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 .
Status of the Claims
Claims 6-10, and 21-28 are pending.
Claims 6-8 are amended.
Claims 21-28 are new.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. 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 § 103 Claim - Necessitated by Amendment
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.
Hochedlinger
Claims 6-10, 21, 23-24, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over:
Hochedlinger (US20190161731A1) (Provided in IDS of 8/22/2025),
As evidenced by Wang (Wang Y, Zhao S. Vascular Biology of the Placenta. San Rafael (CA): Morgan & Claypool Life Sciences; 2010. Chapter 4, Cell Types of the Placenta. Available from: https://www.ncbi.nlm.nih.gov/books/NBK53245/)
Claim interpretation
Claim 6 recites the limitation of “placental cells.” However, “placental cells” are not defined in the specification. According the prior art, placental cells are not a single type of cell, but instead a placenta is made up different cell types. According to Wang, Placenta villi are composed of three layers of components with different cell types in each: (1) syncytiotrophoblasts/cytotrophoblasts that cover the entire surface of the villous tree and bathe in maternal blood within the intervillous space; (2) mesenchymal cells, mesenchymal derived macrophages (Hofbauer cells), and fibroblasts that are located within villous core stroma between trophoblasts and fetal vessels. Hofbauer cells synthesize VEGF and other proangiogenic factors that initiate vasculogenesis in the placenta; and (3) fetal vascular cells that include vascular smooth muscle cells, perivascular cells (pericytes), and endothelial cells. (Wang, first paragraph).
For the purposes of examination, any cell type (including fibroblasts) found in a placenta will be considered to read on a “placental cell”. For example, a fibroblast found in the placenta is a placental cell, but a fibroblast found elsewhere is not a placental cell.
Regarding claim 6, Hochedlinger teaches a composition of matter (Hochedlinger [0005]) comprising a mammalian cell culture media (Hochedlinger [0008]), wherein the cell culture media comprises a supplement comprising forskolin and RepSox (Hochedlinger [0080-0081]).
Hochedlinger teaches a method of deriving expandable myogenic stem cells (which they refer to as induced myogenic progenitor cells iMPC) from different somatic tissues (Hochedlinger [0065], [0230])).
Hochedlinger teaches a method of generating induced Myogenic Progenitor Cells (iMPCs) (i.e., myogenic stem cells), comprising treating a population of somatic cells obtained from a subject with cyclic AMP agonist, and a TGF-β inhibitor for a time and under conditions that induce dedifferentiation of the somatic cells to a population of cells comprising iMPCs. Hochedlinger teaches that in one embodiment, the somatic cells may be fibroblasts, and that the cyclic AMP agonist may be forskolin, and that the TGF-β inhibitor may be RepSox. (Hochedlinger [0006-0008]).
Regarding the placental cell limitation, , Hochedlinger does not give a specific example where they use placental fibroblasts or cells specifically derived from a placenta for their procedure. However, Hochedlinger appears to suggest that their method will work with virtually any somatic cell. Hochedlinger teaches that “muscle progenitor cells can be generated in vitro from somatic cells “ (Hochedlinger [0043]), For Hochedlinger, the term “somatic cells” as used herein refers to cell types in the mammalian body, apart from gametocytes, and undifferentiated stem cells. Examples of somatic cells include, but are not limited to fibroblasts, muscle cells, keratinocytes, melanocytes, and hepatocytes. (Hochedlinger [0050]). Hochedlinger specifies that in an embodiment the somatic cells may include muscle cells or fibroblasts (Hochedlinger [0050]). Wang teaches that fibroblasts are among the cell types that make up placental cells. (Wang, first paragraph). Hochedlinger further suggests that in some embodiments, a somatic cell can be a primary cell isolated from any somatic tissue including, but not limited to brain, liver, lung, gut, stomach, intestine, fat, muscle, uterus, skin, spleen, endocrine organ, bone, etc. (Hochedlinger [0069]).
That is, Hochedlinger does not specifically list placental tissue as a source of somatic cells, but Hochedlinger does suggest that their method may be used with somatic cells generally, that the cells may be obtained from “any somatic tissue.”
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to use somatic placental cells, which includes fibroblast cells, as the source of somatic cells used in Hochedlinger’s method of generating myogenic progenitor cells. One of ordinary skill in the art would have been motivated to do so, since the election of placental cells from among “any somatic tissue” is teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference to arrive at the claimed invention. (MPEP 2143 (I)(A)).
One of ordinary skill in the art would have had a reasonable expectation of success, since Hochedlinger teaches that myogenic stem cells can be generated in vitro with their method from somatic cells (Hochedlinger [0043]).
