DETAILED ACTION
Notice of Pre-AIA or AIA Status
This Office action details a first action on merits for the above referenced application No. Claims 41-56 are pending in this application. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/13/2024 noted and 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
The drawings were received on 09/13/2024. These drawings are acknowledged.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 41-47, 52, 55 and 56 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kotton et al. (US 10,590,392).
Kotton discloses technology relating to the derivation of functional airway organoids (bronchospheres) from human induced pluripotent stem cells (iPSCs), which can be used in models of lung disease and facilitate precision medicine for monogenic airway disorders, such as cystic fibrosis (Col. 4 line 3-8). Bronchospheres derived from CF patients can be used to assess drugs and corrective mutations for functional restoration of CFTR, where a candidate drug or corrective mutation causes the bronchosphere to swell according to wild-type in the presence of forskolin (Col.5 line 33-38). In one embodiments, the airway epithelial organoids comprise cells that also express at least one of the proximal markers selected from the group consisting of: SCGB3A2+, TP63+, MUC5AC+ and Scgb1a1+, and optionally in some embodiments, the NKX2-1 lung progenitors are NKX2-1+ve, CD47hi and CD26lo (i.e., express high levels of CD47 and low levels of CD26) (Col. 6 line 58+). Another aspect relates to a method of treating cystic fibrosis (CF), comprising: (a) differentiating a population of human iPSC or ESCs into NKX2-1 lung epithelial progenitor cells, (b) culturing the NKX2-1 lung epithelial progenitor cells with a low-wnt media to differentiate into airway epithelial cells; and (c) administering the airway epithelial cells obtained in step (b) to the subject. In some embodiments, the population of human iPSC are obtained from the subject with cystic fibrosis, and the method of treating CF further comprises genetically modifying the airway epithelial cells obtained in step (b) to correct a CTFR genetic lesion responsible for the cystic fibrosis in the subject prior to the step (c). In some embodiments, the airway epithelial cells are transplanted into the lungs of the subject (Col. 8 line 48+). FIG. 7D shows a flow cytometry plot for EPCAM by FACS array on day 15 differentiated cells. FIG. 7E shows FACS array results for CD24, CD31, CD45, PDGFRα, and CD26 on day 15 differentiated cells compared to NKX2-1GFP expression (Col. 12 line 62+). In one embodiment, the low-Wnt media comprises one or more steroids. Exemplary steroids for use include but are not limited to; dexamethasone, hydrocortisone, cyclic AMP activation (reads on immunosuppressive agent, Col. 20 line 16-19). In some embodiments, the cells can be used in screening assays to study more complex diseases, such as chronic obstructive pulmonary disease, as well as used in regenerative medicine approaches (e.g. engraftment into lungs or decellularized lung scaffolds) and for cell-based therapies (Col. 20 line 30-34). Advantages of the technology disclosed herein is that the iPSCs can be generated from any patient with only a blood draw and result in an inexhaustible supply of autologous cells (Col. 92 line 29-33). Another embodiment relates to the therapeutic use of human airway epithelial cells, for example, in one embodiment the provides methods for the treatment cystic fibrosis in a subject comprising transplanting into subjects human airway epithelial cells, and in some instances, where the human airway epithelial cells are derived from iPSCs from a subject with CF, where the genetic lesion in the CTFR gene is corrected, e.g., using ex vivo gene editing method commonly known in the art (Col. 27 line 40-49). Additional disclosure includes that by modulating Wnt signaling one can direct lung progenitors derived from human iPSC’s specifically into airway progenitors and these can be used in preclinical models of airway disease for analysis, e.g., researching the mechanism of cystic fibrosis (CF), and/or drug discovery for the treatment of CF (Col.4 line 55-62).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 41-56 are rejected under 35 U.S.C. 103 as being unpatentable over Kotton et al. (US 10.590,392) in view of Reisner et al. (US 2019/0091266) and Donatella Piro et al. (Expert Rev Resp Med, 2(3), 365-380, 2008).
Kotton discloses technology relating to the derivation of functional airway organoids (bronchospheres) from human induced pluripotent stem cells (iPSCs), which can be used in models of lung disease and facilitate precision medicine for monogenic airway disorders, such as cystic fibrosis (Col. 4 line 3-8). Bronchospheres derived from CF patients can be used to assess drugs and corrective mutations for functional restoration of CFTR, where a candidate drug or corrective mutation causes the bronchosphere to swell according to wild-type in the presence of forskolin (Col.5 line 33-38). In one embodiments, the airway epithelial organoids comprise cells that also express at least one of the proximal markers selected from the group consisting of: SCGB3A2+, TP63+, MUC5AC+ and Scgb1a1+, and optionally in some embodiments, the NKX2-1 lung progenitors are NKX2-1+ve, CD47hi and CD26lo (i.e., express high levels of CD47 and low levels of CD26) (Col. 6 line 58+). Another aspect relates to a method of treating cystic fibrosis (CF), comprising: (a) differentiating a population of human iPSC or ESCs into NKX2-1 lung epithelial progenitor cells, (b) culturing the NKX2-1 lung epithelial progenitor cells with a low-wnt media to differentiate into airway epithelial cells; and (c) administering the airway epithelial cells obtained in step (b) to the subject. In some embodiments, the population of human iPSC are obtained from the subject with cystic fibrosis, and the method of treating CF further comprises genetically modifying the airway epithelial cells obtained in step (b) to correct a CTFR genetic lesion responsible for the cystic fibrosis in the subject prior to the step (c). In some embodiments, the airway epithelial cells are transplanted into the lungs of the subject (Col. 8 line 48+). FIG. 7D shows a flow cytometry plot for EPCAM by FACS array on day 15 differentiated cells. FIG. 7E shows FACS array results for CD24, CD31, CD45, PDGFRα, and CD26 on day 15 differentiated cells compared to NKX2-1GFP expression (Col. 12 line 62+). In one embodiment, the low-Wnt media comprises one or more steroids. Exemplary steroids for use include but are not limited to; dexamethasone, hydrocortisone, cyclic AMP activation (reads on immunosuppressive agent, Col. 20 line 16-19). In some embodiments, the cells can be used in screening assays to study more complex diseases, such as chronic obstructive pulmonary disease, as well as used in regenerative medicine approaches (e.g. engraftment into lungs or decellularized lung scaffolds) and for cell-based therapies (Col. 20 line 30-34). Advantages of the technology disclosed herein is that the iPSCs can be generated from any patient with only a blood draw and result in an inexhaustible supply of autologous cells (Col. 92 line 29-33). Another embodiment relates to the therapeutic use of human airway epithelial cells, for example, in one embodiment the invention provides methods for the treatment cystic fibrosis in a subject comprising transplanting into subjects human airway epithelial cells, as disclosed herein, and, in some instances, where the human airway epithelial cells are derived from iPSCs from a subject with CF, where the genetic lesion in the CTFR gene is corrected, e.g., using ex vivo gene editing method commonly known in the art (Col. 27 line 40-49). Additional disclosure includes that by modulating Wnt signaling one can direct lung progenitors derived from human iPSC’s specifically into airway progenitors and these can be used in preclinical models of airway disease for analysis, e.g., researching the mechanism of cystic fibrosis (CF), and/or drug discovery for the treatment of CF (Col.4 line 55-62).
