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 .
DETAILED ACTION
Amendment Entry
1. Applicant's amendment / response filed October 23, 2025 is acknowledged and has been entered. Applicant’s amendment to the specification is also acknowledged and has been entered. Claims 278, 284, and 297 have been amended. Claim 291 has been cancelled. Claims 300-315 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Accordingly, claims 278-290 and 292-315 are pending. Claims 278-290 and 292-299 are under examination.
Withdrawn Rejections / Objections
2. Any objection or rejection not reiterated herein, has been withdrawn.
3. The rejections of claim 291 are moot in light of Applicant's cancellation of the claims.
Priority
4. Applicant’s claim for the benefit of a provisional application under 35 U.S.C. 119 (a)-(d) or (f), 365(a) or (b) or 386(a)111 and 37 C.F.R 1.53(b) is acknowledged. Based on the filing receipt, the effective filing date of this National Stage application, which is a 371 of PCT/IB2020/056632 filed 7/14/2020, is July 15, 2019 which is the filing date of Provisional Application 62/874,306 from which the benefit of priority is claimed.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
5. Claims 278-281, 283, 290, 293-296, and 299 are rejected under 35 U.S.C. 102(a)(1) as being anticipate by Hatt et al. (A new marker set that identifies fetal cells in material circulation with high specificity. Prenatal Diagnosis 34: 1-7 (2014)).
Hatt et al. teach the invention essentially as disclosed and claimed. Hatt et al. teach a method for isolating fetal cells from maternal blood sample of pregnant subjects (Abstract; p. 2, left col. 1st full ¶). The method comprises: (a) contacting the sample comprising a plurality of cells with a plurality of magnetic particles (microbeads) conjugated to a first antibody (i.e. antibodies, ligand) that binds to CD105, an endothelial cell marker; (b) isolating cells that bound to the first antibody which is a monoclonal anti-CD105 antibody to produce an enriched sample by subjecting the sample in a) to magnetic field (magnetic-activated cell sorting: MACS); (c) contacting the enriched sample with a second antibody that specifically binds to a cytokeratin which is anti-cytokeratin antibody conjugated to a fluorescent label to stain the bound fetal cells; and, (d) detecting and isolating single fetal cells that further bound to the fluorescent labeled anti-cytokeratin antibody using MetaCyte automated scanning. The fetal cell is a fetal nucleated red blood cell (fnRBC: fetal nucleated erythrocyte) or a fetal trophoblast (Abstract; p. 1, right col. to p. 2 right col.; Table 3; Figure 2). Hatt et al. also teach contacting the enriched sample with DAPI nuclear stain. The fluorescent-labeled fetal cells are isolated based on immunofluorescent technology (p. 2, left col. 1st full ¶ to right col.; Figure 2). Hatt et al. teach performing genomic or genetic analysis (FISH) on the fetal cells (p. 3, left col. 1st full ¶; p. 3, right col. last full ¶ to p. 4; Figure 2).
Accordingly, Hatt et al. appears to read on Applicant’s claimed invention.
5. Claims 278-283, 287, 290, and 292-299 are rejected under 35 U.S.C. 102(a)(1) as being anticipate by Eckelt et al. (US 2013/0331284) in light of Hatt et al. (Prenatal Diagnosis 34: 1-7 (2014)).
Eckelt et al. disclose a method for isolating fetal cells from a maternal blood sample of a pregnant subject (Abstract). The method comprises: (a) contacting the sample comprising a plurality of cells with a plurality of magnetic particles (beads) conjugated to a first antibody (i.e. antibodies, ligand) that binds to an endothelial cell marker, wherein the endothelial marker is CD105 (endoglin) (Abstract; [0057-0059, 0061-0063, 0065-0073, 0075, 0124, 0144, 0145, 0167, 0253]); (b) isolating cells that bound to the first antibody by subjecting the sample in a) to magnetic field (MACS) to produce an enriched sample [0194, 0195]; (c) contacting the enriched sample with a second antibody (i.e. antibodies) that binds to cytokeratin (CK18, keratin, KRT, CK) antigen (Abstract); [0057-0059, 0061-0063, 0065-0073, 0076, 0124, 0155, 0167, 0171, 0253], wherein the second antibody is an antibody or an antigen binding fragment conjugated to a fluorescent label (reporter dye: fluorescein) [0155, 0167]; and, (d) detecting and isolating single fetal cells that further bound to the second antibody using FACS (Abstract; [0066, 0192, 0223]).
The fetal cell is a fetal nucleated red blood cell (fnRBC: fetal nucleated erythrocyte) [0005, 0207] or a fetal trophoblast [0293]. The magnetic particles are colloidal ferrofluid magnetic particles [0194, 0195]. Eckelt et al. also teach further contacting the enriched sample with an antibody to an epithelial marker and also an anti-CD45 antibody for negative selection of leukocytes [0066, 0071, 0074, 0124, 0163, 0197-0202]. Eckelt et al. further teach contacting the enriched sample with a nuclear stain including DAPI, spectrum green, and spectrum orange [0286, 0287]. The fluorescent-labeled fetal cells are isolated based on immunofluorescent technology, fluorescence activated cell sorting (FACS), or DEPArray (microarray analysis) [0066, 0192, 0222, 0223]. Eckelt et al. teach sequencing the isolated fetal cells and performing genomic or genetic analysis on the fetal cells [0073, 0124, 0219-0222].