Regarding claim 7, Hochedlinger teaches that their resulting iMPCs overexpress MyoD by at least a 20% compared to control after at least 4 days as compared to control. (Hochedlinger, [0025] FIG. 2E, 3B)
Regarding claim 8, Hochedlinger teaches that in various embodiments, the method further comprises culturing the somatic cells and/or population of cells comprising iMPCs with ascorbic acid. (Hochedlinger [0011]). Hochedlinger teaches that ascorbic acid is an important vitamin in the generation of their progenitor-like cell population, i.e., enhances the induction of the iMPC. (Hochedlinger [0229]).
Regarding claim 9 and 10, Hochedlinger contemplates the treatment of acute or chronic muscle injury (Hochedlinger [0103]). Hochedlinger teaches in various embodiments, the iMPC cell composition can be administered intramuscularly by injection, and that artificially prepared tissues produced by expansion and differentiation of iMPCs in culture, alone or in conjunction with other cells and/or a scaffold comprising extracellular materials that can be implanted at a desired site intradermally, intramuscularly, or subcutaneously. (i.e., disposing the expanded iMPC at a site of injury in vivo) (Hochedlinger [0107]).
Regarding claim 21, Hochedlinger teaches a composition of matter (Hochedlinger [0005]) comprising a mammalian cell culture media (Hochedlinger [0008]), wherein the cell culture media comprises a supplement comprising forskolin and RepSox (Hochedlinger [0080-0081]).
Hochedlinger teaches a method of deriving expandable myogenic stem cells (which they refer to as induced myogenic progenitor cells iMPC) from different somatic tissues (Hochedlinger [0065], [0230])).
Hochedlinger teaches a method of generating induced Myogenic Progenitor Cells (iMPCs) (i.e., myogenic stem cells), comprising treating a population of somatic cells obtained from a subject with cyclic AMP agonist, and a TGF-β inhibitor for a time and under conditions that induce dedifferentiation of the somatic cells to a population of cells comprising iMPCs. Hochedlinger teaches that in one embodiment, the somatic cells may be fibroblasts, and that the cyclic AMP agonist may be forskolin, and that the TGF-β inhibitor may be RepSox. (Hochedlinger [0006-0008]).
Regarding the skeletal muscle stem cell limitation, Hochedlinger does not specifically give an example where they actually use a skeletal muscle stem cell as the primary cell, or at least they do not use that exact term “Skeletal muscle stem cell” for a potential somatic cell to be used in their method.
However, Hochedlinger does teach that muscle tissue contains a quiescent population of mononucleated stem cells termed satellite cells, which are located between the basal lamina and sarcolemma of myofibers. (Hochedlinger [0004]). Hochedlinger specifies that the term “muscle cell” refers to a cell of a myogenic lineage and includes satellite cells, myoblasts, myocytes and myotubes. (Hochedlinger [0051]).
Hochedlinger appears to suggest that their method will work with virtually any somatic cell, including muscle cells (which would include satellite cells/ muscle stem cells). Hochedlinger teaches that “muscle progenitor cells can be generated in vitro from somatic cells (e.g., muscle cells)“ (Hochedlinger [0043]), For Hochedlinger, the term “somatic cells” as used herein refers to cell types in the mammalian body, apart from gametocytes, and undifferentiated stem cells. Examples of somatic cells include, but are not limited to fibroblasts, muscle cells, keratinocytes, melanocytes, and hepatocytes. (Hochedlinger [0050]).
Hochedlinger further suggests that in some embodiments, a somatic cell can be a primary cell isolated from any somatic tissue including, but not limited to brain, liver, lung, gut, stomach, intestine, fat, muscle, uterus, skin, spleen, endocrine organ, bone, etc. (Hochedlinger [0069]).
Hochedlinger teaches that in their disclosure the term “cells derived from a muscle biopsy or muscle explant sample” comprise cells from a skeletal muscle fiber that endogenously express MyoD. In one embodiment, the cells are skeletal muscle cells. (Hochedlinger [0052]).
Hochedlinger teaches that the chemicals used in their method can also facilitate the expansion of stem cells isolated directly from muscle tissue. (Hochedlinger [0226]).
However, it would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to use skeletal muscle stem cells as the primary somatic cell component of Hochedlinger’s dedifferentiation method. One of ordinary skill in the art would have been motivated to do so, since Hochedlinger teaches that their method may work with muscle cells generally, including skeletal muscle cells, and muscle cells obtained from biopsies. Hochedlinger teaches that muscle cells are comprised of muscle stem cells in vivo, that their method may also use stem cells, and that those stem cells may be isolated directly from muscle tissue. This is a direct suggestion from Hochedlinger to use muscle stem cells, which would include those found in skeletal muscle, as the primary somatic cell of their method
One of ordinary skill in the art would have had a reasonable expectation of success, since Hochedlinger strongly suggests the use muscle stem cells, which would include those found in skeletal muscle, as the primary somatic cell of their method.
