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 .
Claim Status
As of the Non-Final Office Action mailed 4/22/2025, claims 1, 5, 7-9, 11-17, and 19-20 were pending.
In Applicant's Response filed on 7/22/2025, claims 1, 7-9, 11, 13 were amended and claims 19-20 were canceled.
As such, claims 1, 5, 7-9, and 11-17 are pending and have been examined herein.
Withdrawn Rejections
The rejection of record of claims 1, 5, 7-9, 11-17, and 19-20 under 35 USC § 112(a) for failing to comply with the enablement requirement have been withdrawn in view of Applicant’s amendment to claim 1.
The rejection of record of claims 1 and 11-17 under 35 USC § 102(a)(1) as being anticipated by Clinical Trials (Safety and Preliminary Efficacy Study, 7 Feb 2011; p. 1-14) has been withdrawn in view of Applicant’s amendments to claim 1.
The rejection of record of claims 1, 5, 7, 13-17, and 19-20 under 35 USC § 102(a)(1) and (a)(2) as being anticipated by Han et al (US 20180021380 A1, 20 July 2017) as evidenced by Yoshida et al (Spine, 005; 30(1):55-61 has been withdrawn in view of Applicant’s amendments to claim 1. The rejection of claims 19 and 20 are moot in view of their cancelation.
The rejection of record of claims 8-9 under 35 USC § 103 as being unpatentable over Han et al as applied to claims 1, 13-17, and 19-20 and further in view of Simmons et al (US 11795435 B2) have been withdrawn in view of Applicant’s amendments to claim 1.
New Grounds of Rejections 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.
Claim(s) 1, 5, 7, and 11-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trials (Safety and Preliminary Efficacy Study, 7 February 2011; p. 1-14; referenced herein as “ClinicalTrials”; previously cited) in view of Ghosh (AU 2017216481 A1, 8/16/2017; Published 8/31/2017), Han et al (US 20180021380 A1, 20 July 2017; Published 25 Jan 2018; Ref. 14 of US Patent Documents IDS filed 7/8/2022; previously cited) as evidenced by Yoshida et al (Spine. 2005;30(1):55–61).
ClinicalTrials teaches a study of safety and efficacy of immunoselected (reads on “wherein the mesenchymal lineage precursor or stem cells are isolated by immunoselection” as in instant claim 11), culture-expanded (“wherein the immunoselected cells are culture-expanded prior to administration” as in instant claim 12; “wherein the mesenchymal lineage precursor or stem cells are culture-expanded mesenchymal stem cells” as in instant claim 13) allogeneic adult MPCs for chronic low back pain due to mild-moderate degenerative disc disease at one lumbar level from L1 to S1, where either 6 million or 18 million cells in a hyaluronic acid carrier are injected into the degenerated lumbar disc’s nucleus pulposus (p. 5-6, “Brief Summary”) (“a method of treating lower back pain in a subject in need thereof, the method comprising administering into the nucleus pulposus of an intervertebral disc in a subject a composition comprising mesenchymal precursor or stem cells wherein the lower back pain is associated with a condition other than a degenerated intervertebral disc” as in instant claim 1 in-part; “wherein the composition is administered to the subject at a dose of between about 1x106 cells to about 20x106 cell” as in instant claim 14; “the composition is administered to the subject at a dose of about 6x106 cells” as in instant claim 15; “the composition is administered to the subject at a dose of about 18x106 cells” as in instant claim 16) as a single dose injection (p. 7 “Arms and Interventions”) (“the composition is administered as a single dose” as in instant claim 17). The inclusion criteria for the study included those with a disc height loss of <30% compared to a normal adjacent disc based upon radiographic evaluation and pre-treatment baseline low back pain of at least 40 on a 100 visual analog scale (p. 10, “Criteria”, number 7 and 8) (“(ii) with a disc height loss of less than 30% compared to a normal adjacent disc upon radiographic evaluation . . . (iii) with a visual analog scale (VAS) back pain score greater than 40” as in instant claim 1 in-part). The exclusion criteria for the study excluded those with intact disc bulge/protrusion or focal herniation at the symptomatic level(s) >3mm (p. 10, Exclusion Criteria, number 4) (“(i) with or without contained disc herniation up to a 3mm protrusion” as in instant claim 1 in-part). The reference further teaches that those included in the study had low back pain greater than leg pain (i.e., no significant radiating pain) (p. 10, “Inclusion Criteria”, number 9) and could not have compressive pathology due to stenosis or frankly herniated/sequestered discs (p. 10, “Exclusion Criteria”, number 3) (“with no radiographic evidence of neurological compression” as in instant claim 1 in-part).
