DETAILED ACTION
Applicant’s response filed 9/1/2026 has been received and entered into the application file. All arguments have been fully considered. Claims 8-10, and 13-17 are currently pending. Claims 1-7 and 11-12 are cancelled. Claim 13 is withdrawn. Claims 14-17 are new. Claim 8 is amended.
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Claim Objections - Withdrawn
It is noted that claim 12 has been cancelled.
Applicant’s amendment submitted 9/1/2026 obviates the previous objection to claim 8. Therefore, the objection is withdrawn.
Specification -Objection Withdrawn
Applicant’s amendment to the specification submitted 9/1/2026 is accepted.
REJECTION(S) WITHDRAWN
Claim Rejections - 35 USC § 112
RE: Rejection of Claims 8-12 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:
It is noted that claims 11-12 have been cancelled.
Applicant’s amendment submitted 9/1/2026 has sufficient written description. Therefore, the previous rejection of record is withdrawn.
RE: Rejection of Claims 8-12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite:
It is noted that claims 11-12 have been cancelled.
Applicant’s amendment submitted 9/1/2026 obviates the previous rejection of record. Therefore, the rejection is withdrawn.
Claim Rejections - 35 USC § 102
RE: Rejection of Claim(s) 8-10 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Mummery et al., WO 2014/200340, IDS 8/27/2024) (“Mummery”):
The rejection is withdrawn in view of Applicant’s claim amendments submitted 9/1/2026. However, Applicant’s amendment has necessitated new grounds of rejection as set forth below.
Claim Rejections - 35 USC § 103
RE: Rejection of Claim 11 under 35 U.S.C. 103 as being unpatentable over Mummery, in view of Gerecht; and
Rejection of Claim 12 under 35 U.S.C. 103 as being unpatentable over Mummery:
For the reasons discussed above, the anticipation rejection over Mummery is withdrawn, and thus the obviousness rejections that are based on the same basis are likewise withdrawn. However, the amendment submitted 9/1/2026 has necessitated new grounds of rejection, as set forth below.
NEW GROUND(S) OF REJECTION, NECESSITATED BY AMENDMENT
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.
Claim(s) 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Mummery et al., WO 2014/200340, IDS 8/27/2024, previously cited) (“Mummery”), in view of Ludlow et al., (WO 2011/140137; IDS 8/27/2024) (“Ludlow”), and Gerecht et al., (WO 2015/119642; IDS 8/27/2024, previously cited) (“Gerecht”).
Regarding claims 8-10, Mummery is directed to methods for in vitro production of endothelial cells (ECs), pericytes, pericyte-derived smooth muscle cells and vasculature (page 1, lines 4-6). Mummery teaches improved protocols for differentiation of PSCs (pluripotent stem cells), particularly hPSCs (human pluripotent stem cells) toward EC lineages. The protocols result in very efficient generation of ECs from PSCs, preferably human ESCs (embryonic stem cells) and iPSCs (induced pluripotent stem cells) (page 1, line 26 to page 2, line 4).
It is noted that Mummery teaches that pericytes are perivascular progenitor cells (page 8, lines 10 and 32-33).
Mummery teaches a method comprising,
(a) culturing pluripotent stem cells in defined medium containing Activin A, BMP4, VEGF, preferably VEGF165, and a canonical WNT ligand or GSK3 inhibitor (i.e., CHIR99021) (claim 9), to produce a culture comprising differentiated cells,
(b) culturing the cells obtained in step (a) in defined medium containing VEGF, and a TGFbeta signaling inhibitor (i.e., SB431542) (claim 10), to produce endothelial cells, the pluripotent stem cells are preferably iPSC. The method yields a high number of endothelial cells, and the endothelial cells produced can be purified with CD34 coupled magnetic beads (page 12, lines 21-33; page 19, lines 12-20; page 29, lines 29-33 to page 30, line 1). The method further comprises collecting the cells produced in step (b) and obtaining a collection of cells that comprises more than 90% endothelial cells based on the expression of CD31, CD34 or VE-cadherin (page 13, lines 6-9; claims 7-8). The same method can be used to produce pericytes (i.e., perivascular progenitor cells) and further comprises collecting the cells produced in step (b) and obtaining cells comprising more than 90% pericytes based on the expression of CD31. Preferably, the CD31 negative fraction is collected. The cells are typically negative for CD34 and VE-cadherin (page 14, lines 15-28; claims 9-10). hiPSCs differentiation was induced three days after passing colonies by replacing mTeSR medium with the differentiation media based on BPEL with the addition of activin A, BMP4, VEGF165 and small molecule inhibitor CHIR99021 (claim 9). At day 3, and day 7 of differentiation the media was refreshed with BPEL containing VEGF and SB43152 only (page 26, lines 9-19) (For steps (a)-(c) of claim 8 and claim 10).
