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 .
Claim Status
1. The amendment filed 02/13/2026 has been entered. Claims 1, 2, 4 – 6, 8, 9, 12, 13, and 22 – 24 remain pending. Claims 1, 2, 4 – 6, 8, and 22 – 24 are under consideration.
Election/Restrictions
2. Applicant’s election of Group III in the reply filed on 11/20/2023 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
3. Claims 9, 12, and 13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/20/2023.
Priority
4. This application claims priority to U.S. Provisional Application 62/691,811 filed June 29, 2018.
Withdrawn Claim Rejections
5. The rejection of 1, 2, 4, 6, 8, and 22 rejected under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1 to recite “derived from genetically unaltered lung tissue”.
6. The rejection of claim 5 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1 to recite “derived from genetically unaltered lung tissue”.
7. The rejection of claim 23 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1 to recite “derived from genetically unaltered lung tissue”.
8. The rejection of claim 24 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1 to recite “derived from genetically unaltered lung tissue”.
Claim Interpretation
9. For the purpose of applying prior art, “wherein the population of LSCs and LSC-EXOs are derived from genetically unaltered lung tissue” of claim 1 is interpreted as the LSCs express and secrete endogenous miRNA and decorin that is cargo of the LSC-EXOs.
10. For the purpose of applying prior art, recitation of “when delivered” of claim 1 is interpreted as the pharmaceutical composition of claim 1 has the capacity to be delivered to an animal or human. The claims are drawn to a pharmaceutical composition and not a method. Therefore “when delivered” is an intended use of the claimed pharmaceutical composition.
11. For the purpose of applying prior art, recitation of “is administered to a respiratory tract of the animal or human subject” of claims 6 and 8 is interpreted as the pharmaceutical composition of claim 1 has the capacity to be delivered to a respiratory tract of an animal or human. The claims are drawn to a pharmaceutical composition and not a method. Therefore “is administered” is an intended use of the claimed pharmaceutical composition.
Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
12. Claims 1, 2, 4 – 6, 8, and 22 – 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is drawn to a pharmaceutical composition comprising a population of lung spheroid cell-derived exosomes (LSC-EXOs) in an amount effective for modulating a pulmonary pathological condition when delivered to an animal or human subject in need thereof, wherein the population of LSC-EXOs comprises at least one miRNA and at least one protein, wherein the at least one protein comprises Decorin, and wherein the population of LSCs and LSC-EXOs are derived from genetically unaltered lung tissue.
The specification provides no implicit or explicit support for the context of “wherein the population of LSCs and LSC-EXOs are derived from genetically unaltered lung tissue”. The specification has only provided support for human LSCs generated from whole lung samples and expanded as described in Dinh et al., (2017) Respiratory Research (page 34, lines 14 – 16). Applicant defines “biological tissue” as cells or tissues in vivo and in vitro and teaches that exosomes may be isolated from tissue samples but does not contemplate if the tissue is genetically altered or unaltered (page 10, lines 17 – 18; page 13, lines 28 – 29). Applicants are reminded that it is their burden to show where the specification supports any amendments to the claims. See 37 CFR 1.121 (b)(2)(iii), the MPEP 714.02, 3rd paragraph, last sentence and also the MPEP 2163.07, last sentence.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application. MPEP 2163.06 further notes “When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure [or point to case law supporting incorporation of such a limitation as in the instant case]” (emphasis added).
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.
13. Claim(s) 1, 2, 4, 6, 8, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over of Cheng (WO-2016044681-A1; previously cited), hereinafter Cheng in view of Aliotta (Aliotta, Jason M., et al. Cardiovascular research 100.3 (2013): 354-362.), hereinafter Aliotta in view of Veness-Meehan (Veness-Meehan, Kathleen A., et al. Pediatric research 41.4 (1997): 464-472.), hereinafter Veness-Meehan in view of Westergren-Thorsson (Westergren-Thorsson, Gunilla, et al. The Journal of clinical investigation 92.2 (1993): 632-637.), hereinafter Westergren-Thorsson.
Regarding claim 1, Cheng teaches a pharmaceutical composition of lung spheroid cells (LSCs) in an amount for modulating bleomycin-induced pulmonary fibrosis (page 20 – 21, para. 0099; page 22, para. 00108 – 00110; page 23, para. 00113 – 00114; Figure 4; page 24, para. 00115 - 00120). Cheng teaches a concentration between 90 – 250 x 103 cells/mL (“in an amount”) (page 4, para. 0017). Cheng teaches the LSCs are derived from rat lung tissue and healthy human lung tissue and does not teach genetic alteration of the lung tissue (“wherein the population of LSCs and LSC-EXOs are derived from genetically unaltered lung tissue”) (page 18 – 19, para. 0088 – 0091; page 22, para. 00108; Figure 1A). Cheng does not teach the composition of LSCs comprise exosomes, at least one miRNA or Decorin.