Kotton fails to disclose the lung cell is CD31/CD45- and Epcam+, Sca1+. Sca1- and keratin 17+.
Reisner discloses a method of treating a pulmonary disorder or injury in a subject comprising administering to the subject non-syngeneic pulmonary tissue cells in suspension comprising an effective amount of hematopoietic precursor cells (HPCs) or supplemented with HPCs, to achieve tolerance to the pulmonary tissue cells in the absence of chronic immunosuppressive regimen. A method of inducing donor specific tolerance in a subject in need of a pulmonary cell or tissue transplantation is also disclosed (abstract). Method further comprises conditioning the subject under sublethal, lethal or supralethal conditioning protocol prior to the administering (0011). In one embodiment, the cells comprise a CD34+, CD31+, CD45−, CD105+ marker expression (0201), cells comprise Epcam+ CD24+ SCA1− marker expression (0211), cells comprise Epcam+ CD24+ Podoplanin+ Sca1+ marker expression (0212). In order to facilitate engraftment of the pulmonary tissue cells, and in order to reduce, by at least about 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%, or preferably avoid graft rejection and/or graft versus host disease (GVHD), the method may further advantageously comprise conditioning the subject prior to administration of the pulmonary tissue cells (0315). Additional disclosure includes that the canalicular embryonic lung comprises not only epithelial lung progenitors but also a marked level of HPCs which can induce durable and multi-lineage hematopoietic chimerism (FIGS. 1A-F). These lung hematopoietic progenitors can effectively compete with normal adult bone marrow stem cells (FIGS. 2A-D) and can be utilized in transplantation settings for induction of immune tolerance.
Donatella is made of record to illustrate that it is well known in the art to show that lung and pulmonary epithelial cells contain keratin protein. Donatella discloses that number of studies provide evidence that adult stem cells of mesenchymal origin are a source of AECs. Spees et al. studied the differentiation, cell fusion and nuclear fusion during ex vivo repair of epithelium by human adult stem cells. GFP-expressing human MSCs were cocultured with heat-shocked, small AECs. A subset of the human MSCs rapidly differentiate into epithelium-like cells and they restore the epithelial monolayer. Multipotent, long-lived stem cells have been identified throughout airways and give rise to both transiently amplifying (TA) cells and terminally differentiated daughters and local stem or TA cells contribute to the repopulation of the injured epithelium in different anatomical regions of the lung (page 1). Donatella also discloses that immunocytochemistry and microarray analyses demonstrated that the cells expressed many proteins of epithelial cells, such as keratins (17, 18 and e 19), structural proteins of intermediate filaments and CC26 (a lung epithelial marker of Clara, serous and goblet cells). It was observed that up to 4% of GF+ MSCs added to the cultures were recovered as CD24+ cells and approximately a quarter were binucleated. Since CD24, a mucin-like glycoprotein, is a marker for epithelial cells and not expressed on human MSCs, these results indicate that fusion between adult stem cells and epithelial cells is a frequent event, and also that some of the cells undergo nuclear fusion (page8-9).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to incorporate into Kotton’s composition. The person of ordinary skill in the art would have been motivated to make those modifications because Reisner teaches that the canalicular embryonic lung comprises epithelial lung progenitors as well as a marked level of hematopoietic progenitor cells (HPCs) which can induce durable and multi-lineage hematopoietic chimerism. Therefore, a successful transplantation of lung cells (in suspension) from a mis-matched allogeneic donor can be attained in the absence of chronic immunosuppression by transplantation of lung tissue cells comprising an effective amount of HPCs (0093) and reasonably would have expected success because both Kotton and Reisner teaches conventional approaches and preparation of pharmaceutical compositions include therapeutically effective amount of active ingredients such as suitable for use functional airway organoids (bronchospheres) from human induced pluripotent stem cells (iPSCs) and pulmonary tissue cells that can be used in the same field of endeavor, such as in models of lung disease and facilitate precision medicine for monogenic airway disorders, (cystic fibrosis) and effective to prevent, alleviate or ameliorate symptoms of a disorder (e.g., pulmonary disease or condition) or prolong the survival of the subject being treated.
Conclusion
No claims are allowed at this time.
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/J.R.S/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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