The difference between Clinical Trials and the instant invention is that it does not teach that the MLPSCs are TNAP+ or that the administration is at a dose sufficient to result in at least a 50% reduction in pain as determined by (a) a visual analog scale for at least 6 months after administration; and (b) a reduction of at least 15 points as determined by Oswestry Disability Index (ODI for at least 6 months after administration (related to instant claim 1 in-part).
Ghosh teaches a method of treating a disease in a subject arising from degradation and/or inflammation of connective tissue, the method comprising administering to the subject mesenchymal precursor cells (see claim 1 of Ghosh). The reference teaches that the cells are administered by injection and that the disease is back pain (see claims 8 and 11 of Ghosh). The cells are TNAP+ (p. 10, lines 27-30). Furthermore, injection of the MPCs after 6 months post injection into nucleus pulposus of the degenerative disc shows an increase of 52% in disc height (see p. 45 lines 31-36 and p. 46 line 1-3) (“TNAP+ mesenchymal lineage precursor cells” as in instant claim 1 in-part). This shows that TNAP+ mesenchymal precursor cells can be used to treat back pain and improve disc height.
Han teaches a method for preventing or treating low back pain in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a composition containing adipose tissue-derived mesenchymal stem cells, where the administration occurs via one intervertebral injection (see claim 1 and para 127 of Han). The low back pain may be caused by disc herniation, bulging disc, disc protrusion, disc prolapse, disc scoliosis, or spinal stenosis (para 0068). The mesenchymal stem cells are isolated then cultured in a culture medium for stem cell culture and further subcultured for 3 to 17 passages (para 0046). The amount of mesenchymal stem cells delivered can be 5x105 cells/subject to about 5x107 cells/subject (para 0065). The reference also teaches confirmation of IVD pain reduction based on Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) (table 6 and 7 of Han). For example, patient 2, who initially had a VAS of 7 and ODI of 34 before transplantation, had a VAS of 3 and ODI of 12 at 6 months post-injection, as well as a VAS of 0 and an ODI of 2.2 at 12 months post-injection (table 6 and 7 of Han) (“wherein administration of the MLSPCs is at a dose sufficient to result in at least a 50% reduction in pain as determined by (a) a visual analog scale for at least 6 months after administration; and (b) a reduction of at least 15 points as determined by Oswestry Disability Index (ODI for at least 6 months after administration” as in instant claim 1 in-part).
Finally, evidentiary reference Yoshida evidences that monocyte chemoattractant protein (MCP)-1, a CC chemokine that contributes to the activation and recruitment of macrophages is responsible for the recruitment of macrophages in herniated discs (Introduction, para 1). Inflammatory cytokines such as tumor necrosis factor (TNF) α and interleukin (IL)-1β stimulate intervertebral disc cells to produce MCP-1 in vitro.12 These results raise the possibility that TNF-α and IL-1β induce MCP-1 production in intervertebral disc cells, and, in turn, MCP-1 attracts macrophages into the herniated discs (Introduction para 2). These inflammatory cytokines/chemokine were produced in the nucleus pulposus of herniated discs after the onset of herniation (“expression of Tumor Necrosis Factor . . .” para 1). This evidences that disc herniation results in inflammatory cytokine release in the nucleus pulposus (i.e., results in inflammation). Thus, absent evidence to the contrary, the lower back pain caused by disc herniation as in Clinical Trials, Ghosh, and Han would have inflammation in the intervertebral disc and nucleus pulposus, anticipating “wherein the lower back pain is associated with inflammation in an intervertebral disc” as in instant claim 5 and “wherein the inflammation is in . . . the nucleus pulposus” as in instant claim 7.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to treat chronic lower back pain with injection of mesenchymal precursor stem cells as taught by Clinical Trials, where the cells are TNAP+ as taught by Ghosh, to arrive at the instantly claimed invention. As Ghosh shows mesenchymal precursor cells are TNAP+, one of ordinary skill would have been motivated to subject the mesenchymal precursor cells to immunoselection as taught by Clinical Trials and further select for cells that are TNAP+ as taught by Ghosh with a reasonable expectation of advantageously having a subset of mesenchymal precursor cells that treat back pain and improve disc height after 6 months as taught by the prior art.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to treat chronic lower back pain with injection of mesenchymal precursor stem cells as taught by Clinical Trials, where the administration improves VAS and ODS scores as taught by Han, to arrive at the instantly claimed invention. As Han shows mesenchymal precursor cells can be used to treat low back pain and improve these scores, one of ordinary skill would reasonably expect, prior to the effective filing date, that the injection of cells as taught by Clinical Trials to have the same or similar result as taught by the prior art.