Regarding claim 2, Cheng teaches the pulmonary pathological condition is pulmonary fibrosis (page 23, para. 00114; page 26, para. 00124).
Regarding claim 6, Cheng teaches the pharmaceutical composition of LSCs comprises pharmacologically acceptable adjuvants and/or excipients (page 4, 0017; page 15, para. 0075). Cheng teaches the compositions can be administered by any appropriate means including pulmonary administration (page 15, para. 0075).
Regarding claim 8, Cheng teaches the composition may be formulated as a lyophilizate (page 15, para. 0075). Cheng teaches the compositions can be administered by any appropriate means including pulmonary administration by inhalation by a nebulizer (page 15 – 16, para. 0075).
Cheng does not teach the composition of LSCs comprise exosomes, at least one miRNA or Decorin of claim 1 or “at least one miR99 miRNA” of claim 4 or “LSC-EXOs are isolated from a lung spheroid cell-conditioned medium” of claim 22. However, Cheng teaches LSC-conditioned media promotes survival/proliferation of human lung epithelial cells suggesting a pro-survival and pro-angiogenic role of LSC-secreted factors (page 20, 0097; page 23, 00112; page 26, para. 00123 and 00125; Figure 4F). Cheng teaches in a rat model of pulmonary fibrosis, LSCs outperform adipose-derived mesenchymal stem cells in reducing fibrotic thickening and infiltration, however, the underlying mechanisms need to be further elucidated (page 1, 0006; page 18, 0084; page 24, 00119 – 00120; page 26, 00127; page 27, 0029). Cheng teaches human LSCs inhibit apoptosis, fibrosis, and infiltration in a mouse model of pulmonary fibrosis (page 1, 0006). Cheng teaches LSCs engraft and acquire mature lung phenotypes in recipient lungs, although such small engraftment and differentiation incidents seem insufficient to explain the observed benefits (page 26, 00124).
Regarding “exosomes” of claim 1 and “isolated from a lung spheroid cell-conditioned medium” of claim 22, Aliotta teaches a pharmaceutical composition of lung extracellular vesicles (LEV) isolated from lung cell conditioned media where the lung cells were obtained from lung tissue (page 355, right col. para. 3). Aliotta teaches the EVs were in the traditional exosome size of 30 – 100 nm (page 356, right col. last para.; Supplemental Table 1). Applicant’s specification defines exosomes as small secreted vesicles (typically about 30 nm to about 150 nm) at page 13, lines 14 – 15. Therefore, the LEV of Aliotta meets the limitation of “exosomes” of claim 1. Aliotta teaches mice were injected with 1.5 x 107 LEVs in PBS (page 355, right col. para. 5). Aliotta teaches the lungs were obtained from C57BL/6 mice (“wherein the population of LSCs and LSC-EXOs are derived from genetically unaltered lung tissue”) (page 355, right col. para. 1 and 3).
Regarding “at least one miRNA” of claim 1 that is “at least one miR99” of claim 4, Aliotta teaches the exosomes comprise miR99b (Table 1; page 358, right col. para. 2).
Aliotta does not teach “Decorin” of claim 1. However, Aliotta teaches several proteins were identified in the exosomes (page 358, left col. last para. and right col. para. 1; Table 1; Supplemental Table 2). Aliotta teaches the LEVs are taken up by the pulmonary microcirculation after injection (page 358, right col. para. 3). Aliotta teaches EVs contain numerous DNA, RNA, and protein species and are capable of inducing changes in transcription, translation and surface protein expression in cells with which they come in contact (page 360, left col. para. 3). Aliotta teaches LEVs isolated from healthy mice do not induce pulmonary disease when injected into healthy mice but LEVs isolated from mice with pulmonary hypertension induce significant disease in healthy mice (page 361, left col. para. 2 and right col. last para.). Aliotta teaches pulmonary arterial hypertension (PAH) is a disease characterized by progressive narrowing of the small pulmonary arteries and arterioles due to abnormal cell proliferation, fibrosis, and in situ thrombosis (page 354, left col.). One would have been motivated to combine the teachings of Cheng and Aliotta because Cheng teaches LSC-conditioned media promotes survival/proliferation of human lung epithelial cells suggesting a pro-survival and pro-angiogenic role of LSC-secreted factors and the observed benefits of LSCs in a pulmonary fibrosis model cannot be attributed solely to the small engraftment of LSCs and Aliotta teaches exosomes are found in lung cell conditioned media.
