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 .
NOTE: The Office Action mailed 04/16/2026 is being withdrawn and replaced with the Office Action below because Applicant’s declaration was mislabeled as “Miscellaneous Incoming Letter”. Therefore, only Applicant’s arguments were considered and the declaration by Dr. Sriram Vaidyanathan was not considered.
Below is a re-issue of the Office Action mailed 04/16/2026 in which the Examiner has considered the declaration by Dr. Sriram Vaidyanathan. An initialed and dated copy of the declaration is included.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/12/2026 has been entered.
Claim Status
1. The amendment filed 02/12/2026 has been entered. Claims 1, 3, 12 – 14, and 42 remain pending.
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 Claims 20 – 24, 27 – 35, 39, and 42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
4. Claims 1, 3, and 12 – 14 are under consideration.
Priority
5. 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.
Maintained Claim Rejections
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.
6. Claim(s) 1, 3, 12, and 14 remain 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; previously cited), hereinafter Wagner as evidenced by Bravo (Bravo, Dawn T., et al. International Forum of Allergy & Rhinology. Vol. 3. No. 10. 2013; previously cited), hereinafter Bravo in view of Cornelissen (Cornelissen, Christian G., et al. Annals of biomedical engineering 40.3 (2012): 679-687; previously cited), hereinafter Cornelissen in view of Suzuki (Suzuki, Shingo, et al. Molecular therapy Nucleic acids 5 (2016); previously cited), hereinafter Suzuki. Although maintained, the rejection is revised in view of the amendment to claim 1.
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 “cultured ex vivo” or “embedded in the bioscaffold wherein the bioscaffold comprises fibrin”, or “gene edited” of claim 1 or the airway stem cell expresses wild type CFTR of claim 3 or gene editing to correct mutation at position 508 of mutant CFTR of claim 12 or the composition further comprises airway ciliated cells and/or airway mucus producing cells of claim 14. However, Wagner teaches the cells completely regenerated the upper airway epithelium and formed nasospheres which is important for tissue regeneration and repair (page S267, middle col. paragraph 1).
Regarding “embedded in the bioscaffold wherein the bioscaffold comprises fibrin” and “ex vivo cultured” of claim 1, Cornelissen teaches fibrin gel as a bioscaffold containing respiratory cells (Abstract; page 682, left col. para. 2 – 3 and right col. Figure 2 – 4). Cornelissen teaches the cells embedded in the fibrin bioscaffold developed a multilayered epithelium with basal and apical cells (page 683, left col. para. 1). Cornelissen teaches expansion of the cells and second passage cells were used with the fibrin gel (page 680, right col. para. 1; page 681, left col. para. 2 – 3 and right col. para. 2). Cornelissen teaches staining with a pan-cytokeratin antibody showed strong staining for basal cells (page 683, last para; Figure 7). Cornelissen teaches the cell-seeding process is also very effective because the cells can be embedded into fibrin glue during the molding process and subsequent cell coating of the surface has also been successfully performed (page 684, left col. para. 1).
Regarding claim 14, Cornelissen teaches after 7 days of culture of goblet cell-like differentiation is observed and ciliation of epithelial cells occurs after 14 days (page 683, left col. para. 1; page 686, left col. para. 1 and 4; page 682, right col. para. 3). Cornelissen teaches ciliary motion started after 16 days of cell culture (page 685, right col. para. 4).
Cornelissen does not teach “gene edited” of claim 1 or the airway stem cell expresses wild type CFTR of claim 3 or gene editing to correct mutation at position 508 of mutant CFTR of claim 12. However, Cornelissen teaches fibrin gel is a biomaterial that can be produced as autologous scaffold material from as few as 50 mL of a patient’s own blood and completely autologous production lowers the possibilities of an inflammatory reaction and disease transmission (page 680, left col. para. 1). Cornelissen teaches fibrin hydrogel is used extensively for tissue engineering as it can be cast into complex geometries and easily produced from the patient’s own blood (page 684, left col. para. 1). Cornelissen teaches respiratory cells proliferation adequately on fibrin gel which is crucial for successful tissue engineering of an airway (page 685, left col. para. 4). Cornelissen teaches finding ways to improve differentiation of respiratory epithelium in vitro will be important for the advance of respiratory tissue engineering (page 686, left col. 3).
