DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment filed December 26, 2025, has been received and entered.
Election/Restrictions
Claims 2 and 3 are canceled. Claims 22 and 23 are new.
Claims 1 and 4-23 are pending.
As pointed out in the last Office Action, Applicant elected without traverse the species TNF-α for the pro-inflammatory cytokines, IL-7 for the anti-inflammatory cytokines, and CD73+ for the biomarkers. Upon further consideration, the requirement for election of species for the anti-inflammatory cytokine has been withdrawn.
Claims 1 and 4-23 are examined on the merits.
Claim Objections
Claim 15 is objected to because of the following informalities:
Claim 15 is grammatically incorrect since it recites “wherein the supernatant is cryopreserved once they have been isolated from the MSCs.” Since a single supernatant is recited, then the recitation “they have” should be substituted with “it has.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 4-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is indefinite because it is unclear how “the anti-inflammatory cytokine” can be a combination of anti-inflammatory cytokines (the embodiment of “a combination thereof”). A single anti-inflammatory cytokine (“the anti-inflammatory cytokine”) cannot be a plurality of anti-inflammatory cytokines. Since claim 1 is indefinite, then its dependent claims, claims 4-21, are rendered indefinite. Thus, claims 1 and 4-21 are rejected under 35 U.S.C. 112(b).
Claim 7 is indefinite because it is unclear how “the anti-inflammatory cytokine” can be a combination of anti-inflammatory cytokines (the embodiment of “a combination thereof”). A single anti-inflammatory cytokine (“the anti-inflammatory cytokine”) cannot be a plurality of anti-inflammatory cytokines.
Claim 9 is indefinite because it is unclear how “the biomarker” can be a combination of biomarkers (the embodiment of “a combination thereof”). A single biomarker (“the biomarker”) cannot be a plurality of biomarkers.
Claim 13 is rendered indefinite by the recitation “the pro-inflammatory cytokine.” Parent claim 1 recites “pro-inflammatory cytokines.” It is unclear which one of the pro-inflammatory cytokines of parent claim 1 is “the pro-inflammatory cytokine” of claim 13. Also, the recitation of “stimulation with the pro-inflammatory cytokine” is confusing since parent claim 1 recites stimulation with pro-inflammatory cytokines, as opposed to a single pro-inflammatory cytokine.
Claim 17 is rendered indefinite by the recitation “the pro-inflammatory cytokine.” Parent claim 1 recites “pro-inflammatory cytokines.” It is unclear which one of the pro-inflammatory cytokines of parent claim 1 is “the pro-inflammatory cytokine” of claim 17. Also, the recitation of “stimulated with the pro-inflammatory cytokine” is confusing since parent claim 1 recites stimulation with pro-inflammatory cytokines, as opposed to a single pro-inflammatory cytokine.
Claim 22 is indefinite because it is unclear how “the anti-inflammatory cytokine” can be a combination of anti-inflammatory cytokines (the embodiment of “a combination thereof” in step (b)). A single anti-inflammatory cytokine (“the anti-inflammatory cytokine”) cannot be a plurality of anti-inflammatory cytokines. Since claim 22 is indefinite, then its dependent claim, claims 23, is rendered indefinite. Thus, claims 22 and 23 are rejected under 35 U.S.C. 112(b).
Notice Re: Prior Art Available Under Both Pre-AIA and AIA
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.
Claim Rejections - 35 USC § 102
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, 4-11, 13, 22, and 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ito (Journal of Reproductive Immunology. 2010. 84: 75-85), as evidenced by Moseley (Cytokine & Growth Factor Reviews. 2003. 14: 155-174).
Ito discloses determining the effect of IL-17 on TNFα-induced IL-8 secretion in human amniotic mesenchymal (HAM) cells (page 80, last paragraph; abstract). As evidenced by Moseley, IL-17 has been designated IL-17A (page 155, first and second paragraphs). Thus, IL-17 taught in Ito is directed to IL-17A. Ito specifically discloses stimulating HAM cells with various concentrations of IL-17 in combination with TNFα (page 82, left column; Figure 5, in particular Figure 5D and the legend on page 82). Therefore, Ito discloses stimulating a population of MSCs (HAM cells) with pro-inflammatory cytokines comprising IL-17A and TNF-α, anticipating the first step of instant claim 1.