Regarding “Decorin” of claim 1, Veness-Meehan teaches rat lungs express decorin (Figure 1; page 8, para. 3 – 4). Veness-Meehan teaches decorin mRNA is present in rat lung and its level increases as the rat ages (page 10, para. 2; Figure 3A, C, E). Veness-Meehan teaches decorin protein is present in rat lung connective tissue surrounding bronchi and blood vessels, airway epithelium and alveolar walls (page 13, para. 1; Figure 4A, C, E). Veness-Meehan teaches decorin expression decreases in rat lungs with hyperoxia injury and the level of decorin decrease increases with age (Figure 1; page 10, para. 2; Figure 3 B, D, F; Figure 4B, D, F; page 13). Veness-Meehan teaches oxygen exposure decreases decorin protein in lung connective tissue (page 13; Figure 4B). Veness-Meehan teaches the temporal and spatial changes in decorin expression support a role for decorin in the cellular response to oxygen-induced lung injury (page 20, last para.). Veness-Meehan teaches decorin is a proteoglycan in the lung and is thought to regulate collagen fiber thickness in fibrotic reactions through inhibition of fibril formation and is therefore likely to participate in the response to injury (page 2, para. 2). Veness-Meehan teaches proteoglycans are components of the ECM that change in response to different forms of injury and are likely to influence the healing process through their effects on matrix assembly and cell adhesion, and through growth factor interactions (page 18, para. 1). Veness-Meehan teaches decorin expression changes occur in bleomycin-induced pulmonary fibrosis (page 18, para. 1). Veness-Meehan teaches TGF-β decreases decorin expression (page 18, para. 1). Veness-Meehan teaches decorin modulates TGF-β activity by reversibly binding to the growth factor and neutralizing its expression and removal of such an inhibitory influence over TGF-β may promote ECM deposition, fibrosis, and tissue remodeling around large vessels and airways (page 20, para. 1). Veness-Meehan teaches because decorin binds to triple helical collagen and appears to inhibit collagen fibril formation, decreased decorin concentrations might contribute to increased mature collagen formation and fibrosis (page 19, para. 2). Veness-Meehan teaches decorin binds to fibronectin and thrombospondin, inhibiting cell adhesion which might be an additional mechanism by which decorin contributes to the abnormal alveolarization seen in hyperoxic lung injury (page 19, para. 2). One would have been motivated to combine the teachings of Cheng, Aliotta, and Veness-Meehan to select lung tissue with endogenous decorin to derive LSCs and LSC-EXOs because Veness-Meehan teaches decorin is a proteoglycan in the lung and is likely to participate in the response to injury and proteoglycans are likely to influence the healing process and lung injury reduces decorin expression in lung tissue and Cheng teaches in a rat model of pulmonary fibrosis, LSCs reduce fibrotic thickening and infiltration, however, the underlying mechanisms need to be further elucidated and Aliotta teaches EVs contain numerous DNA, RNA, and protein species and are capable of inducing changes in transcription, translation and surface protein expression in cells with which they come in contact.
Westergren-Thorsson teaches TGF-β1 mRNA increased while decorin mRNA decreased in lung tissue in a rat model of bleomycin-induced pulmonary fibrosis (Abstract; page 633, right col. last para.; page 634, left col. para. 1 and right col.; page 635, right col. para. 1 – 2). Westergren-Thorsson teaches pulmonary fibrosis is the final pathway of many interstitial lung diseases and is characterized by a massive production of fibrous connective tissue around the alveoli (page 632, left col.). Westergren-Thorsson teaches in the early stage of fibrosis, TGF-β is found in macrophages dispersed in the alveolar interstitium and in organized clusters and later TGF-β is primarily associated with ECM in regions of increased cell number (page 632, right col. para. 1). Westergren-Thorsson teaches decreasing a concentration of decorin may enhance the effects of TGF-β via a lower degree of immobilization of the growth factor (page 636, left col. para. 3).
