DETAILED ACTION
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 .
Priority
Applicants claim for priority to a provisional application 63/243,606 is acknowledged. The effective filing date for claims 1-2, 5, 8, 10, 15, 19, 23, 27, 29, 32, 33, 37, 38, 48, 50, 52, 63, and 85 is Sept. 13, 2021.
Claim Status
In the reply filed on Nov. 24, 2025, Applicant has amended claim 1, and 5; and canceled claims 3-4, 6-7, 9, 11-14, 16-18, 20-22, 24-26, 28, 30, 31-36, 39-47, 49, 51, 53-62, 64-71, 73-75, 77-84 and 86-99. Claims 72 and 76 are withdrawn.
Applicant’s election without traverse of Group I (i.e. drawn to drawn to an in vitro method for producing human pluripotent stem cell (PSC)-derived cardiac progenitor cells of which differentiation of mesoderm cells, from cell aggregates, into cardiac progenitor cells is done in the presence of a Wnt inhibitor that promotes cardiac specification) was filed in the reply filed on 2/27/2025. Thus, Claims 72 and 76 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 Feb. 27, 2025.
Currently, claims 1-2, 5, 8, 10, 15, 19, 23, 27, 29, 37-38, 48, 50, 52, 63 and 85 are under examination in this Office Action.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 102
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 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.
Claims 1-2, 10, 15, 19, 29, and 37-38 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Palecek et al., (US 2013/0189785 A1, published 2013; cited IDS 02/26/2025).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on May 23, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Claim Interpretation: Claim 1c has been amended to recite a conditional step “by adding a Wnt inhibitor to promote cardiac specification” (lines 8-9), which results in in step (c) not being required by the claim. Therefore, this rejection is directed to claim 1 steps (a) and (b).
Regarding claim 1, Palecek discloses an in vitro method for producing human pluripotent stem cell (PSC)-derived committed cardiac progenitor cells (see e.g. abstract, claim 1, Example 1, para. 86-95)). Further, Palecek discloses (a) culturing PSCs in the presence of a Wnt agonist (i.e. CHIR99021, “CH”) to initiate differentiation and a survival agent (i.e. small molecule, XAV939)(para. 15, 76); (b) further culturing the cell aggregates in the presence of a Wnt agonist (i.e. CHIR99021, “CH”) for a period of time sufficient to produce a population of mesoderm cells (see e.g. Example 1, para. 48, 70, 75), and thereby producing a population of committed cardiac progenitor cells.
Regarding claim 2, Palecek discloses wherein the PSCs are induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs)(see e.g. Example 1, para. 46, 68).
Regarding claim 10, Palecek discloses wherein the Wnt agonist of step (a) is CHIR 99021(see e.g. Example 1).
Regarding claim 15, Palecek discloses wherein the Wnt signaling agonist of step (b) is CHIR 99021(see e.g. Example 1).
Regarding claim 19, Palecek discloses wherein the culture of step (b) further comprises Activin A and BMP4 signaling antagonists (see e.g. Example 7, para. 119).
Regarding claim 29, Palecek discloses wherein the Wnt inhibitor of step (c) is IWR1 (see e.g. Example 1, para. 75-76).
Regarding claim 37-38, Palecek discloses wherein the culture of step (c) further comprises a BMP inhibitor, DMH1 (see e.g. Example 7, para. 119).
Therefore, the teachings of Palecek anticipates the instant claims.
Claims 1-2, 5, 10, 15, 29, and 63 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chien et al., (US20160053229 A1, published 2016; cited IDS 11/13/2023).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on May 23, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Claim Interpretation: Claim 1c has been amended to recite a conditional step “by adding a Wnt inhibitor to promote cardiac specification” (lines 8-9), which results in in step (c) not being required by the claim. Therefore, this rejection is directed to claim 1 steps (a) and (b).
Regarding claim 1 and 2, Chien discloses an in vitro method for producing human pluripotent stem cell (PSC)-derived committed cardiac progenitor cells (i.e. cardiomyogenic ventricular progenitor cells)(see e.g. abstract, claim 1, Example 1, paras. 123-143, 157-159, and 208-214, fig. 1).