Regarding claim 23 and 24, Hochedlinger teaches that in an embodiment, the concentration of forskolin is 1μM to 10 μM (Hochedlinger [0080]. Hochedlinger teaches that in an embodiment, the concentration of RepSox is 1μM to 10 μM. (Hochedlinger [0081]).
Regarding claims 26 and 27, Hochedlinger teaches that their resulting muscle progenitor cells may be expanded to numbers useful for therapeutic purposes and can be maintained for long periods of time in culture (e.g., >4 months). (Hochedlinger [0043])
In example 1, Hochedlinger reports a method to reprogram or dedifferentiate mouse fibroblasts into myogenic cells with characteristics of muscle stem and progenitor cells. The resulting myogenic stem cell cultures were passaged for over 6 months while maintaining the potential for self-renewal and differentiation into contracting myofibers. Stated differently, Hochedlinger’s cells can be maintained in culture without loss of phenotype for at least 6 months. (Hochedlinger [0223], Claim 32).
Hochedlinger does not specifically give an example where their resulting cells are passaged not more than four times, or the specific number of passages that the resulting cells are subjected to. However, it would It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to passage Hochedlinger’s resulting myogenic stem cells for not less than five passages. One of ordinary skill in the art would have been motivated to do so, since the skilled artisan could routinely be motivated to use the cells immediately, or after 1, 2, 3, or 4 passages for example. It isn’t exactly clear from Hochedlinger’s example 2, but it appears that Hochedlinger immediately subjected the resulting myogenic stem cells to immunofluorescence staining. ( Hochedlinger [0228]). This suggests that the resulting cells were not serially cultured at all prior to being tested, -which would be zero passages.
One of ordinary skill in the art would have had a reasonable expectation of success, since Hochedlinger teaches that their cells maintain their phenotype for an extended period of time, which suggests that the cells may be used anytime between when they are generated and even after up to 6 months of cell culture, which requires regular cell culture passages.
Hochedlinger and Gharaibeh
Claims 6-10, and 21-28 are rejected under 35 U.S.C. 103 as being unpatentable over:
Hochedlinger (US20190161731A1) (Provided in IDS of 8/22/2025).
Gharaibeh, B., Lu, A., Tebbets, J. et al. Isolation of a slowly adhering cell fraction containing stem cells from murine skeletal muscle by the preplate technique. Nat Protoc 3, 1501–1509 (2008).
Claims 6-10, 21, 23-24, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Hochedlinger.
Regarding claim 22, Hochedlinger teaches a method of deriving expandable myogenic stem cells (which they refer to as induced myogenic progenitor cells iMPC) from different somatic tissues (Hochedlinger [0065], [0230])).
Hochedlinger teaches a method of generating induced Myogenic Progenitor Cells (iMPCs) (i.e., myogenic stem cells), comprising treating a population of somatic cells obtained from a subject with cyclic AMP agonist, and a TGF-β inhibitor for a time and under conditions that induce dedifferentiation of the somatic cells to a population of cells comprising iMPCs. Hochedlinger teaches that in one embodiment, the somatic cells may be fibroblasts, and that the cyclic AMP agonist may be forskolin, and that the TGF-β inhibitor may be RepSox. (Hochedlinger [0006-0008]).
Regarding the dermal cell limitation, Hochedlinger teaches on example where the cells used are adult mouse tail tip fibroblasts (i.e. dermal cells), which are successfully dedifferentiated to myogenic stem cells. (Hochedlinger [0234, 0224]).
Regarding the pre-plating limitation, Hochedlinger does not teach the pre-plating of primary cells prior to de-differentiation in order to sort out adherent dermal/fibroblast cells from other types of cells.
However, Hochedlinger does teach sorting the dermal primary cells prior to subjecting them to dedifferentiation, just by a different method. Based on Hochedlinger’s disclosure, their sorting method appears to be via FACS (they mention sorting based on the Thy1 marker). To exclude the possibility that MyoD expression and small molecule treatment amplifies a pre-existing myogenic progenitor cell type present in the cultures, sorted MEFs and adult tail tip fibroblasts (TTFs) were sorted based on the fibroblast-associated marker Thy1 before inducing reprogramming with MyoD and small molecules (FIG. 5A) (Hochedlinger [0234] [0254]).