Ito found that IL-17 significantly augmented the TNFα-induced secretion of IL-8 in a dose-dependent manner (page 82; Figure 5D legend). Therefore, Ito discloses producing an anti-inflammatory cytokine that is IL-8, anticipating the second step of instant claim 1. Furthermore, Figure 5D shows the amount of IL-8 secreted for various concentrations of IL-17 in combination with TNFα. Since Figure 5D shows the amount of IL-8 secreted, then IL-8 was quantified. Therefore, Ito discloses quantifying the anti-inflammatory cytokine (IL-8) from said MSCs (HAM cells), anticipating the last step of instant claim 1. Measuring the IL-8 secretion from stimulation of the MSCs (HAM cells) by IL-17 and TNFα is directed to assessing the potency of the human MSCs (HAM cells). As such, Ito anticipates instant claims 1 and 7 (IL-8).
Regarding instant claim 4, for the experiment involving IL-17 in combination with TNFα, Ito discloses that conditioned medium was collected after 24 hours of culture and the concentration of IL-8 was determined by ELISA (legend of Figure 5 on page 82). Therefore, HAM cells were stimulated with IL-17 (i.e., IL-17A, as evidenced by Moseley) and TNFα for 24 hours. Since 24 hours falls within the claimed range, then instant claim 4 is anticipated.
Regarding instant claim 5, Figure 5D shows IL-8 secretion was obtained for IL-17 at concentrations of 10, 100, and 1000 pg/mL in combination with 1000 pg/mL TNFα. Each of these concentrations for IL-17 (i.e., IL-17A) and TNFα fall within the claimed range. Therefore, instant claim 5 is anticipated.
Regarding instant claim 6, Ito discloses obtaining the amniotic membrane from the chorion of a placenta, and isolating the human amniotic mesenchymal (HAM) cells from the amniotic tissue (page 78, left column, last paragraph). See also page 80, right column, last paragraph, which discloses that the HAM cells were isolated from chorioamniotic membranes. Therefore, the MSCs (HAM cells) of Ito were derived from an amniotic membrane; also, since the amniotic tissue is part of a placenta, then the MSCs of Ito were derived from a placenta. As such, instant claim 6 (an amniotic membrane, a placenta) is anticipated.
Regarding instant claims 8 and 9, prior to measuring the IL-8 levels in culture medium of HAM cells stimulated with IL-17 or TNFα, Ito discloses detecting the IL-17 receptor A (IL-17RA) on the surface of the HAM cells (paragraph bridging pages 80 and 81). This is directed to checking for an expression of a biomarker on the MSCs (HAM cells) before stimulation with the pro-inflammatory cytokines, wherein the biomarker is IL-17RA+ of instant claim 9. Therefore, Ito anticipates instant claims 8 and 9 (non-elected species IL-17RA+).
Regarding instant claims 10 and 11, Ito discloses that the HAM cells were incubated in 12-well plates (page 78, right column, second paragraph). Therefore, Ito discloses seeding the MSCs (HAM cells) onto a substrate (a 12-well plate directed to a ‘cell culture well plate’ of instant claim 11) before stimulation with the pro-inflammatory cytokines. As such, instant claims 10 and 11 are anticipated.
Regarding instant claim 13, Ito discloses that the HAM cells were first cultured in a culture medium, and thereafter incubated in 12-well plates (page 78, right column, second paragraph). This signifies that the cells of the initial culture (directed to cells of a population of MSCs) were divided into different wells of a plate. The cells in each well is directed to a smaller population of MSCs (HAM cells). As such, Ito discloses dividing the MSCs into smaller populations of MSCs before stimulation with the pro-inflammatory cytokines, anticipating instant claim 13.
Regarding instant claim 22, Ito additionally discloses stimulating the HAM cells with IL-17 only (paragraph bridging pages 80 and 81; Figure 5D on page 82). Figure 5D includes IL-8 secretion measurements for HAM cells stimulated only with IL-17 at various concentrations. This stimulation and obtaining those measurements for Figure 5D meet steps (a)-(c) of instant claim 22, wherein the anti-inflammatory cytokine is IL-8. The stimulation and obtaining IL-8 secretion measurements for HAM cells stimulated with various concentrations of IL-17 and TNFα as shown in Figure 5D, are directed to steps (d)-(f) of instant claim 22. See the discussion above with respect to instant claim 1. In preparing the data for providing Figure 5D, then human mesenchymal stem cells (the HAM cells) are assessed. Therefore, Ito anticipates instant claim 22. In providing the effect of only IL-17 (i.e., IL-17A) on IL-8 secretion in the same figure (Figure 5D) showing the effect of IL-17 with TNFα on IL-8 secretion, then Ito teaches comparing the first measurement (IL-8 secretion measurement for HAM cells stimulated only with IL-17) with the second measurement (IL-8 secretion measurement for HAM cells stimulated with IL-17 and TNFα). It is evident from Figure 5D that the second measurement is greater than the first measurement for each of the IL-17 concentrations tested. Therefore, instant claim 23 is anticipated.