Regarding claim 1a, 5, and 10, Chien discloses (a) culturing PSCs in the presence of a Wnt agonist (i.e. CHIR-98014) to initiate differentiation and a survival agent (i.e. ROCK inhibitor Y-27632) to form cell aggregates (see e.g. Example 1, paras. 123-143, 157-159, and 208-214, fig. 1).
Regarding claim 1b and 15, Chien discloses (b) further culturing the cell aggregates in the presence of a Wnt agonist (i.e. CHIR-98014) for a period of time sufficient to produce a population of mesoderm cells (see e.g. Example 1, paras. 123-143, 157-159, and 208-214, fig. 1).
Regarding claim 29, Chien discloses differentiating the population of mesoderm cells in the presence of a Wnt inhibitor (i.e. Wnt-C59 a Porcn inhibitor) to promote cardiac specification thereby producing a population of committed cardiac progenitor cells (see e.g. Example 1, paras. 123-143, 157-159, and 208-214, fig. 1).
Regarding claim 63, Chien discloses further comprising differentiating the population of committed cardiac progenitor cells to a population of vascular endothelial cells in the presence of fibroblast growth factor (i.e. FGFR3) or vascular endothelial growth factor (VEGF)(see e.g. paras. 14, 218, Example 8).
Therefore, the teachings of Chien anticipate the instant claims.
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.
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.
Claims 1-2, 5, 10, 15, 19, 23, 27, 29, 37-38, 48, 50, 52, 63 and 85 are rejected under 35 U.S.C. 103 as being unpatentable over Chien et al., (US2016/0053229 A1, published 2016; cited IDS 11/13/2023, prior art of record), Dalton et al. (WO2010/011352A2, published 2010; cited IDS 11/13/2023, prior art of record), Kreke et al., (US2018/0169150A1, published 2018) Kattman, et al. (Cell stem cell 8.2: 228-240, published 2011; cited IDS 11/13/2023, prior art of record), and Kawamura (US2015/0337266 A1, published 2015, prior art of record), as evidence by Evseenko et al. (Proceedings of the National Academy of Sciences 107.31: 13742-13747, published 2010).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on May 23, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Regarding claim 1, 2, and 85, Chien discloses an in vitro method for producing human pluripotent stem cell (PSC)-derived committed cardiac progenitor cells (i.e. cardiomyogenic ventricular progenitor cells)(see e.g. abstract, claim 1, Example 1, paras. 14, 123-143, 157-159, and 208-214, fig. 1).
Regarding claim 1a, 5, 10, and 85, Chien discloses (a) culturing PSCs in the presence of a Wnt agonist (i.e. CHIR-98014) to initiate differentiation and a Rho-associated kinase (ROCK) inhibitor (i.e. Y-27632) to form cell aggregates (see e.g. Example 1, paras. 14, 123-143, 157-159, and 208-214, fig. 1).
Regarding claim 1b and 15, Chien discloses (b) further culturing the cell aggregates in the presence of a Wnt agonist (i.e. CHIR-98014) for a period of time sufficient to produce a population of mesoderm cells (see e.g. Example 1, paras. 14, 123-143, 157-159, and 208-214, fig. 1).
Regarding claim 1c, 29, and 85, Chien discloses differentiating the population of mesoderm cells in the presence of a Wnt inhibitor (i.e. Wnt-C59) to promote cardiac specification thereby producing a population of committed cardiac progenitor cells (see e.g. Example 1, paras. 14, 123-143, 157-159, and 208-214, fig. 1).
Regarding claim 1c, 27, and 85, Chien discloses the markers for mesoderm cells, cardiac progenitor and cardiomyocytes were identified by the markers CXCR4 (see e.g. para. 14, 217, Example 2).
Chien is silent regarding the populations percentage that are positive for CD56, and wherein at least 20% positive of the population is positive for CXCR4, more than 30% positive for CXCR4, and 60% positive for CD56.