Response to Arguments
Applicant's arguments filed 7/22/2025 have been fully considered but they are not persuasive. Please note that while previously cited Clinical Trials and Han are used in the above rejection, the argument regarding these references are moot because the new ground of rejection utilizes the teachings of Clinical Trials to render obvious the newly added limitations of “with or without contained disc herniation up to a 3 mm protrusion with no radiographic evidence of neurological compression;(ii) with disc height loss of less than 30% compared to a normal adjacent disc based upon radiographic evaluation; and(iii) with a visual analog scale (VAS) back pain score greater than 40”, Han, which renders obvious the newly added limitation of “wherein administration of the MLSPCs is at a dose sufficient to result in at least a 50% reduction in pain as determined by (a) a visual analog scale (VAS) for at least 6 months after administration; and (b) a reduction of at least 15 points as determined by Oswestry Disability Index (ODI) for at least 6 months after administration”, and newly cited Ghosh, which renders obvious the newly added limitation of “TNAP+ mesenchymal lineage precursor or stem cells (MLPSCs)” in instant claim 1. Newly cited reference Ghosh and previously cited Clinical Trials and Han, in combination defeat the matter specifically challenged in the arguments regarding the previously posited 102 rejections.
Claim(s) 8-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trials (Safety and Preliminary Efficacy Study, 7 February 2011; p. 1-14; referenced herein as “ClinicalTrials”; previously cited) in view of Ghosh (AU 2017216481 A1, 8/16/2017; Published 8/31/2017), Han et al (US 20180021380 A1, 20 July 2017; Published 25 Jan 2018; previously cited) as applied to claims 1, 5, 7, and 11-17 above, and further in view of Simmons et al (US 11,795,435 B2, 4 May 2016; previously cited).
The teachings of Han were recited in the above 35 U.S.C. 102 rejection as applied to claim 1 of which claim 5 and 7-9 depend. The teachings will not be repeated here.
The difference between Han and the invention as instantly claimed is that it does not teach that the lower back pain is associated with inflammation in an intervertebral disc (related to instant claim 5), that the inflammation is in a intervertebral disc space, or the nucleus pulposus, or annulus fibrosus of the intervertebral disc (related to claim 7), that the MLPSCs release TGF-beta 1 when cultured in an amount of at least 2800 pg/106 cells, or at least 2810 pg/106 cells, or at least 2820 pg/106 cells, or at least 2830 pg/106 cells, or at least 2840 pg/106 cells, or at least 2850 pg/106 cells, or at least 2860 pg/106 cells, or at least 2870 pg/106 cells, or at least 2880 pg/106 cells, or at least 2890 pg/106 cells, or at least 2900 pg/106 cells, or at least 2910 pg/106 cells, or at least 2920 pg/106 cells, or at least 2930 pg/106 cell, or at least 2940 pg/106 cells, or at least 2950 pg/106 cells, or at least 2960 pg/106 cells, or at least 2970 pg/106 cells, or at least 2980 pg/106 cells, or at least 2990 pg/106 cells, or at least 3000 pg/106 cells (related to claim 8), or that the MLPSCs release TGF-beta 1 when cultured in an amount of at least 400 pg/ml (related to claim 9).
