper airway diseases such as cystic fibrosis, self-renewing progenitor cells may be functionally defective, or compromised in their ability, to regenerate cells that maintain normal mucociliary clearance and a genetic defect in the CFTR gene leads to defective nasal mucosal epithelial barrier, mucostasis, and secondary infections (Abstract; page 841, right col. last paragraph; page 842, left col. paragraph 1).  Regarding gene edited sinus basal stem cell that expresses Krt5, Wagner (Wagner, Darcy E., et al.  Annals of the American Thoracic Society 13.8 (2016): S259-S278) teaches Krt5 expressing sinus basal stem cells isolated from humans (page S267, left col. last paragraph).  Therefore, the claimed gene edited sinus basal stem cell expressing Krt5 is a product of nature exception and recites a judicial exception.  Regarding embedded in a bioscaffold, the specification discloses that “a bioscaffold refers to a substrate or matrix on which cells can grow and may be derived from or made from natural or synthetic tissues or cells or other natural or synthetic materials” (page 21, 0101).  Thus, “bioscaffold” encompasses isolated Krt5 expressing sinus basal stem cells in epithelium from turbinates as evidenced by Ruysseveldt (page 632, right col. paragraph 1; page 633, right col. paragraph 1 – 3; page 634, left col. paragraph 4 and right col. last paragraph; Figure 1).  Therefore, the claimed gene edited sinus basal stem cell expressing Krt5 embedded in a bioscaffold isolated from a subject is a product of nature exception and recites a judicial exception.   
	In Step 2A Prong Two, examiners evaluate whether the claim recites additional elements that integrate the exception into a practical application of that exception.  This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application.  No additional elements are recited in claim 1 or 3 and therefore the claims do not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception.  Claim 12 recites “to correct an amino acid mutation at position 508 of a mutated CFTR protein”.  The broadest reasonable interpretation of this limitation includes natural correction through DNA repair mechanisms to encompass sinus basal stem cells expressing Krt5 and a CFTR with a wild type sequence.  Claim 14 recites “wherein the composition further comprises airway ciliated cells and/or airway mucus producing cells”.  The broadest reasonable interpretation of this limitation includes isolated Krt5 expressing sinus basal stem cells in epithelium from turbinates as evidenced by Ruysseveldt (page 632, right col. paragraph 1; page 633, right col. paragraph 1 – 3; page 634, left col. paragraph 4 and right col. last paragraph; Figure 1).  Accordingly, the additional elements do not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception (Step 2A, prong 2, No). 
	
	In Step 2B, the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements adds an inventive concept into the claim.  As discussed with respect to Step 2A Prong Two, the additional recited elements are at best the equivalent of merely adding the words “apply it” to the judicial exception.  Mere instructions to apply an exception cannot provide an inventive concept.  At Step 2B, the evaluation of the insignificant extra-solution activity consideration takes into account whether or not the extra-solution activity is well-known.  Here, recitation of “gene edited” is recited at a high level of generality to include naturally occurring gene editing processes.  Thus, the additional recited elements do not amount to significantly more and do not provide an inventive concept (Step 2B: No).  
	Markedly different characteristics can be expressed as the product' s structure, function, and/or other properties. In accordance with this analysis, a product that is purified or isolated, for example, will be eligible when there is a resultant change in characteristics sufficient to show a marked difference from the product' s naturally occurring counterpart. If the claim recites a nature-based product limitation that does not exhibit markedly different characteristics, the claim is directed to a ‘‘product of nature”  exception (a law of nature or naturally occurring phenomenon), and the claim will require further analysis to determine eligibility based on whether additional elements add significantly more to the exception. 
	Limitations that were found not to be enough to qualify as ‘‘significantly more”  when recited in a claim with a judicial exception include: Adding the words ‘‘apply it”  (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer; simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, e.g., a claim to an abstract idea requiring no more than a generic computer to perform generic computer functions that are well-understood, routine and conventional activities previously known to the industry; adding insignificant extrasolution activity to the judicial exception, e.g., mere data gathering in conjunction with a law of nature or abstract idea; or generally linking the use of the judicial exception to a particular technological environment or field of use.  
	In the instant case, the limitations of the claims do not impose limits on the claim scope such that they are not markedly different in structure from a naturally occurring product.