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 Cheng regarding a pharmaceutical composition comprising LSCs derived from lung tissue that is not genetically altered for treating pulmonary fibrosis with the teachings of Aliotta regarding a pharmaceutical composition of lung cell-derived exosomes that contain protein and miRNA and where the lung tissue was not genetically altered with the teachings of Veness-Meehan regarding lung tissue expresses decorin and in response to injury decorin levels decrease with the teachings of Westergren-Thorsson regarding decorin levels decrease in lung tissue in a rat model of pulmonary fibrosis to arrive at the claimed pharmaceutical composition comprising a population of lung spheroid cell-derived exosomes (LSC-EXOs) in an amount effective for modulating a pulmonary pathological condition when delivered to an animal or human subject in need thereof, wherein the population of LSC-EXOs comprises at least one miRNA and at least one protein, wherein the at least one protein comprises Decorin, and wherein the population of LSCs and LSC-EXOs are derived from genetically unaltered lung tissue. One would have been motivated to combine the teachings of Cheng, Aliotta, Veness-Meehan, and Westergren-Thorsson in a pharmaceutical composition comprising LSCs and LSC-EXOs derived from lung tissue with endogenous decorin and miRNA for treating a pulmonary pathological condition as Cheng teaches in a rat model of pulmonary fibrosis, LSCs reduce fibrotic thickening and infiltration, however, the underlying mechanisms need to be further elucidated and Cheng teaches LSC-conditioned media promotes survival/proliferation of human lung epithelial cells and Aliotta teaches EVs contain numerous DNA, RNA, and protein species and are capable of inducing changes in transcription, translation and surface protein expression in cells with which they come in contact and Veness-Meehan teaches lung tissue contains the proteoglycan decorin and decorin is likely to participate in the response to injury and proteoglycans are likely to influence the healing process through their effects on matrix assembly and cell adhesion and through growth factor interactions and Westergren-Thorsson teaches decreased decorin as seen in a model of pulmonary fibrosis may enhance the effects of TGF-β. One would have a reasonable expectation of success in combining the teachings as Cheng teaches human LSCs inhibit apoptosis, fibrosis, and infiltration in a mouse model of pulmonary fibrosis and Aliotta teaches exosomes derived from healthy lung cells do not cause pulmonary dysfunction and Veness-Meehan and Westergren-Thorsson teach the level of decorin in the lung decreases in response to lung injury.
14. Claim(s) 5 is rejected under 35 U.S.C. 103 as being unpatentable over Cheng (WO-2016044681-A1; previously cited), hereinafter Cheng in view of Aliotta (Aliotta, Jason M., et al. Cardiovascular research 100.3 (2013): 354-362.), hereinafter Aliotta in view of Veness-Meehan (Veness-Meehan, Kathleen A., et al. Pediatric research 41.4 (1997): 464-472.), hereinafter Veness-Meehan in view of Westergren-Thorsson (Westergren-Thorsson, Gunilla, et al. The Journal of clinical investigation 92.2 (1993): 632-637.), hereinafter Westergren-Thorsson as applied to claims 1, 2, 4, 6, 8, and 22 above, and further in view of Pandit (Pandit, Kusum V., et al. American journal of respiratory and critical care medicine 182.2 (2010): 220-229; previously cited), hereinafter Pandit.
Cheng in view of Aliotta, Veness-Meehan, and Westergren-Thorsson make obvious the limitations of claim 1 as set forth above. Aliotta teaches the exosomes contain various miRNAs but does not teach let-7 miRNA of claim 5. However, Veness-Meehan teaches TGF-β decreases decorin expression (page 18, para. 1). Veness-Meehan teaches decorin modulates TGF-β activity by reversibly binding to the growth factor and neutralizing its expression and removal of such an inhibitory influence over TGF-β may promote ECM deposition, fibrosis, and tissue remodeling around large vessels and airways (page 20, para. 1). Westergren-Thorsson teaches TGF-β1 mRNA increased while decorin mRNA decreased in lung tissue in a rat model of bleomycin-induced pulmonary fibrosis (Abstract; page 633, right col. last para.; page 634, left col. para. 1 and right col.; page 635, right col. para. 1 – 2). Westergren-Thorsson teaches decreasing a concentration of decorin may enhance the effects of TGF-β via a lower degree of immobilization of the growth factor (page 636, left col. para. 3). Westergren-Thorsson teaches that the changes seen in the bleomycin-induced fibrosis model may also occur in other pathological conditions such as idiopathic pulmonary fibrosis (page 636, left col. para. 4).