However, the prior art of Dalton teaches a method of generating CXCR4+/CD56+ cardiac progenitors by incubation of pluripotent stem cells with a Wnt inhibitor (i.e. agonist) (see e.g. pages 14-15, 17-19, 61-65, and figs. 8-19). and discloses at least 20% positive and more than 30% positive of the population of mesoderm cells (i.e. MMC) are positive for CXCR4 and about 61% of the population of mesoderm cells are positive for CD56 at day 6 of culture (see e.g. fig. 10C, pages 17 and 61-65).
Although Dalton does not explicitly teach less than 60% of the population of mesoderm cells are positive for CD56. However, the prior art of Kreke discloses optimized methods for generating cardiac stem cells that express CD56 are at an average of about 20 to about 50 percent (see e.g. para. 23, fig. 13).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of Chien with at least 20% positive or more than 30% positive of the mesoderm population that is positive for CXCR4 and less than 60% positive for CD56 as taught by Dalton and Kreke because both Dalton and Kreke disclose optimized methods for generating committed cardiac progenitor cells (see e.g. abstracts, respectively). Dalton discloses methods of generation committed cardiac progenitor cells expressing CXCR4 and CD56 over a time period of 3-6 days (see e.g. Fig. 6). However, the prior art of Evseenko discloses that while CD56+ cells represent the earliest multipotent mesodermal progenitors at about day 3, CD56+ cells are capable of giving rise to all of the above progenitor cell phenotypes related to mesodermal lineages, and become more committed (e.g. cardiac progenitor cells) by day 7 of induction (see e.g. page 13746, and fig. 4). A person of ordinary skill in the art would have then optimize the culturing time period and obtain a less than 60% positive expression of CD56+ cells (as taught by Dalton and Kreke), because the mesoderm cell population would be more committed to cardiac progenitor cells as evidence by Evseenko. Thus, a person of ordinary skill in the art would have optimized the culture time period in order to generate specific cardiac progenitor cells. Moreover, person of ordinary skill in the art would have had predictable results with a reasonable expectation of success because both Dalton and Chien discloses method of obtaining cardiac progenitor cells expressing CXCR4 (see e.g. claim 92, and para. 170, respectively).
Regarding claim 19, and 37-38, as stated supra, Chien discloses (b) further culturing the cell aggregates in the presence of a Wnt agonist (i.e. CHIR-98014) for a period of time sufficient to produce a population of mesoderm cells (see e.g. Example 1 paras. 119, 123-143, 157-159, and 208-214, fig. 1).
Chien does not explicitly state wherein the culture of step (b) and (c) further comprises an Activin agonist (i.e. inhibitor) and/or a BMP inhibitor.
However, the prior art of Dalton discloses methods of generating CXCR4+/CD56+ cardiac progenitors with the Activin agonist (i.e. SB431542)(see e.g. pages 14, 26, and Fig. 14). Further Dalton discloses methods of obtaining committed cardiac progenitors by culturing with a BMP inhibitor dorsomorphin (i.e. Compound C)(see e.g. pages 14, 26, and Fig. 14).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the cardiac progenitor cells methods (as taught by Chien) and incorporate the step of culturing with a Activin agonist and a BMP inhibitor as taught by Dalton because Dalton discloses optimized methods for generating committed cardiac progenitor cells (See e.g. figs. 1, 8, 11-16, and 20). Further, Dalton and Chien both disclose methods of obtaining cardiac progenitor cells for the benefit of improving damaged cardiac and/or vascular tissue (see e.g. claim 92, and para. 170, respectively). A person of ordinary skill in the would have had predictable results because Chien discloses methods for promoting cardiac progenitor cells (see e.g. Example 1), and Dalton discloses methods for generating committed cardiac progenitors’ cells (see e.g. pages 14, 26, and Fig. 14). Thus, a person of ordinary skill in the art would have had a reasonable expectation of success because both Chien and Dalton discloses methods for generating cardiac progenitor cells (see e.g. abstract, respectively).