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.
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 12 is rejected under 35 U.S.C. 103 as being unpatentable over Ito, as evidenced by Moseley.
As discussed above, Ito (as evidenced by Moseley) anticipates claims 1, 4-11, 13, 22, and 23. Ito differs from claim 12 in that Ito does not expressly disclose that seeding of the MSCs (HAM cells) onto the substrate (a 12-well plate) lasts from 1 hour to 24 hours.
However, it would have been an obvious matter of routine experimentation to select the length of time of seeding the HAM cells (MSCs) onto the well plate, including a time falling within the range of from 1 hour to 24 hours, in order to ensure that the concentration of the cells is at a suitable concentration for measurement of IL-8 secreted by stimulation. Therefore, instant claim 12 is rendered obvious.
Claims 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Ito, as evidenced by Moseley, in view of Ostanin (Cell Technologies in Biology and Medicine. 2011. 1: 133-141. Previously cited).
As discussed above, Ito (as evidenced by Moseley) anticipates claims 1, 4-11, 13, 22, and 23. Ito differs from claim 14 in that Ito does not disclose isolating a supernatant of the MSCs (HAM cells) after stimulation with the pro-inflammatory cytokines. Ito further differs from claim 15 in that Ito does not expressly disclose that the supernatant is cryopreserved once it has been isolated from the MSCs.
Ostanin discloses comparative analysis of mesenchymal stromal cells isolated from different human tissue sources (abstract). The cells were compared by the levels of induced production of cytokines, including chemokines that include IL-8 (abstract). In particular, the levels of spontaneous and stimulated production of cytokines in response to endotoxin were evaluated (paragraph bridging pages 135 and 136). Aliquots of collected supernatants of MSC cultures were frozen and stored at -80ºC before analysis, and then cytokine/chemokine concentrations were measured (page 135, last paragraph through page 136, left column, second paragraph). The freezing and storage at -80ºC is directed to cryopreservation.
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to isolate a supernatant of the HAM cells (MSCs) after stimulation with IL-17 (i.e., IL-17A) and TNFα, and cryopreserve the supernatant when performing the method of Ito. One of ordinary skill in the art would have been motivated to do this because the supernatant would have been expected to contain the IL-8 to be measured since IL-8 is secreted by the HAM cells, and because such cryopreservation was recognized for MSC culture supernatants before measuring cytokines in said MSC culture supernatants, as indicated in Ostanin. Thus, instant claims 14 and 15 are rendered obvious.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Ito, Moseley, and Ostanin as applied to claims 14 and 15 above, and further in view of Bielekova (US 2017/0242043).
As discussed above, Ito (as evidenced by Moseley) in view of Ostanin renders obvious claims 14 and 15. The references differ from claim 16 in that they do not expressly disclose that the supernatant is analyzed with an electrochemiluminescence immunoassay to determine the levels of anti-inflammatory cytokines produced by the HAM cells (MSCs).
Bielekova discloses quantifying cytokines/chemokines, including IL-8, using commercially-available or newly developed electrochemiluminescence sandwich immunoassays (paragraph [0011]).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to substitute the ELISA used to measure the concentration of IL-8 (page 77, left column, second paragraph of Ito) with an electrochemiluminescence sandwich immunoassay for the predictable result of measuring the concentration of IL-8 in the supernatant when performing the method rendered obvious by Ito (as evidenced by Moseley) in view of Ostanin. It would have been a matter of simple substitution for one known technique for measuring IL-8 for another. There would have been a reasonable expectation of success in measuring the concentration of IL-8 of the supernatant with an electrochemiluminescence sandwich immunoassay because Bielekova teaches the measurement of IL-8 in a cultured supernatant from a mammalian cell culture by that technique (paragraph [0011]). Therefore, instant claim 16 is rendered obvious.
Claims 9 and 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over Ito, as evidenced by Moseley, in view of Magatti (Cell Transplantation. 2018. 27(1): 31-44) and Chinnadurai (Cell Reports. 2018. 22: 2504-2517. Previously cited).