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.

11. 	Claim(s) 1 – 3, 12, 14, 17, and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wagner (Wagner, Darcy E., et al.  Annals of the American Thoracic Society 13.8 (2016): S259-S278.), hereinafter Wagner as evidenced by and in view of Bravo (Bravo, Dawn T., et al. International Forum of Allergy & Rhinology. Vol. 3. No. 10. 2013.), hereinafter Bravo in view of Ott (US-20170326273-A1, Filed 5/15/2017, Published 11/16/2017; previously cited), hereinafter Ott which is cited on the IDS filed 06/21/2021 in view of Suzuki (Suzuki, Shingo, et al. Molecular therapy Nucleic acids 5 (2016).), hereinafter Suzuki.  
	Regarding claim 1, Wagner teaches Krt5 expressing sinus basal stem cells isolated from humans (“expresses Krt5” and “is a sinus basal stem cell isolated from a subject”) (page S267, left col. last paragraph) as evidenced by Bravo (Abstract; page 842, left col. last paragraph; page 844, right col. paragraph 2).  Wagner does not teach “bioscaffold”, “embedded in the bioscaffold” or “gene edited” of claim 1 or claims 2, 3, 12, 14, 17, and 18.  However, Wagner teaches the cells completely regenerated the upper airway epithelium and formed nasospheres (page S267, middle col. paragraph 1).  
	Bravo teaches sinus tissues were not harvested from patients with severe sinus disease such as cystic fibrosis (page 842, left col. last paragraph).  Bravo teaches in several upper airway diseases such as cystic fibrosis, self-renewing progenitor cells may be functionally defective, or compromised in their ability, to regenerate cells that maintain normal mucociliary clearance (Abstract; page 841, right col. last paragraph).  Bravo teaches a genetic defect in the CFTR chloride transport gene leads to defective nasal mucosal epithelial barrier, mucostasis, and secondary infections (page 842, left col. paragraph 1).  Bravo teaches upon in vitro culture, clonal cells were confirmed to spontaneously differentiate into epithelial cells (Abstract; page 847, left col. paragraph 1).  Bravo teaches it is valuable to understand the cellular and molecular players responsible for the restoration for the restoration of upper airway respiratory mucosa and whether these components may be dysregulated in upper airway disorders (page 842, left col. paragraph 1).  Bravo teaches use of promising progenitor cell pools may be of clinical significance to better understand the cellular contributors involved in regeneration of the epithelial barrier in inflammatory disease of the upper airway respiratory tract (page 847, right col. paragraph 1).  Bravo teaches upper airway epithelial progenitor cells may hold promise for future functional regenerative therapies of the nasal mucosal epithelium (page 847, right col. paragraph 2).  Bravo does not teach “bioscaffold”, “embedded in the bioscaffold” or “gene edited” of claim 1 or claims 2, 3, 12, 14, 17, and 18.    
	Regarding “bioscaffold” and “embedded in a bioscaffold” of claim 1 and claims 2, 14, 17, and 18, Ott teaches a composition of isolated basal epithelial stem cells from a donor in decellularized rat lung scaffolds (“bioscaffold” and “embedded in the bioscaffold” of claim 1; claim 2; “lung tissue” of claim 17, and claim 18) where the cells express Krt5 and comprises ciliated cells as determined by expression of acetylated α tubulin expression (claim 14) (page 2, 0025; Figure 2A; page 16, 0101; page 17, 0115 and 0119; page 18, 0133). 
Ott does not teach “gene edited” of claim 1 or claims 3 and 12.  However, Ott teaches use of the composition to restore some lung function in patients with impaired or reduced lung capacity such as those with cystic fibrosis (page 15, 0093).  Ott teaches lung transplants represent a final hope for many patients with cystic fibrosis, however, the wait time for lung transplant results in a 30% mortality rate (page 1, 0004).  Ott teaches the development of techniques to engineer organs for transplantation may ultimately provide a solution for end-stage organ failure without the risk of rejection (page 1, 0004).   
Regarding “gene edited” of claim 1 and claims 3 and 12, Suzuki teaches correcting the F508del mutation (claim 3 and 12) in airway epithelial cell-derived cystic fibrosis iPSCs with small/short DNA fragments and sequence-specific TALENS (“gene edited” of claim 1) (Abstract; page 2, left col. last paragraph – right col. paragraph 1; Figure 2).  Suzuki teaches the TALEN strategy shows no apparent off-target events and appears to be seamless in the sense that there are no other alterations in the targeted region (page 6, right col. paragraph 3).  Suzuki teaches that corrected cystic fibrosis (CF) stem cells can be differentiated into ciliated airway epithelial-like cells that showed wild-type CFTR functional activity and thus usefulness in cell therapy for CF (page 3, left col. paragraph 3; page 6, left col. paragraph 1 – 2; page 8, left col. paragraph 2).  Suzuki teaches the F508del mutation is found in ~70% of all CF alleles (page 1, left col. paragraph 1).  Suzuki teaches since CF-associated pathologies result in extensive tissue damage, treatment of CF will require a comprehensive strategy that both corrects the underlying genetic defect and repairs/regenerates damaged tissues (page 1, left col. paragraph 1).  Suzuki teaches reprogramming of patient-specific stem cells have the potential of generating transplantable, autologous cells/tissues that circumvent rejection by the host immune response, enhancing the potential for successful engraftment and tissue repair and avoiding the need for immunosuppressive drugs (page 1, right col. paragraph 1).  Suzuki teaches further refinement of cell differentiation protocols should be able to produce cells that will successfully rebuild damaged airways (page 1, right col. paragraph 1).  Suzuki teaches restoration of the wild-type CFTR function in the repaired tissues will be critical in ameliorating the dysfunction associated with the CFTR mutation (page 1, right col. paragraph 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 Wagner regarding Krt5 expressing sinus basal stem cells isolated from humans with the teachings of Bravo regarding the sinus basal stem cells spontaneously differentiate into epithelial cells with the teachings of Ott regarding a composition of basal stem cells isolated from a subject embedded in a decellularized rat lung scaffold with the teachings of Suzuki regarding gene editing stem cells to correct the F508del mutation to arrive at the claimed composition comprising gene edited sinus basal stem cells isolated from a subject that express Krt5 wherein the cells are embedded in a bioscaffold.  One would have been motivated to combine the teachings of Wagner, Bravo, Ott, and Suzuki to develop therapies for cystic fibrosis as Bravo teaches upper airway epithelial progenitor cells may hold promise for future functional regenerative therapies of the nasal mucosal epithelium and Ott teaches the wait time for a lung transplant for cystic fibrosis patients results in a 30% mortality rate and Suzuki teaches since CF-associated pathologies result in extensive tissue damage, treatment of CF will require a comprehensive strategy that both corrects the underlying genetic defect and repairs/regenerates damaged tissues and Suzuki teaches reprogramming of patient-specific stem cells have the potential of generating transplantable, autologous cells/tissues that circumvent rejection by the host immune response, enhancing the potential for successful engraftment and tissue repair and avoiding the need for immunosuppressive drugs.  One would have a reasonable expectation of success in combining the teachings as Wagner teaches the sinus basal stem cells completely regenerated the upper airway epithelium Ott teaches use of the composition to restore some lung function in patients with CF and Suzuki teaches that corrected CF stem cells can be differentiated into airway epithelial-like cells that showed wild-type CFTR functional activity and thus usefulness in cell therapy for CF.  