Pandit teaches let-7d miRNA is present in control lung tissue (Figure 1; page 224, left col. para. 2). Pandit teaches let-7d is also present in lung tissue from patients with pulmonary fibrosis but let-7d levels were significantly decreased relative to control lung tissue and TGF-β down-regulated let-7d expression (Abstract; Figure 3B; page 224, left col. para. 2 and right col. para. 1; page 228, left col. para. 3). Pandit teaches in Figure 2 that let-7d is a TGF-β target where treating lung cancer cells with TGF-β resulted in decreased expression of let-7d (Figure 2; page 223, left col. para. 2 and right col.; page 224, left col. para. 1). Pandit teaches the down-regulation of let-7d in pulmonary fibrosis and the profibrotic effects of this down-regulation in vitro and in vivo suggest a key regulatory role for let-7d miRNA in preventing lung fibrosis (Abstract; page 227, left col. last para. and right col. para. 1). Pandit teaches inhibition of let-7d in vivo causes hemorrhagic lungs (page 225, right col. para. 2; page 226, left col. and right col.; page 227, left col. para. 1; Figure 6). Pandit teaches idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually lethal fibrotic lung disease and is incurable (page 220, right col. para. 1; page 228, left col. last para.). Pandit teaches alveolar epithelial cells undergo EMT in response to TGF-β and in vivo, cells coexpressing epithelial and mesenchymal markers are found in IPF lungs and in mice after intranasal delivery of TGF-β (page 220, right col. last para.; page 221, 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 Cheng regarding a pharmaceutical composition comprising LSCs derived from lung tissue that is not genetically altered for treating pulmonary fibrosis with the teachings of Aliotta regarding a pharmaceutical composition of lung cell-derived exosomes that contain protein and miRNA and where the lung tissue was not genetically altered with the teachings of Veness-Meehan regarding lung tissue expresses decorin and in response to injury decorin levels decrease with the teachings of Westergren-Thorsson regarding decorin levels decrease in lung tissue in a rat model of pulmonary fibrosis with the teachings of Pandit regarding let-7d miRNA is present in control lung tissue but is down-regulated in IPF lung tissue to arrive at the claimed pharmaceutical composition wherein the at least one miRNA comprises at least one let-7 miRNA. One would have been motivated to combine the teachings of Cheng, Aliotta, Veness-Meehan, Westergren-Thorsson, and Pandit in a pharmaceutical composition to treat pulmonary fibrosis comprising LSCs and LSC-EXOs derived from lung tissue with endogenous decorin and let-7 miRNA as Aliotta teaches EVs contain numerous DNA, RNA, and protein species and are capable of inducing changes in transcription, translation and surface protein expression in cells with which they come in contact and Westergren-Thorsson teaches that the changes seen in the bleomycin-induced fibrosis model regarding decreased decorin and increased TGF-β may also occur in idiopathic pulmonary fibrosis and Pandit teaches the down-regulation of let-7d in pulmonary fibrosis and the profibrotic effects of this down-regulation in vitro and in vivo suggest a key regulatory role for let-7d miRNA in preventing lung fibrosis and Pandit teaches IPF is incurable. One would have a reasonable expectation of success in combining the teachings as Cheng teaches human LSCs inhibit apoptosis, fibrosis, and infiltration in a mouse model of pulmonary fibrosis and Aliotta teaches exosomes derived from healthy lung cells do not cause pulmonary dysfunction and Veness-Meehan and Westergren-Thorsson teach decorin inhibits TGF-β signaling and Pandit teaches let-7d is present in control lung tissue but is decreased by TGF-β in lung tissue of pulmonary fibrosis patients.
15. Claim(s) 23 is rejected under 35 U.S.C. 103 as being unpatentable over Cheng (WO-2016044681-A1; previously cited), hereinafter Cheng in view of Aliotta (Aliotta, Jason M., et al. Cardiovascular research 100.3 (2013): 354-362.), hereinafter Aliotta in view of Veness-Meehan (Veness-Meehan, Kathleen A., et al. Pediatric research 41.4 (1997): 464-472.), hereinafter Veness-Meehan in view of Westergren-Thorsson (Westergren-Thorsson, Gunilla, et al. The Journal of clinical investigation 92.2 (1993): 632-637.), hereinafter Westergren-Thorsson as applied to claims 1, 2, 4, 6, 8, and 22 above, and further in view of Zhang (Zhang S, et. al. Int J Mol Sci. 2017 Mar 15;18(3):633; previously cited), hereinafter Zhang as evidenced by Pandit (Pandit, Kusum V., et al. American journal of respiratory and critical care medicine 182.2 (2010): 220-229; previously cited), hereinafter Pandit.
Cheng in view of Aliotta, Veness-Meehan, and Westergren-Thorsson make obvious the limitations of claim 1 as set forth above. Aliotta teaches the exosomes contain various miRNAs but does not teach miR-151a or miR-30a of claim 23.
Zhang teaches the mechanisms regarding the control of IPF progression by miRNAs remain poorly understood (page 2, para. 1). Zhang teaches circulating levels of miR-30a is expression level is lower in IPF patients (page 2, para. 3; Figure 1A – C). Zhang teaches lung cells and lung cancer cells express miR-30a and the level of miR-30a is decreased when the cells are treated with H2O2 (Figure 1C – F; page 2, para. 3). Control lung tissue expresses miR-30a and lung tissue from pulmonary fibrosis patients express miR-30a but at lower levels relative to control tissue as evidenced by Pandit (Figure 1; page 223, left col. para. 1; page 227, left col. para. 2). Zhang teaches miR-30a could act as a potential therapeutic for IPF (Abstract). Zhang teaches an agomir of miR-30a administered to mouse lung reduced pulmonary fibrosis (page 5, para. 1; Figure 4 – 5). Zhang teaches IPF is a chronic, progressive and lethal fibrotic lung disease and the most life-threatening idiopathic disease, presenting a mortality rate that exceeds those of numerous cancers (page 1, para. 1). Zhang teaches their findings together with the clinical data of patients with IPF provide evidence that miR-30a upregulation exerts an antifibrotic effect and protective function against pulmonary injury (page 8, para. 3). Zhang teaches a novel approach to prevent pulmonary fibrosis damage and treat pulmonary fibrosis is miR-30a.