Simmons teaches a method for determining the biological activity or therapeutic efficacy of cultured mesenchymal lineage precursor cells or stem cells based on their released TGF-beta levels in culture (abstract). The method provides (i) obtaining a population comprising mesenchymal lineage precursor or stem cells; (ii) culturing the cells in a culture medium; and (iii) determining the amount of TGFβ1 released by the cells into the culture medium, wherein an amount of at least about 2800 pg/106 cells TGFβ1 is indicative of biological activity or therapeutic efficacy. For example, an amount of at least about at 2810 pg/106 cells TGFβ1, at least about 2820 pg/106 cells TGFβ1, at least about 2830 pg/106 cells TGFβ1, at least about 2840 pg/106 cells TGFβ1, at least about 2850 pg/106 cells TGFβ1, at least about 2860 pg/106 cells TGFβ1, at least about 2870 pg/106 cells TGFβ1, at least about 2880 pg/106 cells TGFβ1, at least about 2890 pg/106 cells TGFβ1, at least about 2900 pg/106 cells TGFβ1, at least about 2910 pg/106 cells TGFβ1, at least about 2920 pg/106 cells TGFβ1, at least about 2930 pg/106 cells TGFβ1, at least about 2940 pg/106 cells TGFβ1, at least about 2950 pg/106 cells TGFβ1, at least about 2960 pg/106 cells TGFβ1, at least about 2970 pg/106 cells TGFβ1, at least about 2980 pg/106 cells TGFβ1, at least about 2990 pg/106 cells TGFβ1, or at least about 3000 pg/106 cells TGFβ1 is indicative of biological activity or therapeutic efficacy (col 1 lines 63-67; col 2 lines 1-20) (“wherein the MLPSCs release TGF-beta 1 when cultured in an amount of at least about 2800 pg/106 cells, or at least 2810 pg/106 cells, or at least 2820 pg/106 cells, or at least 2830 pg/106 cells, or at least 2840 pg/106 cells, or at least 2850 pg/106 cells, or at least 2860 pg/106 cells, or at least 2870 pg/106 cells, or at least 2880 pg/106 cells, or at least 2890 pg/106 cells, or at least 2900 pg/106 cells, or at least 2910 pg/106 cells, or at least 2920 pg/106 cells, or at least 2930 pg/106 cell, or at least 2940 pg/106 cells, or at least 2950 pg/106 cells, or at least 2960 pg/106 cells, or at least 2970 pg/106 cells, or at least 2980 pg/106 cells, or at least 2990 pg/106 cells, or at least 3000 pg/106 cells” as in instant claim 8). It further teaches that the amount of TGF-beta 1 being released by the cells into the culture medium in the amount of at least about 400 pg/ml is also indicative of therapeutic efficacy (col 2, lines 27-30) ( “wherein the MLPSCs release TGF-beta 1 when cultured in an amount of at least about 400 pg/ml” as in instant claim 9).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed to administer mesenchymal precursor cells to treat chronic lower back pain as taught by Clinical Trials, Ghosh, and Han in combination, where the mesenchymal precursor cells release TGF-beta 1 when cultured, as taught by Simmons, and arrive at the instantly claimed invention. As Simmons shows that mesenchymal precursor cells release at least 2800 pg/106 cells or 400 pg/ml TGF-b1 when cultured, one of ordinary skill would have modified the method of Clinical Trials, Ghosh, and Han in combination to measure TGF-beta 1 release into culture media for the reasonable expectation of advantageously measuring and ensuring the therapeutic efficacy of the mesenchymal stem cells as taught by Simmons.
Response to Arguments
Applicant has not provided any arguments challenging the specific teachings of cited reference Simmons nor has Applicant attempted to distinguish instant claims 8-9 from the teachings of Simmons.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Ghosh et al (J Neurosurg Spine, 9 March 2012; 16:479-488), which teaches the immunoselection of STRO-3+ (i.e., TNAP+) MPSCs to restore extracellular matrix of chronic low back pain due to discs (see Ghosh disclosure throughout).
Ichim (US 9598673 B2, 5/18/2007; Published 3/21/2017), which teaches, e.g., inhibition of disc degeneration by injecting 5x106-40x109 mesenchymal stem cells (see disclosure throughout).
Riordan (US 20180036348 A1, 8/4/2017; Published 2/8/2018), which teaches, e.g., a method of reducing back pain in a patient by administering STRO-3+ mesenchymal stem cells to a patient (see disclosure throughout).
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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/G.R./Examiner, Art Unit 1632
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632