12. 	Claim(s) 1 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wagner (Wagner, Darcy E., et al.  Annals of the American Thoracic Society 13.8 (2016): S259-S278.), hereinafter Wagner as evidenced by and in view of Bravo (Bravo, Dawn T., et al. International Forum of Allergy & Rhinology. Vol. 3. No. 10. 2013.), hereinafter Bravo in view of Ott (US-20170326273-A1, Filed 5/15/2017, Published 11/16/2017; previously cited), hereinafter Ott which is cited on the IDS filed 06/21/2021 in view of Suzuki (Suzuki, Shingo, et al. Molecular therapy Nucleic acids 5 (2016).), hereinafter Suzuki in view of Schwank (Schwank, Gerald, et al. Cell stem cell 13.6 (2013): 653-658; previously cited), hereinafter Schwank, which is cited on the IDS filed 06/05/2024 as evidenced by Janda (Janda, Claudia Y., et al. Nature 545.7653 (2017): 234-237.), hereinafter Janda.   
	Wagner in view of Bravo, Ott, and Suzuki make obvious the limitations of claim 1 as set forth above.  Suzuki teaches TALENS and CRISPR/Cas9 nuclease mediate DNA double strand breaks by enhancing the efficiency of homologous recombination between donor plasmid DNA and a genomic target (page 2, left col. paragraph 1) but does not teach gene editing using CRISPR/Cas of claim 13.  However, Suzuki teaches a study that corrected the F508del CFTR mutation using CRISPR/Cas9 to facilitate homologous recombination in CF adult intestinal stem cells (page 6, right col. paragraph 3).     
Schwank teaches CRISPR/Cas gene editing to correct deletion of position 508 in the CFTR protein CRISPR/Cas in intestinal stem cells (page 655, right col. paragraph 2; Figure 1E; page 657, left col. paragraph 3; Figure 2G).  Schwank teaches the corrected F508 del allele was fully functional and was able to rescue the CFTR phenotype in organoids (page 657, left col. paragraph 2).  Intestinal organoids represent a model for personalized CF drug screening as evidenced by Janda (page 236, left col. paragraph 1).  Schwank teaches the gene editing method provides a potential strategy for future gene therapy in patients and that the advantage of combining gene correction strategies with organoid culture technology rests in the possibility of clonal expansion of single adult patient stem cells and the selection of recombinant clonal organoid cultures harboring the desired, exact genetic change (page 657, left col. last paragraph).
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 Suzuki regarding TALENS and CRISPR/Cas9 nuclease mediate DNA double strand breaks by enhancing the efficiency of homologous recombination between donor plasmid DNA and a genomic target with the teachings of Schwank regarding CRISPR/Cas gene edited cells to arrive at the claimed composition comprising CRISPR/Cas gene edited sinus basal stem cells isolated from a subject that express Krt5 wherein the cells are embedded in a bioscaffold.  One would have been motivated to combine the teachings of Suzuki and Schwank for therapeutic compositions for cystic fibrosis as Suzuki teaches reprogramming of patient-specific stem cells have the potential of generating transplantable, autologous cells/tissues that circumvent rejection by the host immune response, enhancing the potential for successful engraftment and tissue repair and avoiding the need for immunosuppressive drugs and Schwank teaches the gene editing method provides a potential strategy for future gene therapy in patients.  One would have a reasonable expectation of success in combining the teachings as Schwank teaches the CRISPR/Cas corrected F508 del allele was fully functional and was able to rescue the CFTR phenotype.  