Regarding claim 23 and 48, as discussed above, Chien discloses differentiating the population of mesoderm cells in the presence of a Wnt inhibitor and the cardiac progenitor marker PDGFRα (see e.g. para. 14). As discussed above, Dalton teaches at least 6% of the population of mesoderm cells express CD56 prior to step (c) (see e.g. pages 14-15, 17-19, 61-65, and figs. 8-19).
Chien is silent regarding wherein at least 40% of the population of mesoderm cells express KDR and PDGFRα prior to or during step (c), and less than 20% of the population of committed cardiac progenitor cells are positive for KDR and PDGFR.
However, the prior art of Kattman discloses wherein at least 40% of the population of mesoderm cells express KDR and PDGFRα prior to or during step (c) and less than 20% of the population of committed cardiac progenitor cells are positive for KDR and PDGFR. (see e.g. abstract, figs. 1, 3-5, page 234).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods (as taught by Chien) to incorporate the population of mesoderm cells express KDR and PDGFRα as taught by Kattman because Kattman discloses that the emergence of the cardiac mesoderm can be monitored by co-expression of KDR and PDGFRα and the process was dependent on optimal levels of Activin/Nodal and BMP signaling (see e.g. abstract). A person of ordinary skill in the art would have had predictable results of obtaining a population of committed cardiac progenitor cells with a reasonable expectation of success because Chien and Kattman both disclose method for obtaining a cardiac mesoderm population of cells (see e.g. abstracts, respectively).
Regarding claims 48, 50, and 52, as discussed above, Chien discloses the markers for mesoderm cells, cardiac progenitor, and cardiomyocytes that were identified by the marker CXCR4 (see e.g. para. 14, 217, Example 2).
Chien is silent regarding the population of committed cardiac progenitor cells are 80% positive for PDGFRα, and CD56.
However, the prior art of Dalton discloses wherein the population of committed cardiac progenitor cells are positive for PDGFRα and CD56 (figs. 7-10 and 42). Further, Dalton discloses that the expression of PDGFRα and CD56 (i.e. NCAM) is at least 80% and at day 6 (see e.g. fig. 9). Additionally, Dalton discloses cryopreserving the population of committed cardiac progenitor cells that are at least 70% positive for PDGFRα (see e.g. fig. 9, page 59), less than 40% positive for KDR (see e.g. fig. 8-10), and less than 20% for sarcomeric alpha actinin (i.e. SAA or Sarc. Actin) (see e.g. fig. 4,6c)(See e.g. pages 40, 59).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of Chien with the percentages of the population of mesoderm cells that are positive for PDGFRα, CD56, KDR, SAA, as taught by Dalton because Dalton discloses the potential for cardiac progenitor cells C56Cs (i.e. CXCR4, PDGFRα, and CD56) to treat damaged and/or inflamed tissue in a patient (see e.g. page 3, 7, 45-46, 62-63, and claim 33, fig. 15-16). Furthermore, Dalton that the expression of PDGFRα increases at day 8 (see e.g. fig. 42). Thus, a person of ordinary skill in the art would have been able to optimize the culturing time period and obtain at least 80% of the population of committed cardiac progenitor cells that are positive for PDGFRα and CD56 (figs. 7-10 and 42) as taught by Dalton because the mesoderm cell population would be more committed to cardiac progenitor cells. Thus, a person of ordinary skill in the art would have optimized the culture time period in order to obtain at least 80% of the population that are positive for PDGFRα and CD56 and are specific cardiac progenitor cells. Moreover, person of ordinary skill in the art would have had predictable results with a reasonable expectation of success because both Dalton and Chien discloses method of obtaining cardiac progenitor cells expressing CXCR4 (see e.g. claim 92, and para. 170, respectively).
Regarding claims 52, as stated supra, Chien and Dalton et al., are silent regarding the population is less than 20% positive for Epithelial Cell Adhesion Molecule (EpCAM).