Further regarding claim 8 and the limitation directed to separating CD31-CD140b+ perivascular progenitor cells and separating CD31+CD140b- endothelial cells, it is noted that Mummery (page 13, lines 6-30) teaches fractionation (i.e., separating) of cells based on marker profile, wherein the endothelial cells are positive for CD31 and negative for PDGFRb (synonymous with CD140b) and Mummery (page 14, line 24 to page 15, line 13) teaches fractionation (i.e., separating) of the perivascular progenitor cells, wherein the perivascular progenitor cells are negative for CD31 and positive for PDGFRb (synonymous with CD140b), thus meeting the limitation of claim 8, step (d).
Further regarding claim 8 and the limitation directed at delivering the endothelial cells and the perivascular progenitor cells to a lung scaffold, it is noted that although Mummery teaches the prepared cells are useful for future tissue engineering applications (page 36, line 30 to page 37, line 2), Mummery does not further comment on seeding/delivering said cells to a lung scaffold. However, Ludlow teaches of respiratory tissue scaffolds that are implantable into the lung, i.e. a lung scaffold, and the scaffold is suitable for seeding a first cell population that is an adipose-derived smooth muscle cell (Ad-SMC) population and a second cell population that is a respiratory cell population derived from lung (e.g. p. 46, lines 13-18). The polymeric matrix or scaffold is suitable for implantation at, on, or into a part of the lung, and the polymeric matrix or scaffold is shaped to conform to at least a part of the native respiratory tissue such as lung, alveolar tissue, and bronchiolar tissue (e.g. p. 46, lines 7-12). The Ad-SMCs may be derived from capillaries, arterioles, or the SMCs may be derived from the perivascular niche containing pericytes (e.g. p. 10, lines 6-8). Ludlow teaches scaffolds that have been seeded with a cell population may be referred to as “constructs” (e.g. p. 59, lines 34-35). Respiratory tissue constructs that include a scaffold, a first cell population of a smooth muscle cell population (SMC) and a second cell population that is a respiratory cell population that is subsequently seeded on the scaffold that has been pre-seeded with SMCs (e.g. p. 60, lines 9-16). Ludlow teaches the constructs can be used to provide a lung tissue structure to a subject for reconstruction, augmentation or replacement of respiratory tissue (e.g. p. 60, lines 35-38). Ludlow further teaches blood vessel scaffolds to form blood vessel constructs comprising a first cell population that is a smooth muscle cell population and a second cell population that is an endothelial cell population (e.g. p. 61, lines 36, to p. 62, line 6).
Therefore, given that Mummery teaches the endothelial cells (ECs) and perivascular progenitor cells are useful for tissue engineering purposes, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to deliver the endothelial cells and the perivascular cells to a lung scaffold since Ludlow has demonstrated the successful preparation of a respiratory tissue scaffold comprising a smooth muscle cell population derived from perivascular cells and an endothelial cell population. Ludlow teaches the respiratory tissue scaffold can be used to provide at least a part of the native respiratory tissue such as alveolar tissue, which contains endothelial cells. Thus, the second cell population of respiratory cell population derived from a lung as taught by Ludlow would encompass endothelial cells. Therefore, it would be obvious for one of ordinary skill in the art to deliver two cell populations including SMCs that are derived from pericytes and respiratory cells such as endothelial cells to seed the lung scaffold taught by Ludlow in order to treat a subject for reconstruction, augmentation or replacement of respiratory tissue with reasonable expectation of success. Further, Ludlow also teaches blood vessel scaffolds to form blood vessel constructs comprising a first cell population that is a smooth muscle cell population and a second cell population that is an endothelial cell population. Since the lungs include alveolar tissue having blood vessels wrapping around alveolar, it would be obvious for one of ordinary skill in the art to deliver the endothelial cells and the perivascular cells to a lung scaffold in order to form blood vessels in the lung scaffold for reconstruction, augmentation or replacement of respiratory tissue with reasonable expectation of success.
One having ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so in order to produce a cell culture comprising endothelial cells or pericytes with more than 90% purity via the differentiation of hiPSCs as taught by Mummery or to provide respiratory tissue scaffold or constructs to a subject for reconstruction, augmentation or replacement of respiratory tissue as taught by Ludlow with reasonable expectation of success.
Further regarding claim 8 and the limitation “maintaining hypoxic culture conditions of 4% or less of O2”, it is noted that Mummery does not specifically teach maintaining hypoxic culture conditions of 4% or less of O2. However, Gerecht is directed to differentiation of pluripotent stem cells (PSCs) under hypoxic conditions toward early vascular cells (EVCs) and teaches that low oxygen tension is a critical regulator of the developing or regenerating vasculature (Abstract and [0003]), wherein the cells have positive expression of VE-cadherin ([0012]). Gerecht’s method cultures under hypoxic conditions that are characterized by oxygen concentrations less than 10%, and more specifically ranging from 1% to 10% oxygen (O2) ([0048]).
Thus, Gerecht has established it was known to employ hypoxic conditions to promote differentiation of pluripotent stem cells to endothelial lineage.