Regarding “gene edited” of claim 1 and the airway stem cell expresses wild type CFTR of claim 3 and gene editing to correct mutation at position 508 of mutant CFTR of claim 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 Cornelissen regarding a fibrin bioscaffold for respiratory cells with the teachings of Suzuki regarding gene editing stem cells to correct the F508del mutation to arrive at the claimed composition comprising an airway stem cell and a bioscaffold, wherein the airway stem cell expresses cytokeratin 5 and is embedded in the bioscaffold, wherein the bioscaffold comprises fibrin, and wherein the airway stem cell is a sinus basal stem cell isolated from a subject and is gene edited. One would have been motivated to combine the teachings of Wagner, Cornelissen, and Suzuki in a composition to treat respiratory disorders as 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 Cornelissen teaches respiratory cells proliferation adequately on fibrin gel which is crucial for successful tissue engineering of an airway 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.
7. Claim(s) 13 remains 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; previously cited), hereinafter Wagner as evidenced by Bravo (Bravo, Dawn T., et al. International Forum of Allergy & Rhinology. Vol. 3. No. 10. 2013; previously cited), hereinafter Bravo in view of Cornelissen (Cornelissen, Christian G., et al. Annals of biomedical engineering 40.3 (2012): 679-687; previously cited), hereinafter Cornelissen in view of Suzuki (Suzuki, Shingo, et al. Molecular therapy Nucleic acids 5 (2016); previously cited), hereinafter Suzuki as applied to claims 1, 3, 12, and 14 above, and further 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; previously cited), hereinafter Janda.
Wagner in view of Cornelissen 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 wherein the gene edited airway stem cell is gene edited using a CRISPR nuclease system. 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.
New Rejections
8. Claim(s) 1, 3, 12, and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ott (US-10624992-B2; Filed 05/04/2017; Published 04/21/2020), hereinafter Ott in view of Cornelissen (Cornelissen, Christian G., et al. Annals of biomedical engineering 40.3 (2012): 679-687; previously cited), hereinafter Cornelissen in view of Wagner (Wagner, Darcy E., et al. Annals of the American Thoracic Society 13.8 (2016): S259-S278; previously cited), hereinafter Wagner as evidenced by Bravo (Bravo, Dawn T., et al. International Forum of Allergy & Rhinology. Vol. 3. No. 10. 2013; previously cited), hereinafter Bravo in view of Suzuki (Suzuki, Shingo, et al. Molecular therapy Nucleic acids 5 (2016); previously cited), hereinafter Suzuki.
Regarding claim 1, Ott teaches a composition comprising Krt5+ basal stem cells (“airway stem cell expresses cytokeratin 5”) isolated from donor lung tissue that were expanded ex vivo (“cultured ex vivo”) in decellularized rat lung or intact human lung scaffolds (“bioscaffold” and “embedded in the bioscaffold”) (col. 34, lines 38 – 48; col. 35, lines 9 – 18; Figure 2B and 2C; col. 36, lines 9 – 67; Figure 5). Ott teaches culturing the cells in the bioscaffold for 7 days (col. 35, lines 9 – 11). Ott teaches the airway stem cells were isolated from a subject (col. 34, lines 38 – 39) but does not teach “the airway stem cell is a sinus basal stem cell” or that the sinus basal stem cell is “gene edited” or the “bioscaffold comprises fibrin”.
Regarding claim 14, Ott teaches the composition comprises ciliated cells (col. 35, lines 18 – 25; col. 1, lines 49 – 55).
Ott does not teach “the airway stem cell is a sinus basal stem cell” or that the sinus basal stem cell is “gene edited” or the “bioscaffold comprises fibrin” of claim 1 or the airway stem cell expresses wild type CFTR of claim 3 and gene editing to correct mutation at position 508 of mutant CFTR of claim 12. However, Ott teaches lung transplants represent a final hope for many patients experiencing conditions typified by lung failure such as COPD, cystic fibrosis, pulmonary hypertension, lung cancers, and congenital lung diseases, and typical wait time for a lung transplant can be two years or more, resulting in a 30% mortality rate for those on the waiting list (col. 1, lines 32 – 38). 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 (col. 1, lines 38 – 41). Ott teaches the composition can be used in a method of restoring lung function in patients having diseases that impair or reduce lung capacity such as cystic fibrosis, COPD, emphysema, lung cancer, and others (col. 28, lines 45 – 59). Ott teaches their results demonstrate the regenerative potential and bi-lineage capacity of human airway stem cells, which are useful in whole lung tissue bioengineering and ex vivo organ culture (col. 2, lines 1 – 4). Ott teaches basal epithelial cells characteristically express p63 and Krt5 and Krt14 and function as stem cells for the lung airway during repair (col. 31, lines 44 – 48). Ott teaches basal lung epithelial cells have been classified as multipotent adult tissue stem cells, which have the ability to generate basal, ciliated and Clara cells following injury (col. 31, lines 49 – 53).