However, the prior art of Kawamura discloses culturing cardiac progenitor cell that is less than 20% positive for Epithelial Cell Adhesion Molecule (EpCAM)(see e.g. fig. 24, para. 67).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of Chien to incorporate the cardiac progenitor cell that is positive for EpCAM as taught by Kawamura because Kawamura teaches that EpCAM is a marker for iPS cells to have differentiation potency to cardiac progenitors (see e.g. fig. 24, para. 67). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success combining the EpCAM positive cells as taught by Kawamura with the cardiac progenitor cells as taught by Chien and Dalton to obtain committed cardiac progenitor cells.
Regarding claim 63, Chien discloses further comprising differentiating the population of committed cardiac progenitor cells to a population of vascular endothelial cells in the presence of fibroblast growth factor (i.e. FGFR3) or vascular endothelial growth factor (VEGF)(see e.g. paras. 14, 218, Example 8).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that the Wnt inhibitor that is used for cardiomyocyte specification is once the cells begin to become CD56 and CXCR4, as shown in FIG. 3A, which is at a certain time point during cardiac differentiation, which has never been well described in the prior art (Remarks, page 8-9). Further, Applicant asserts unexpected results regarding the time point and that efficient cardiac specification only occurred if the CXCR4 positive population had just began to express CD56, and that robust expression of CD56 was one indication that too much CHIR 99021 was used or the cell densities were too low” (Remarks, page 8-9).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicant argument that the prior art does not describe a certain time point during cardiac differentiation and the time point of the cell’s expression CXCR4, the claims do not require a time point during differentiation or a time frame of expressing CXCR4. Contrary to Applicants assertion the claims recite “adding” which is a conditional limitation and does not recite a time period or the concentration of agonist that is used during culturing. In response to applicant's argument that that robust expression of CD56 was one indication that too much CHIR 99021 was used, or that the cell densities were too low, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In the instant case the prior art of Chien, Dalton, Kreke as evidence by Evseenko disclose that a person of ordinary skill in the art would use the cardiac progenitor markers CXCR4 and CD56 to obtain committed cardiac progenitor cells. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., time and cell density) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the instant case, the claims do not recite a culturing period, time frame of adding an agonist, or a cells density amount. It is noted that the independent claim generally recites a Wnt agonist and is not specific CHIR99021 and does not disclose an amount or time period.
Applicant argues that the aspect of determining when to add the Wnt inhibitor by measuring when at least 20% positive of the population of mesoderm cells are positive for CXCR4 and less than 60% of the population of mesoderm cells are positive for CD56 could not have been predicated based on the disclosure of Chien (i.e. CXCR4 from day 2 or day 3) (Remarks, page 8-9).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
As discussed above, the claim does not recite a time from for the population of mesoderm cells are positive for CD56 (i.e. CXCR4 from day 2 or day 3). Therefore, the arguments are not commensurate in scope with the claims. It is noted that Chien is silent regarding the marker CD56, but does disclose the marker CXCR4 for mesoderm cells, cardiac progenitor and cardiomyocytes (see e.g. para. 14, 217, Example 2), and the prior art of Dalton is cited for CXCR4+/CD56+ cardiac progenitors by incubation of pluripotent stem cells with a Wnt agonist and a TGF inhibitor (see e.g. pages 14-15, figs. 8, 14-19). Further, the prior art of Kreke discloses optimized methods for generating cardiac stem cells that express CD56 are at an average of about 20 to about 50 percent (see e.g. para. 23, fig. 13). In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Applicant asserts that the declaration under 37 CFR 1.132 filed by the inventor Chad Koonce on 11/24/2025 is sufficient to overcome the rejection of instant claims because the cultures above 60% positive for CD56 as taught by Dalton have a reduced potential to become cardiomyocytes as shown by the decreased percentage of SAA-positive cells (see Exhibit A)(Remarks, page 9). Further, Applicant argues that Dalton discloses a cell population is comprised of “CXCR4/CD56 positive cells, such as in FIG. 10B, where the cells are 81 % positive for CD56 and 90% positive for CXCR4 FIG. 17”. Applicant asserts that Dalton does not adding a Wnt inhibitor at a specific timepoint in the differentiation process. (Remarks, page 8-9).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. As discussed above, the claim does not recite a specific timepoint in the differentiation process were the population of mesoderm cells are positive for CD56 (i.e. CXCR4 from day 2 or day 3). Therefore, the arguments are not commensurate in scope with the claims. It is noted that Chien is silent regarding the marker CD56, but does disclose the marker CXCR4 for mesoderm cells, cardiac progenitor and cardiomyocytes (see e.g. para. 14, 217, Example 2). Further, the prior art of Dalton is cited for CXCR4+/CD56+ cardiac progenitors by incubation of pluripotent stem cells with a Wnt agonist and a TGF inhibitor (see e.g. pages 14-15, figs. 8, 14-19).