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 Cheng regarding a pharmaceutical composition comprising LSCs derived from lung tissue that is not genetically altered for treating pulmonary fibrosis with the teachings of Aliotta regarding a pharmaceutical composition of lung cell-derived exosomes that contain protein and miRNA and where the lung tissue was not genetically altered with the teachings of Veness-Meehan regarding lung tissue expresses decorin and in response to injury decorin levels decrease with the teachings of Westergren-Thorsson regarding decorin levels decrease in lung tissue in a rat model of pulmonary fibrosis with the teachings of Zhang regarding miR-30a miRNA is down-regulated in IPF and a miR-30a agomir reduces pulmonary fibrosis to arrive at the claimed pharmaceutical composition wherein the at least one miRNA comprises at least one of miR-30a miRNA. One would have been motivated to combine the teachings of Cheng, Aliotta, Veness-Meehan, Westergren-Thorsson, and Zhang in a pharmaceutical composition to treat pulmonary fibrosis comprising LSCs and LSC-EXOs derived from lung tissue with endogenous decorin and miR-30a miRNA as Aliotta teaches EVs contain numerous DNA, RNA, and protein species and are capable of inducing changes in transcription, translation and surface protein expression in cells with which they come in contact and Westergren-Thorsson teaches that the changes seen in the bleomycin-induced fibrosis model regarding decreased decorin and increased TGF-β may also occur in idiopathic pulmonary fibrosis and Zhang teaches a novel approach to prevent pulmonary fibrosis damage and treat pulmonary fibrosis is miR-30a. One would have a reasonable expectation of success in combining the teachings as Cheng teaches human LSCs inhibit apoptosis, fibrosis, and infiltration in a mouse model of pulmonary fibrosis and Aliotta teaches exosomes derived from healthy lung cells do not cause pulmonary dysfunction and Veness-Meehan and Westergren-Thorsson teach decorin inhibits TGF-β signaling and Zhang teaches an agomir of miR-30a administered to mouse lung reduced pulmonary fibrosis.
16. Claim(s) 24 is rejected under 35 U.S.C. 103 as being unpatentable over Cheng (WO-2016044681-A1; previously cited), hereinafter Cheng in view of Aliotta (Aliotta, Jason M., et al. Cardiovascular research 100.3 (2013): 354-362.), hereinafter Aliotta in view of Veness-Meehan (Veness-Meehan, Kathleen A., et al. Pediatric research 41.4 (1997): 464-472.), hereinafter Veness-Meehan in view of Westergren-Thorsson (Westergren-Thorsson, Gunilla, et al. The Journal of clinical investigation 92.2 (1993): 632-637.), hereinafter Westergren-Thorsson as applied to claims 1, 2, 4, 6, 8, and 22 above, and further in view Hong (Hong, Xuan, et al. " Tumor Biology 37.12 (2016): 16029-16038; previously cited), hereinafter Hong in view of Shien (Shien, Kazuhiko, et al. PLoS One 9.2 (2014): e87900; previously cited), hereinafter Shien.
Cheng in view of Aliotta, Veness-Meehan, and Westergren-Thorsson make obvious the limitations of claim 1 as set forth above but do not teach the proteins recited in claim 24. However, Veness-Meehan teaches TGF-β decreases decorin expression (page 18, para. 1). Veness-Meehan teaches decorin modulates TGF-β activity by reversibly binding to the growth factor and neutralizing its expression and removal of such an inhibitory influence over TGF-β may promote ECM deposition, fibrosis, and tissue remodeling around large vessels and airways (page 20, para. 1). Westergren-Thorsson teaches decreasing a concentration of decorin may enhance the effects of TGF-β via a lower degree of immobilization of the growth factor (page 636, left col. para. 3). Westergren-Thorsson teaches that the changes seen in the bleomycin-induced fibrosis model may also occur in other pathological conditions (page 636, left col. para. 4).