Regarding “wherein the bioscaffold comprises fibrin” of claim 1, Cornelissen teaches fibrin gel as a bioscaffold for respiratory cells (Abstract; page 682, left col. para. 2 – 3 and right col. Figure 2 – 4). Cornelissen teaches the cell-seeding process is also very effective because the cells can be embedded into fibrin glue during the molding process and subsequent cell coating of the surface has also been successfully performed (page 684, left col. para. 1). Cornelissen teaches after 7 days of culture of goblet cell-like differentiation is observed and ciliation of epithelial cells occurs after 14 days (page 683, left col. para. 1; page 686, left col. para. 1 and 4; page 682, right col. para. 3). Cornelissen teaches ciliary motion started after 16 days of cell culture (page 685, right col. para. 4). Cornelissen does not teach “the airway stem cell is a sinus basal stem cell” or “gene edited” of claim 1 or the airway stem cell expresses wild type CFTR of claim 3 and gene editing to correct mutation at position 508 of mutant CFTR of claim 12. However, Cornelissen teaches fibrin gel is a biomaterial that can be produced as autologous scaffold material from as few as 50 mL of a patient’s own blood and completely autologous production lowers the possibilities of an inflammatory reaction and disease transmission (page 680, left col. para. 1). Cornelissen teaches fibrin hydrogel is used extensively for tissue engineering as it can be cast into complex geometries and easily produced from the patient’s own blood (page 684, left col. para. 1). Cornelissen teaches respiratory cells proliferation adequately on fibrin gel which is crucial for successful tissue engineering of an airway (page 685, left col. para. 4). Cornelissen teaches finding ways to improve differentiation of respiratory epithelium in vitro will be important for the advance of respiratory tissue engineering (page 686, left col. 3). One would have been motivated to combine the teachings of Ott and Cornelissen to include fibrin in the scaffold of Ott because both teach scaffolds for culturing respiratory cells including ciliated cells for tissue regeneration and Cornelissen teaches cells cultured on the fibrin gel resulted in ciliary motion starting after 16 days of cell culture.
Regarding “the airway stem cell is a sinus basal stem cell” of claim 1, Wagner teaches Krt5 and p63 expressing sinus basal stem cells isolated from humans (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 “gene edited” of claim 1 or the airway stem cell expresses wild type CFTR of claim 3 and gene editing to correct mutation at position 508 of mutant CFTR of claim 12. However, Wagner teaches Dr. Dawn Bravo has translated what has been discovered with regard to lung basal epithelial progenitors to the murine and human nasal epithelium where the nasal epithelium harbors an accessible source of progenitors with potential for cell therapy, the nasal epithelial basal cell (NEBC) that expresses both p63 and Krt5 and is highly proliferative (page S267, left col. para. 3). Wagner teaches the NEBC completely regenerated the upper airway epithelium (page S267, middle col. para. 1). One would have been motivated to combine the teachings of Ott, Cornelissen, and Wagner because Ott and Wagner teach p63 and Krt5 expressing basal stem cells for tissue regeneration and Wagner teaches what has been discovered with lung basal epithelial progenitors translates to murine and human sinus basal stem cells, and because collecting sinus basal stem cells would be less invasive than collecting lung basal stem cells and Ott, Cornelissen, and Wagner teach airway cells for tissue regeneration.
Regarding “gene edited” of claim 1 and the airway stem cell expresses wild type CFTR of claim 3 and gene editing to correct mutation at position 508 of mutant CFTR of claim 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 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 Ott regarding a composition comprising airway stem cells isolated from a subject that express Krt5 that are cultured ex vivo and embedded in a bioscaffold with the teachings of Cornelissen regarding a fibrin gel as a bioscaffold for respiratory cells where the cells differentiate and have ciliary motion with the teachings of Wagner regarding Krt5+ sinus basal stem cells with the teachings of Suzuki regarding gene edited stem cells to correct the F508del mutation in CFTR to arrive at the claimed composition for airway tissue regeneration, comprising an airway stem cell and a bioscaffold, wherein the airway stem cell expresses cytokeratin 5 (Krt5) and is cultured ex vivo and embedded in the bioscaffold, wherein the bioscaffold comprises fibrin, and wherein the airway stem cell is a sinus basal stem cell isolated from a subject and is gene edited. One would have been motivated to combine the teachings of Ott, Cornelissen, Wagner and Suzuki in a composition for treating cystic fibrosis as Ott teaches lung transplants represent a final hope for many patients experiencing conditions typified by lung failure such as COPD, cystic fibrosis, pulmonary hypertension, lung cancers, and congenital lung diseases, and typical wait time for a lung transplant can be two years or more, resulting in a 30% mortality rate for those on the waiting list and Ott teaches organs engineered for transplantation may ultimately provide a solution for end-stage organ failure without the risk of rejection and Cornelissen teaches fibrin gel is a biomaterial that can be produced as autologous scaffold material and completely autologous production lowers the possibilities of an inflammatory reaction and disease transmission and Cornelissen teaches finding ways to improve differentiation of respiratory epithelium in vitro will be important for the advance of respiratory tissue engineering and Suzuki teaches 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 and 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. One would have a reasonable expectation of success in combining the teachings as Ott teaches basal epithelial cells characteristically express p63 and Krt5 and Krt14 and function as stem cells for the lung airway during repair and Cornelissen teaches after 7 days of culture with fibrin goblet cell-like differentiation is observed and ciliation of epithelial cells occurs after 14 days and ciliary motion started after 16 days of cell culture and 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 and 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.
9. Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ott (US-10624992-B2; Filed 05/04/2017; Published 04/21/2020), hereinafter Ott in view of Cornelissen (Cornelissen, Christian G., et al. Annals of biomedical engineering 40.3 (2012): 679-687; previously cited), hereinafter Cornelissen in view of Wagner (Wagner, Darcy E., et al. Annals of the American Thoracic Society 13.8 (2016): S259-S278; previously cited), hereinafter Wagner as evidenced by Bravo (Bravo, Dawn T., et al. International Forum of Allergy & Rhinology. Vol. 3. No. 10. 2013; previously cited), hereinafter Bravo
in view of Suzuki (Suzuki, Shingo, et al. Molecular therapy Nucleic acids 5 (2016); previously cited), hereinafter Suzuki as applied to claims 1, 3, 12, and 14 above, and further 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; previously cited), hereinafter Janda.
Ott in view of Cornelissen, Wagner, 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 Ott regarding a composition comprising airway stem cells isolated from a subject that express Krt5 that are cultured ex vivo and embedded in a bioscaffold with the teachings of Cornelissen regarding a fibrin gel as a bioscaffold for respiratory cells where the cells differentiate and have ciliary motion with the teachings of Wagner regarding Krt5+ sinus basal stem cells with the teachings of Suzuki regarding gene edited stem cells to correct the F508del mutation in CFTR and 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 wherein the gene edited airway stem cell is gene edited using a CRISPR nuclease system. One would have been motivated to combine the teachings Ott, Cornelissen, Wagner, Suzuki and Schwank for therapeutic compositions for treating 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.
Applicant’s Declaration/ Response to Declaration
10. The Declaration under 37 CFR 1.132 filed 02/12/2026 is insufficient to overcome the rejection of claims 1, 3, 12, and 14 based upon the teachings of Cornelissen applied under 35 U.S.C. 103 as set forth in the last Office action because: the facts presented are not germane to the rejection at issue because the claims are drawn to a composition and not a method of engraftment of the composition.
Dr. Vaidyanathan declares that even though Cornelissen demonstrates that airway cells can be cultured in fibrinogen in vitro, there is no teachings that such engraftment would succeed in vivo and that a material that supports cell proliferation in vitro does not guarantee support for in vivo engraftment and multi-lineage differentiation. Dr. Vaidyanathan declares on page 2 (item 5) and page 3 (item 6) and Figure 2A that fibrinogen performed similarly to Matrigel at 60 days post-transplant. Dr. Vaidyanathan declares on page 4 (item 7) that Cornelissen’s teaching of in vitro culturing of airway cells in fibrinogen does not render obvious the in vivo engraftment of airway cells in a fibrin scaffold.
Response: This is not found persuasive because the claims are drawn to a composition and not a method of engraftment. The composition of Cornelissen is a fibrin gel and not Biosilk which Dr. Vaidyanathan’s declaration states generates a rudimentary epithelium in contrast to either fibrinogen or Matrigel. Further, Cornelissen teaches that as no significant differences in respiratory epithelia cells’ proliferation, function, and differentiation could be observed between cells grown on fibrin gel compared to cells on a collagen-coated, microporous surface, we concluded that fibrin gel might prove a suitable scaffold for respiratory tissue engineering and merits further investigation to overcome the limitations associated with scaffolds currently in use (Abstract).
It is noted that recitation of “for airway tissue regeneration” is an intended use of the claimed composition and the claims are not drawn to a method of engraftment. Recitation of “cultured ex vivo” is given the broadest reasonable interpretation to mean that the claimed airway stem cell is isolated from a subject and cultured and not to mean that tissue comprising an airway basal stem cell is cultured. Should Applicant amend claim 1 to further limit the airway basal stem cell and/or provide arguments to address how the expanded cells of Cornelissen in the maintained rejection or the expanded cells of Ott in the new rejection are structurally different from the claimed ex vivo cultured airway stem cell, the rejection may be overcome upon further search and consideration.