Declaration under 37 CFR 1.132
The declaration under 37 CFR 1.132 filed Nov. 24, 2025, is not sufficient to overcome the rejection of claim 103 based upon Chien et al., (US2016/0053229 A1, published 2016; cited IDS 11/13/2023, prior art of record), Dalton et al. (WO2010/011352A2, published 2010; cited IDS 11/13/2023, prior art of record), Kreke et al., (US2018/0169150A1, published 2018) Kattman, et al. (Cell stem cell 8.2: 228-240, published 2011; cited IDS 11/13/2023, prior art of record), and Kawamura (US2015/0337266 A1, published 2015, prior art of record), as evidence by Evseenko et al. (Proceedings of the National Academy of Sciences 107.31: 13742-13747, published 2010).
The declaration under 37 CFR 1.132 filed by the inventor Chad Koonce on 11/24/2025 is insufficient to overcome the rejection of instant claims based upon 35 U.S.C 103 as set forth in this Office action for the following reasons: It includes statements which amount to an affirmation that the claimed subject matter functions as it was intended to function. This is not relevant to the issue of nonobviousness of the claimed subject matter and provides no objective evidence thereof. See MPEP § 716. In the instant case, the declaration only refers to adding a Wnt inhibitor as described in the referenced application and not to the individual claims of the application. As such the declaration does not show that the objective evidence of nonobviousness is commensurate in scope with the claims.
It is noted that Applicant asserts that the cultures above 60% positive for CD56 as taught by Dalton have a reduced potential to become cardiomyocytes. As discussed above, a person of ordinary skill in the art would have then optimize the culturing time period and obtain a less than 60% positive expression of CD56+ cells (as taught by Dalton and Kreke), because the mesoderm cell population would be more committed to cardiac progenitor cells as evidence by Evseenko. Thus, a person of ordinary skill in the art would have optimized the culture time period in order to generate specific cardiac progenitor cells. Moreover, person of ordinary skill in the art would have had predictable results with a reasonable expectation of success because both Dalton and Chien discloses method of obtaining cardiac progenitor cells expressing CXCR4 (see e.g. claim 92, and para. 170, respectively). As discussed above, the claims do not require a time period. Therefore, the arguments are not commensurate in scope with the claims.