Hence, taking into hand the teaching of Gerecht, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to maintain hypoxic culture conditions of 10% or less (claimed range overlaps the prior art range) of O2 during the culturing of hiPSCs toward endothelial cells because Gerecht teaches low oxygen tension, such as 1% O2 condition, enhances endothelial fate of human pluripotent stem cells. It would be obvious for one of ordinary skill in the art to culture the hiPSCs taught by Mummery in hypoxic condition to produce endothelial cells in order to enhance endothelial lineage commitment as taught by Gerecht with reasonable expectation of success. One of ordinary skill in the art would try different hypoxic condition, including 4% or less O2 condition, to optimize and enhance the efficiency of differentiating hiPSCs into endothelial cells with reasonable expectation of success.
One having ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so in order to produce a cell culture comprising endothelial cells or pericytes with more than 90% purity via the differentiation of hiPSCs as taught by Mummery or to increase expression of VEcad as taught by Gerecht with reasonable expectation of success.
Claim(s) 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Mummery, in view of Ludlow and Gerecht, as applied to claims 8-10 above, and further in view of Ott et al., (US 2017/0015963; IDS 8/27/2024) (“Ott”).
The teaching of Mummery, in view of Ludlow and Gerecht is set forth above.
Regarding claim 14, it is noted the teaching of Mummery, in view of Ludlow and Gerecht, does not further teach providing a multiphase culture program to the scaffold that comprises (1) a first phase including delivering a first medium comprising pro-angiogenic factors, and (2) a second phase including delivering a second medium comprising serum pro-angiogenic factors, forskolin and hydrocortisone, the second medium configured to promote vascular stabilization and barrier function functionality (claim 14). The combined prior art does not teach.
Ott teaches a lung tissue matrix is seeded with cells (e.g. [0087]), wherein regenerative cells can include human mesenchymal stem cells and human umbilical vein endothelial cells (e.g. [0088]). The lung tissue matrix can be alternatively or further seeded with differentiated cell types such as epithelial cells and endothelial cells. For example, a lung matrix can be seeded with endothelial cells via the vasculature through the arterial line or the venous line, and seeded with epithelial cells via the airway through the tracheal line. The lung matrix can be seeded with one or more cell types including mesenchymal cells, epithelial cells and/or human umbilical vein endothelial cells (HUVEC) (e.g. [0089]). EGM-2 kits may be used for endothelial cells (e.g. EGM-2 BulletKit by Lonza). Customized media can be used for seeding endothelial cells. Ott teaches a first phase of culture, wherein cell seeded constructs are perfused with an angiogenic media (i.e., a first medium) for 2-30 days to increase endothelial cell expansion, migration, and metabolism. The first cell medium comprises a high concentration of cytokines, such as VEGF at 5-100 ng/ml and bFGF at 5-100 ng/ml (i.e. pro-angiogenic factors), and PMA may be used. Ott teaches a second phase of culture that employs a tightening media (i.e., a second medium) comprising lower levels of pro-angiogenic cytokines (e.g. 0.1-5 ng/ml VEGF, FGF and PMA, claim 17) but containing hydrocortisone, which promotes tight junction formation and reduces pulmonary edema, which is used to promote vascular maturation (e.g. [0090]). EGM-2 Bulletkit medium by Lonza contains 10 ml fetal bovine serum (FBS) in 500 ml medium. Thus, there is 2% of serum in the EGM-2 medium, which overlaps with the 0.5-2% serum in second medium (claim 17).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to perform the first phase including delivering a first medium comprising pro-angiogenic factors, and perform a second phase including delivering a second medium comprising serum pro-angiogenic factors, forskolin and hydrocortisone, the second medium configured to promote vascular stabilization and barrier function functionality because Ott teaches in a first phase, cell seeded constructs may be perfused with an angiogenic media for 2-30 days to increase endothelial cell expansion, migration, and metabolism, and in a second phase, tightening media comprising lower levels of cytokine (e.g. 0.1-5 ng/ml VEGF, FGF and PMA) and containing hydrocortisone can be used to promote vascular maturation.
One having ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so in order to increase endothelial cell expansion and migration and promote vascular maturation in order to provide a mature lung organ as taught by Ott with reasonable expectation of success.
Regarding claim 15, Ludlow (page 33, lines 33-36) and Ott ([0090]) teach using the pro-angiogenic factor VEGF, thus meeting the limitation of claim 15.
Regarding claim 16, it is noted that, in the first phase, 2-30 days taught by Ott encompasses 6 days of the first phase as claimed, and since Ott also teaches a second phase culturing, it would be obvious for one of ordinary skill in the art to try different days of culturing, such as 2 days of second phase culturing, in order to optimize the culturing condition to promote vascular maturation.
One having ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so in order to provide a mature lung organ as taught by Ott with reasonable expectation of success.
Regarding claim 17, Ott teaches the second phase of culture employs a tightening media (i.e., a second medium), wherein the second medium comprises lower levels of pro-angiogenic cytokines (e.g. 0.1-5 ng/ml VEGF, FGF and PMA) ([0090]). In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Response to Remarks
As set forth above, the previous rejections of record have been withdrawn in view of Applicant’s amendments.
Applicant’s remarks have been fully considered but are not found persuasive for the reasons set forth above under the new grounds of rejection specifically addressing the newly amended limitations.
Conclusion
No claim is allowed. No claim is free of prior art.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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