Hong teaches decorin is expressed in normal lung tissue and its expression is significantly decreased in lung cancer (Figure 1; page 16031, right col. para. 2). Hong teaches decorin is synthesized in the stroma and interacts with TGF-β (page 16030, left col. para. 2). Hong teaches decorin expression in the tumor stroma of patients with lung cancer was significantly associated with the pathology where higher negative rates of decorin was found in adenocarcinoma compared to squamous cell carcinoma (page 16031, right col. para. 3 – 4; Table 2; Figure 2). Hong teaches reduced expression of decorin in stroma was correlated with shorter disease free survival (DFS) and overall survival (OS) (page 16031, right col. last para.; Figure 3 – 6). Hong teaches lung cancer is a leading cause of cancer death worldwide and it is necessary to understand the molecular mechanisms mediating tumorigenesis and metastasis in lung cancer and to identify novel biomarkers to help assess the prognosis and to screen targets for targeted therapy (page 16029, right col. para. 1). Hong teaches tumor-related stromal cells in the tumor microenvironment can be recruited by cancer cells to support tumor growth (page 16029, right col. last para.).
Shien teaches DKK3 is reported to be a tumor suppressor and its expression is significantly down-regulated in lung adenocarcinomas and squamous cell carcinomas compared with normal lung tissue (page 2, left col. para. 1). Shien teaches administering an adenovirus expressing DKK3 to mice with xenograft A549 lung tumors suppressed tumor growth (page 5, left col. para. 2 and right col. para. 1; Figure 3). Shien teaches DKK3 has therapeutic potential for lung cancer (page 7, left 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 Cheng regarding a pharmaceutical composition comprising LSCs derived from lung tissue that is not genetically altered for treating pulmonary fibrosis with the teachings of Aliotta regarding a pharmaceutical composition of lung cell-derived exosomes that contain protein and miRNA and where the lung tissue was not genetically altered with the teachings of Veness-Meehan regarding lung tissue expresses decorin and in response to injury decorin levels decrease with the teachings of Westergren-Thorsson regarding decorin levels decrease in lung tissue in a rat model of pulmonary fibrosis with the teachings of Hong regarding decorin is expressed in normal lung tissue and the level of decorin is decreased in lung cancer tissue with the teachings of Shien regarding DKK3 is expressed in normal lung tissue and the level of DKK3 is decreased in lung cancer tissue and DKK3 suppresses lung tumor growth to arrive at the claimed pharmaceutical composition wherein the at least one protein further comprises DKK3. One would have been motivated to combine the teachings of Cheng, Aliotta, Veness-Meehan, Westergren-Thorsson, Hong, and Shein in a pharmaceutical composition to treat lung cancer comprising LSCs and LSC-EXOs derived from lung tissue with endogenous decorin and DKK3 as Aliotta teaches EVs contain numerous DNA, RNA, and protein species and are capable of inducing changes in transcription, translation and surface protein expression in cells with which they come in contact and Westergren-Thorsson teaches that the changes seen in the bleomycin-induced fibrosis model regarding decreased decorin and increased TGF-β may also occur in other pathological conditions and Hong teaches lung cancer is a leading cause of cancer death worldwide and Shien teaches DKK3 has therapeutic potential for lung cancer. One would have a reasonable expectation of success in combining the teachings as Cheng teaches the pharmaceutical composition can be used to treat lung cancer and Aliotta teaches exosomes derived from healthy lung cells do not cause pulmonary dysfunction and Veness-Meehan and Westergren-Thorsson teach decorin inhibits TGF-β signaling and Shien teaches DKK3 suppresses lung tumor growth in vivo.
Applicant’s Arguments/ Response to Arguments
17. Applicant Argues: On page 5, last para., Applicant states that support for the amendment to claim 1 can be found throughout the originally filed specification including paragraphs 0219 – 0221, Examples 1 – 3 and Figure 5, which disclose how the LSC-EXOs of the present claims were generated without the use of any genetic alteration (e.g., adenoviral infection).
Response to Arguments: The previous rejection of the claims over the prior art has been withdrawn in view of the amendment to claim 1. However, the amendment is not supported by Applicant’s disclosure as the scope of “genetically unaltered” lung tissue has not been contemplated.
Applicant Argues: On page 6 – 8, para. 1 – 2, Applicant disagrees with the Examiner’s interpretation and use of Kolb especially that Kolb discloses “endogenous decorin”.