Applicant argues that the prior art of Laflamme teaches directed differentiation using activin A and BMP4, the prior art of Kattman discloses that the emergence of cardiac mesoderm cells from human ESCs can be monitored by co-expression of KDR and PDGFRα, and the prior art of Kawamura teaches culturing cardiac progenitor cells that are less than 20% positive for EpCam, and does not overcome the deficiencies of Chien (i.e. expressing 20% positive for CXCR4 or less than 60% positive for CD56 as markers of cardiac mesoderm (Remarks, page 9-11).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In response to Applicants arguments, that the prior art of Kattman and Kawamura are not cited for teaching the use of CXCR4 or CD56, as stated supra, the prior art of Chien, Dalton, and Kreke et al., are cited for teaching the markers CXCR4 and CD56. It is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, Chien discloses an in vitro method for producing human pluripotent stem cell (PSC)-derived committed cardiac progenitor cells (i.e. cardiomyogenic ventricular progenitor cells)(see e.g. abstract, claim 1, Example 1, paras. 123-143, 157-159, and 208-214, fig. 1). Further, it is noted that the prior art of Dalton discloses the differentiation of hESC-derived MMCs expressing CD56 (NCAM) under 50% at passage 23 and around 60% at day 2 (see page 6 and fig. 9) for producing cardiac progenitor cells. Additionally, the prior art of Kreke discloses optimized methods for generating cardiac stem cells that express CD56 are at an average of about 20 to about 50 percent (see e.g. para. 23, fig. 13). Accordingly, it would have been obvious for a person of ordinary skill in the art to have optimized the culture time period in order to generate specific cardiac progenitor cells.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Chien et al., (US2016/0053229 A1, published 2016; cited IDS 11/13/2023, prior art of record), Dalton et al. (WO2010/011352A2, published 2010; cited IDS 11/13/2023, prior art of record), Kreke et al., (US2018/0169150A1, published 2018) Kattman, et al. (Cell stem cell 8.2: 228-240, published 2011; cited IDS 11/13/2023, prior art of record), and Kawamura (US2015/0337266 A1, published 2015, prior art of record), as evidence by Evseenko et al. (Proceedings of the National Academy of Sciences 107.31: 13742-13747, published 2010), as applied to claims 1-2, 5, 10, 15, 19, 23, 27, 29, 37-38, 48, 50, 52, 63 and 85, above and in further view of Niebruegge, et al. (Biotechnology and bioengineering 102.2: 493-507, published 2009; cited IDS 11/13/2023, prior art of record).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on May 23, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
The teachings of Chien et al., apply here as indicated above.
Regarding claim 8, Chien discloses an in vitro method for producing human pluripotent stem cell (PSC)-derived committed cardiac progenitor cells (i.e. cardiomyogenic ventricular progenitor cells)(see e.g. abstract, claim 1, Example 1, paras. 123-143, 157-159, and 208-214, fig. 1), as discussed above.
Chien is silent regarding the method culturing cells in suspension culture in one or more bioreactors.
However, the prior art of Niebruegge discloses the beneficial effects of stirred bioreactor culture, aggregate size-control and hypoxia (4% oxygen tension) on both cell growth and cell differentiation towards cardiomyocytes (see e.g. abstract).
Regarding claim 8, Niebruegge wherein the method comprises culturing cells in suspension culture in one or more bioreactors (i.e. Rotomix VWR, Roller-bottle culture, and DasGip cellferm-pro) (see page 495).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of Chien to incorporate culturing cells in suspension culture in a bioreactor system as taught by Niebruegge because Niebruegge teaches that well characterized cardiomyocytes and their progenitors would be a valuable resource of pre-clinical transplantation studies and drug screening and tissue engineering protocols. A person of ordinary skill in the art would have wanted to incorporating culturing cells cardiomyocytes and their progenitors as taught by Chien in a bioreactor system as taught by Niebruegge because Niebruegge teaches the ability to control the size of an aggregate, in a manner that can be incorporated into a scalable differentiation bioprocess, may contribute to a more homogeneous and synchronized cell production system (see page 503). Therefore, incorporating the cardiomyocytes and their progenitors as taught by Chien with the bioreactor system as taught by Niebruegge would have led to predictable results with a reasonable expectation of success because both teach using cardiac progenitor cells for drug screening methods. Furthermore, an artisan of ordinary skill in the art of (i.e. cell culturing cardiomyocyte progenitor cells) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that the prior art of record does not teach the amended claim 1. Applicant asserts that Niebruegge does not overcome the deficiencies of Chien and does not teach using CXCR4 or CD56. (Remarks, page 9).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants arguments, the prior art of Niebruegge is not cited for teaching the use of CXCR4 or CD56, as stated supra, the prior art of Chien, Dalton, and Kreke et al., are cited for teaching the markers CXCR4 and CD56. Contrary to Applicants assertion the prior art of Niebruegge discloses the generation of derived mesoderm and cardiac cells (see e.g. title and abstract).
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claim is 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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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631
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