Applicant’s Arguments/ Response to Arguments
11. Applicant Argues: On page 5, para. 1, Applicant asserts that neither Wagner nor Bravo teach “embedded in the bioscaffold wherein the bioscaffold comprises fibrin” or “gene edited” of claim 1 and Wagner and Bravo do not teach that the airway stem cell is cultured ex vivo in the bioscaffold. On page 5, para. 2, Applicant asserts that Cornelissen teaches only in vitro proliferation of respiratory cell in a fibrin gel and does not teach that airway stem cells are cultured ex vivo and embedded in the bioscaffold for airway tissue regeneration. On page 6, para. 2, Applicant asserts that none of the cited references alone or in combination teach or suggest all the features of the currently amended claims, specifically that the stem cell is cultured ex vivo and embedded in the bioscaffold. On page 6, para. 5 – 7, Applicant asserts that Schwank and Janda do not teach or suggest that the stem cell is cultured ex vivo and embedded in the bioscaffold.
Response to Arguments: Amended claim 1 recites “wherein the airway stem cell expresses cytokeratin 5 (Krt5) and is cultured ex vivo and embedded in the bioscaffold” and does not recite culturing the airway stem cell ex vivo in the bioscaffold. It is noted that the claims are drawn to a composition and not a method of making the composition. However, Cornelissen teaches after 7 days of culture goblet cell-like differentiation is observed and ciliation of epithelial cells occurs after 14 days (page 683, left col. para. 1; page 686, left col. para. 1 and 4; page 682, right col. para. 3). Cornelissen teaches expansion of the cells and second passage cells were used with the fibrin gel (page 680, right col. para. 1; page 681, left col. para. 2 – 3 and right col. para. 2).
Regarding “embedded in the bioscaffold”, Cornelissen teaches fibrin gel as a bioscaffold containing respiratory cells (Abstract; page 682, left col. para. 2 – 3 and right col. Figure 2 – 4) and Cornelissen teaches the cell-seeding process is also very effective because the cells can be embedded into fibrin glue during the molding process and subsequent cell coating of the surface has also been successfully performed (page 684, left col. para. 1).
Regarding “gene edited”, 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).
A new rejection of the claims is set forth above in which Ott teaches a composition comprising Krt5+ basal stem cells (“airway stem cell expresses cytokeratin 5”) isolated from donor lung tissue that were expanded ex vivo (“cultured ex vivo”) in decellularized rat lung or intact human lung scaffolds (“bioscaffold” and “embedded in the bioscaffold”) (col. 34, lines 38 – 48; col. 35, lines 9 – 18; Figure 2B and 2C; col. 36, lines 9 – 67; Figure 5). Ott teaches culturing the cells in the bioscaffold for 7 days (col. 35, lines 9 – 11).
Applicant Argues: On page 5, paragraph 3 – 5, Applicant asserts a Declaration Dr. Vaidyanathan is provided. Dr. Vaidyanathan asserts that Cornelissen’s teaching of in vitro culturing of airway cells does not render obvious the in vivo engraftment of airway cells in fibrin scaffold and Cornelissen teaches transplantation of decellularized matrices for respiratory tissue engineering, which is fundamentally different from the claimed invention. Dr. Vaidyanathan asserts that the success on in vitro stem cells proliferation within a scaffold does not prove success of in vivo engraftment. Applicant asserts that Cornelissen’s teaching of in vitro culturing is not connected to the claimed invention of ex vivo cultured airway stem cells in a bioscaffold for airway tissue regeneration.
Response to Arguments: In response to Dr. Vaidyanathan’s comments, the claims do not recite “in vivo engraftment of airway cells in fibrin scaffold” and Cornelissen does not teach transplanting decellularized matrices. It is noted that recitation of “for airway tissue regeneration” is an intended use of the claimed composition and the claims are not drawn to a method of engraftment. Recitation of “cultured ex vivo” is given the broadest reasonable interpretation to mean that the claimed airway stem cell is isolated from a subject and cultured and not to mean that tissue comprising an airway basal stem cell is cultured. Should Applicant amend claim 1 to further limit the airway basal stem cell and/or provide arguments to address how the expanded cells of Cornelissen in the maintained rejection or the expanded cells of Ott in the new rejection are structurally different from the claimed ex vivo cultured airway stem cell, the rejection may be overcome upon further search and consideration.
Conclusion
No claims allowed.
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/ZANNA MARIA BEHARRY/Examiner, Art Unit 1632
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