Response to Arguments: The previous rejection of the claims citing the teachings of Kolb have been withdrawn in view of the amendment to claim 1. In the new rejection, Veness-Meehan teaches rat lungs express decorin (Figure 1; page 8, para. 3 – 4). Veness-Meehan teaches decorin mRNA is present in rat lung and its level increases as the rat ages (page 10, para. 2; Figure 3A, C, E). Veness-Meehan teaches decorin protein is present in rat lung connective tissue surrounding bronchi and blood vessels, airway epithelium and alveolar walls (page 13, para. 1; Figure 4A, C, E). Veness-Meehan teaches decorin expression decreases in rat lungs with hyperoxia injury and the level of decorin decrease increases with age (Figure 1; page 10, para. 2; Figure 3 B, D, F; Figure 4B, D, F; page 13). Veness-Meehan teaches oxygen exposure decreases decorin protein in lung connective tissue (page 13; Figure 4B). Veness-Meehan teaches the temporal and spatial changes in decorin expression support a role for decorin in the cellular response to oxygen-induced lung injury (page 20, last para.). Westergren-Thorsson teaches TGF-β1 mRNA increased while decorin mRNA decreased in lung tissue in a rat model of bleomycin-induced pulmonary fibrosis (Abstract; page 633, right col. last para.; page 634, left col. para. 1 and right col.; page 635, right col. para. 1 – 2). Westergren-Thorsson teaches pulmonary fibrosis is the final pathway of many interstitial lung diseases and is characterized by a massive production of fibrous connective tissue around the alveoli (page 632, left col.). Westergren-Thorsson teaches in the early stage of fibrosis, TGF-β is found in macrophages dispersed in the alveolar interstitium and in organized clusters and later TGF-β is primarily associated with ECM in regions of increased cell number (page 632, right col. para. 1). Westergren-Thorsson teaches decreasing a concentration of decorin may enhance the effects of TGF-β via a lower degree of immobilization of the growth factor (page 636, left col. para. 3). Therefore, Veness-Meehan and Westergren-Thorsson teach that genetically unaltered lung tissue has endogenous decorin and one would have been motivated to combine the teachings of Cheng, Aliotta, Veness-Meehan, and Westergren-Thorsson in a pharmaceutical composition comprising LSCs and LSC-EXOs derived from lung tissue with endogenous decorin and miRNA for treating a pulmonary pathological condition as Cheng teaches in a rat model of pulmonary fibrosis, LSCs reduce fibrotic thickening and infiltration, however, the underlying mechanisms need to be further elucidated and Cheng teaches LSC-conditioned media promotes survival/proliferation of human lung epithelial cells and Aliotta teaches EVs contain numerous DNA, RNA, and protein species and are capable of inducing changes in transcription, translation and surface protein expression in cells with which they come in contact and Veness-Meehan teaches lung tissue contains the proteoglycan decorin and decorin is likely to participate in the response to injury and proteoglycans are likely to influence the healing process through their effects on matrix assembly and cell adhesion and through growth factor interactions and Westergren-Thorsson teaches decreased decorin as seen in a model of pulmonary fibrosis may enhance the effects of TGF-β. One would have a reasonable expectation of success in combining the teachings as Cheng teaches human LSCs inhibit apoptosis, fibrosis, and infiltration in a mouse model of pulmonary fibrosis and Aliotta teaches exosomes derived from healthy lung cells do not cause pulmonary dysfunction and Veness-Meehan and Westergren-Thorsson teach the level of decorin in the lung decreases in response to lung injury.
Applicant Argues: On page 8, Applicant asserts that the Examiner’s issuance of new grounds of rejection under 35 USC 103 for at least the third time after Applicant has overcome the previous rejections is inconsistent with the USPTO’s policy of compact prosecution, especially considering that thirteen prior art references have been cited during the prosecution of this application, many of which have been overcome. Applicant submits that "[t]he Office's policy of compact prosecution requires that both examiners and applicants provide the information necessary to raise and resolve the issues related to patentability expeditiously." (Official Gazette of 07 November 2003). Whenever practicable, an Office Action should indicate how rejections may be overcome and how objections and informalities may be resolved. The rationale is that a failure to follow this approach can lead to unnecessary delays in the prosecution of the application (See, e.g., MPEP § 2106II.). Accordingly, Applicant respectfully requests withdrawal of all remining rejections and allowance of the claims as currently amended.
Response to Arguments: In response, MPEP § 2106II refers to establishing broadest reasonable interpretation of claim as a whole. MPEP 2173.06 (I) states that “The goal of examination is to clearly articulate any rejection early in the prosecution process so that the applicant has the chance to provide evidence of patentability and otherwise reply completely at the earliest opportunity. See MPEP § 706. Under the principles of compact prosecution, the examiner should review each claim for compliance with every statutory requirement for patentability in the initial review of the application and identify all of the applicable grounds of rejection in the first Office action to avoid unnecessary delays in the prosecution of the application. See 37 CFR 1.104(a)(1) ("On taking up an application for examination or a patent in a reexamination proceeding, the examiner shall make a thorough study thereof and shall make a thorough investigation of the available prior art relating to the subject matter of the claimed invention. The examination shall be complete with respect both to compliance of the application . . . with the applicable statutes and rules and to the patentability of the invention as claimed, as well as with respect to matters of form, unless otherwise indicated.").” The Examiner has reviewed the amended claims for compliance with every statutory requirement for patentability and provided the information regarding issues related to patentability in this Office action.
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Z.M.B./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
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