13. 	Claim(s) 1, 18, and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wagner (Wagner, Darcy E., et al.  Annals of the American Thoracic Society 13.8 (2016): S259-S278.), hereinafter Wagner as evidenced by and in view of Bravo (Bravo, Dawn T., et al. International Forum of Allergy & Rhinology. Vol. 3. No. 10. 2013.), hereinafter Bravo in view of Ott (US-20170326273-A1, Filed 5/15/2017, Published 11/16/2017; previously cited), hereinafter Ott which is cited on the IDS filed 06/21/2021 in view of Suzuki (Suzuki, Shingo, et al. Molecular therapy Nucleic acids 5 (2016).), hereinafter Suzuki in view of in view of Gubbels (Gubbels, Samuel P., et al. Otolaryngology—Head and Neck Surgery 134.6 (2006): 1028-1035.), hereinafter Gubbels.
Wagner in view of Bravo, Ott, and Suzuki make obvious the limitations of claim 1 and 18 as set forth above but do not teach claim 19.  However, Ott teaches isolated basal cells can recapitulate a fully differentiated airway epithelium when seeded onto denuded mouse tracheas and in response to injury, they can rapidly proliferate confirming their important function in injury repair (page 5, 0044).  Ott teaches solid organ bioengineering based on native ECM scaffolds has fueled regenerative medicine approaches to end organ failure (page 4, 0042).  Ott teaches combining regenerative cell populations with corresponding biological matrices to form living, functional grafts and ECM scaffolds can be readily generated (page 4, 0042).    
	Gubbels teaches tracheal reconstruction using porcine small intestine submucosa (SIS) (Abstract).  Gubbels teaches most of the subjects that underwent reconstruction of a tracheal defect using SIS were clinically normal (page 1034, left col. paragraph 2).  Gubbels teaches SIS possesses many qualities desirable in a tracheal stent including complete graft integration with robust respiratory mucosa (page 1034, right col. paragraph 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 Ott regarding a composition of basal stem cells isolated from a subject embedded in a decellularized rat lung scaffold with the teachings of Gubbels regarding pSIS to reconstruct the trachea to arrive at the claimed composition where the decellularized ECM membrane is pSIS.  One would have been motivated to combine the teachings of Ott and Gubbels for therapeutic compositions for cystic fibrosis as Ott teaches solid organ bioengineering based on ECM scaffolds has fueled regenerative medicine approaches and Gubbels teaches SIS possesses many qualities desirable in a tracheal stent including complete graft integration with robust respiratory mucosa.  One would have a reasonable expectation of success in combining the teachings as Ott teaches use of the composition to restore some lung function in patients with CF and Gubbels teaches most of the subjects that underwent reconstruction of a tracheal defect using SIS were clinically normal.
	 