Gharaibeh teaches a procedure, known as the modified preplate technique, which is used to isolate muscle cells on the basis of selective adhesion to collagen-coated tissue culture plates. By employing this technique to murine skeletal muscle, Gharaibeh has been able to isolate a rapidly adhering cell (RAC) fraction within the earlier stages of the process, whereas a slowly adhering cell (SAC) fraction containing muscle-derived stem cells was obtained from the later stages of the process. (Gharaibeh, Abstract). The preplate technique involves culturing digested muscle tissue for a set period to allow the fibroblastic cell fraction to attach while transferring the supernatant containing the myogenic fraction into a new plate, thus enriching for the desired cells.
The skilled artisan would recognize that Gharaibeh’s protocol in effect “sorts” the rapidly adherent fibroblast-like cell fraction (RAC) from slowly adherent cells (SAC) cells in a given cell biopsy. In Gharaibeh’s case they were interested in sorting the slowly adherent cells (SAC) from a skeletal muscle cell biopsy and enriching the slowly adherent cells over several serial pre-plating steps (Gharaibeh, Figure 2). However, the skilled artisan would recognize that this procedure could be used to isolate the rapidly adherent cell fraction (fibroblasts) as well, since the rapidly adherent cells are in effect separated from other cell types/ slowly adherent cells.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to use Gharaibeh’s protocol to sort fibroblasts/dermal cells for use as primary cells in Hochedlinger’s de-differentiation method. One of ordinary skill in the art would have been motivated to do so, since the election of a different sorting method for fibroblast/dermal cells would be combining prior art elements according to known methods to yield predictable results. (MPEP 2143 (I)(A).
Hochedlinger already teaches that in at least an embodiment they pre-sort their primary dermal cells (TTFs) via FACS. (Hochedlinger [0234] [0254]). That is, they teach the need for sorting dermal primary cells, they just don’t teach the sorting method taught by Gharaibeh, which sorts fibroblast-like cells based on adherence, instead of by fluorescent labeling/ FACS. Gharaibeh then teaches an effective method of separating adherent (fibroblast) cells from other cells (slowly adherent cells).
One of ordinary skill in the art would have had a reasonable expectation of success, since Gharaibeh’s used their pre-plate method to sort adherent (fibroblast-like) cells from slowly adherent cells.
Regarding claim 25, Hochedlinger teaches that in an embodiment, the concentration of forskolin is 1μM to 10 μM (Hochedlinger [0080]. Hochedlinger teaches that in an embodiment, the concentration of RepSox is 1μM to 10 μM. (Hochedlinger [0081]).
Regarding claim 28, Hochedlinger teaches that their resulting muscle progenitor cells may be expanded to numbers useful for therapeutic purposes and can be maintained for long periods of time in culture (e.g., >4 months). (Hochedlinger [0043])
In example 1, Hochedlinger reports a method to reprogram or dedifferentiate mouse fibroblasts into myogenic cells with characteristics of muscle stem and progenitor cells. The resulting myogenic stem cell cultures were passaged for over 6 months while maintaining the potential for self-renewal and differentiation into contracting myofibers. Stated differently, Hochedlinger’s cells can be maintained in culture without loss of phenotype for at least 6 months. (Hochedlinger [0223], Claim 32).
Hochedlinger does not specifically give an example where their resulting cells are passaged not more than four times, or the specific number of passages that the resulting cells are subjected to. However, it would It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to passage Hochedlinger’s resulting myogenic stem cells for not less than five passages. One of ordinary skill in the art would have been motivated to do so, since the skilled artisan could routinely be motivated to use the cells immediately, or after 1, 2, 3, or 4 passages for example. It isn’t exactly clear from Hochedlinger’s example 2, but it appears that Hochedlinger immediately subjected the resulting myogenic stem cells to immunofluorescence staining. ( Hochedlinger [0228]). This suggests that the resulting cells were not serially cultured at all prior to being tested, -which would be zero passages.
One of ordinary skill in the art would have had a reasonable expectation of success, since Hochedlinger teaches that their cells maintain their phenotype for an extended period of time, which suggests that the cells may be used anytime between when they are generated and even after up to 6 months of cell culture, which requires regular cell culture passages.
Response to Arguments
Applicant argues that Hochedlinger does not teach the use of placental cells, or a pre-plating selection step, which overcomes the previous 35 USC §102 anticipation rejection. The examiner agrees. However, in light of the amendments new rejections have been applied.
Applicant argues that Hochedlinger does not teach the use of skeletal muscle stem cells, and while applicant is correct that Hochedlinger does not provide a specific working example of their method using skeletal muscle stem cells, Hochedlinger still strongly suggests the use of skeletal muscle stem cells as the primary somatic cell to be used in their dedifferentiation method. (See rejection of claims 21 and 24).
Conclusion
6-10, and 21-28 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to THOMAS RUSSE AMICK whose telephone number is (571)272-5474. The examiner can normally be reached 7:30-5 M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/THOMAS R. AMICK/ Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
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