As discussed above, Ito (as evidenced by Moseley) anticipates claims 1, 4-11, 13, 22, and 23. Ito differs from claim 9 in that Ito does not expressly disclose, before stimulation with the pro-inflammatory cytokines (IL-17A and TNFα), checking for an expression of CD73+ (elected species) as the biomarker on the HAM cells (MSCs); instead, Ito discloses the non-elected species IL-17RA+ as the biomarker. Ito differs from claim 17 in that Ito does not expressly disclose performing a viability assay on the HAM cells (MSCs) after they have been stimulated with the pro-inflammatory cytokines (Examiner’s interpretation, IL-17A and TNF-α). Ito further differs from claim 18 in that Ito does not expressly disclose that the viability assay is an ATP detection assay, a tetrazolium reduction assay, a resazurin reduction assay, a protease viability marker assay, a sodium-potassium ratio assay, a cytolysis or membrane leakage assay, a mitochondrial activity or caspase assay, a functional assay, a genomic and proteomic assay or any combination thereof. Ito further differs from claim 19 in that Ito does not expressly disclose that the viability assay comprises the use of flow cytometry. Ito further differs from claim 20 in that Ito does not expressly disclose that the viability of the HAM cells (MSCs) after stimulation with the pro-inflammatory cytokines (IL-17A and TNF-α) is greater than 70% when compared to the same MSC population (HAM cells) treated with a vehicle. Ito further differs from claim 21 in that Ito does not expressly disclose assigning a grade to the potency of the HAM cells (MSCs) based on the amount of produced anti-inflammatory molecules.
Magatti discloses human amniotic cells from placenta as valid candidates for therapeutic treatments (abstract). Human amniotic cells include human amniotic mesenchymal stromal cells (hAMSCs), and hAMSCs express classical MSCs markers including CD73 (page 32, left column, second paragraph). Also, Magatti teaches that hAMSCs have emerged as valid candidates for the potential use in inflammatory and immune-based disorders (page 32, left column, third paragraph).
Chinnadurai discloses that assays that inform on MSC immune potency need to be defined in advanced clinical trials (abstract). For early-phase human clinical trials, release criteria for cellular biopharmaceuticals include viability (page 2504, left column, first paragraph). In clinical trials where MSCs are administered as a pharmaceutical agent, 70% viability is used as the major release criterion (page 2513, left column, first paragraph). Trypan blue viability was used in laboratory studies of MSCs in combination with automated cell counting and flow cytometric proliferation assay (page 2513, left column, first paragraph; page 2515, left column, second paragraph).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to apply the cell viability testing and criteria of Chinnadurai to the HAM cells after performing the method disclosed by Ito. One of ordinary skill in the art would have been motivated to do this because HAM cells (i.e. hAMSCs as disclosed in Magatti) are valid candidates for therapeutic treatments, including use in inflammatory and immune-based disorders, so their cellular viability would have been of interest to the skilled artisan since cellular viability is a criteria for the use of MSCs as therapeutics for humans, as indicated in Chinnadurai. Therefore, instant claims 17, 18 (functional assay), 19, 20 (since Ito teaches the steps of instant claim 1, then the claimed viability would have necessarily been possessed by the HAM cells), and 21 (since HAM cells are a valid candidate for the treatment of inflammatory disorders, based on Magatti, then it would have been obvious to assign the potency of the HAM cells to treat inflammatory disorders based on the amount of produced anti-inflammatory molecules) are rendered obvious. Further still, before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to check for the expression of CD73+ of the HAM cells before stimulation with the pro-inflammatory cytokines (IL-17A and TNFα). One of ordinary skill in the art would have been motivated to do this for identification of the HAM cells as the cells isolated from the amniotic membrane. Thus, instant claim 9 (elected species CD73+) is rendered obvious.
Response to Arguments
Applicant’s arguments, filed December 26, 2025, with respect to the rejections under 35 U.S.C. 112(b) of claims 7 and 10-12, the rejection under 35 U.S.C. 103 of claims 1-14 and 16 as being unpatentable over Putra in view of Samsonraj, the rejection under 35 U.S.C. 103 of claim 15 as being unpatentable over Putra and Samsonraj in further view of Ostanin, and the rejection under 35 U.S.C. 103 of claims 17-21 as being unpatentable over Putra and Samsonraj in further view of Chinnadurai, have been fully considered and are persuasive. In particular, the rejections under 35 U.S.C. 112(b) have been overcome by the amendments to claims 7, 10, and 11. The rejections under 35 U.S.C. 103 have been overcome by the amendment to claim 1 because Putra does not disclose stimulating a population of MSCs with pro-inflammatory cytokines comprising IL-17A and TNF-α; Putra does not teach IL-17A for the stimulation. Therefore, these rejections have been withdrawn.
However, upon further consideration, new grounds of rejection are made in view of the newly cited reference Ito, as necessitated by the amendments to the claims. In addition to new rejections under 35 U.S.C. 102 and 103 based on Ito (also, in combination with newly cited references and previously cited references), the amendments to the claims necessitated a new claim objection and new rejections under 35 U.S.C. 112(b).
Conclusion
No claims are 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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Sef
/SUSAN E. FERNANDEZ/Examiner, Art Unit 1651
/DAVID W BERKE-SCHLESSEL/Primary Examiner, Art Unit 1651
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