Applicant’s Arguments/ Response to Arguments
14. 	Applicant Argues:  On page 4, Applicant argues Ott and Schwank do not teach “sinus basal stem cell”.  On page 5, last paragraph and page 6, paragraph 1, Applicant asserts Ott and Schwank fail to disclose all of the limitations of currently amended claim 1 and claim 19 is not obvious over Ott and Schwank.     
	Response to Arguments:  The previous rejection of claim 1 has been withdrawn and new rejections are set forth above which teaches a Krt5 expressing sinus basal stem cell isolated from humans as taught by Wagner (page S267, left col. last paragraph) and evidenced by Bravo (Abstract; page 842, left col. last paragraph; page 844, right col. paragraph 2).        

Applicant Argues:  On page 5, paragraph 2, Applicant argues there is no motivation to combine the teachings of Ott and Schwank to arrive at the present invention and Ott relates to engineering airway stem cells whereas Schwank relates to engineering intestinal stem cells to correct a gene mutation.  Applicant argues a person of ordinary skill in the art would not be motivated to combine the teachings of Ott and Schwank     
	Response to Arguments:  This is not found persuasive because Janda teaches intestinal organoids represent a model for personalized cystic fibrosis (CF) drug screening (page 236, left col. paragraph 1).  Additionally, Dekkers (Dekkers, Johanna F., et al. Nature medicine 19.7 (2013): 939-945.) teaches cystic fibrosis is caused by mutations in CFTR where it functions in the lung and intestine (Abstract; page 939, left col. paragraph 1).  Dekkers teaches intestinal culture for assaying CFTR function that will facilitate diagnosis, functional studies, drug development and personalized medicine in cystic fibrosis (page 939, right col. last paragraph; page 940, left col. paragraph 1; page 944, left col. paragraph 4 – 5; and right col. paragraph 5).  Further, in the new rejection set forth above, Suzuki teaches TALENS and CRISPR/Cas9 nuclease mediate DNA double strand breaks by enhancing the efficiency of homologous recombination between donor plasmid DNA and a genomic target (page 2, left col. paragraph 1) and Suzuki teaches a study that corrected the F508del CFTR mutation using CRISPR/Cas9 to facilitate homologous recombination in CF adult intestinal stem cells (page 6, right col. paragraph 3).  Schwank teaches CRISPR/Cas gene editing to correct deletion of position 508 in the CFTR protein CRISPR/Cas in intestinal stem cells (page 655, right col. paragraph 2; Figure 1E; page 657, left col. paragraph 3; Figure 2G).  Schwank teaches the corrected F508 del allele was fully functional and was able to rescue the CFTR phenotype in organoids (page 657, left col. paragraph 2).  Ott teaches use of the composition to restore some lung function in patients with impaired or reduced lung capacity such as those with cystic fibrosis (page 15, 0093).  Therefore, one would be motivated to combine the teachings of Ott and Schwank to repair the F508del CFTR mutation in CF patients in a therapeutic composition for CF patients.  


Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZANNA M BEHARRY whose telephone number is (571)270-0411. The examiner can normally be reached Monday - Friday 7:30 am - 4:30 pm.
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/Z.M.B./Examiner, Art Unit 1632          

/ANOOP K SINGH/Primary Examiner, Art Unit 1632