With respect to the recitation of cytokeratin in claim 278, Hatt et al., as discussed supra, teach using magnetic particle-conjugated anti-CD105 antibody to bind CD105 as endothelial marker of fetal cells and fluorophore-conjugated anti-cytokeratin (anti-CK) antibody to bind CK antigen as a fetal marker of fetal cells to both isolate and stain fetal cells present in maternal blood sample. As such and absent evidence to the contrary, the CK marker as taught by Eckelt et al. is not limited to its characterization as epithelial marker as confirmed in the teaching of Hatt et al.
With respect to claims 281 and 282, magnetic particles are inherently formed from ferromagnetic material and when in particulate form, are inherently in colloidal suspension; hence, colloidal ferrofluid magnetic particles, as recited in claims 281 and 282 [0194, 0195]. Accordingly, Eckelt et al. in light of Hatt et al. appears to read on Applicant’s claimed invention.
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.
6. Claim 289 is rejected under 35 U.S.C. 103 as being unpatentable over Hatt et al. (Prenatal Diagnosis 34: 1-7 (2014)) or Eckelt et al. (US 2013/0331284) in light of Hatt et al. (Prenatal Diagnosis 34: 1-7 (2014)) in view of MA et al. (Differential expression profile of long non-encoded RNA in placenta of patient with pre-eclampsia. China Academic Journal Electronic Publishing House. English Abstract (2017)- IDS) and Schwabe et al. (WO 2017/062672 A2- IDS).
Eckelt et al. and Hatt et al. are discussed supra. Eckelt et al. and Hatt et al. differ from the instant invention in failing to teach a fetal cell marker which is Triggering Receptor Expressed on Myeloid Cells Like 2 (TREML2).
MA et al. teach that Triggering Receptor Expressed on Myeloid Cells Like 2 (TREML2, TREM2, TREM-like transcript 2) is shown to be significantly up-regulated in placenta containing a developing fetus (i.e. fetal cell marker) of preeclampsia (PE) subjects (Abstract).
Schwabe et al. teach developing and providing TREM2 antibodies that specifically bind to TREM2 protein.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have incorporated TREML2 as taught by MA into the method of Eckelt and Hatt as a fetal cell marker and further use anti-TREML2 antibodies developed by Schwabe to capture and isolate fetal cells from a sample obtained from a maternal pregnant subject because MA taught that TREML2 is expressed and up-regulated as a fetal cell marker in samples of PE subjects.
7. Claims 284-286 are rejected under 35 U.S.C. 103 as being unpatentable over Eckelt et al. (US 2013/0331284) in light of Hatt et al. (Prenatal Diagnosis 34: 1-7 (2014)) in view of Liberti et al. (WO 02/06790 A1- IDS).
Eckelt et al. and Hatt et al. are discussed supra. Eckelt et al. and Hatt et al. differ from the instant invention in failing to teach magnetic particles coupled to a first and a second exogenous aggregation enhancing factor (EAEF).
Liberti et al. disclose compositions and methods which enhance analysis of biological entities such as cells by eliminating interfering magnetic clusters created by naturally occurring aggregators of colloidal magnetic particles (Abstract). Liberti et al. specifically teach a reagent composition comprising magnetic particles coupled to a first exogenous aggregation enhancing factor (EAEF) which comprises a first member of a specific binding pair which may be any one of antigen-antibody, biotin-streptavidin, receptor-hormone, receptor-ligand, agonist-antagonist, lectin-carbohydrate, Protein A- antibody Fc, avidin-biotin, biotin analog-avidin, desthiobiotin-streptavidin, desthiobiotin-avidin, iminobiotin-streptavidin, and iminobiotin-avidin (p. 17, lines 18-32; p. 18, lines 26-32). Liberti et al. further teach adding to the test sample a second EAEF to induce aggregation of the magnetic particles which comprises the other member of the specific binding pair (p. 17, lines 32 to p. 18, line 9; p. 18, lines 26-32).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have incorporated the EAEF as taught by Liberti into the method of Eckelt and Hatt while performing enrichment and isolation of fetal cells from samples obtained from maternal pregnant subjects because Liberti taught that EAEF is efficient in controlling magnetic particle aggregation and inhibiting or removing endogenous aggregation factors involved in cell selection and isolation methods. One of ordinary skill would have had reasonable expectation of success in incorporating the teaching of Liberti into the fetal cell enrichment and isolation method of Eckelt and Hatt because all of Eckelt, Hatt, and Liberti teach analogous art in specific cell selection, enrichment, and isolation methods.
8. Claim 288 is rejected under 35 U.S.C. 103 as being unpatentable over Eckelt et al. (US 2013/0331284) in light of Hatt et al. (Prenatal Diagnosis 34: 1-7 (2014)) in view of Chuang et al. (Meiotic Competent Human Germ Cell-like Cells Derived from Human Embryonic Stem Cell Induced by BMP4WNT3A Signaling and OCT4/EpCAM (Epithelial Cell Adhesion Molecule) Selection. Journal of Biological Chemistry 287 (18): 14389-14401 (April 27,2012)).
Eckelt et al. and Hatt et al. are discussed supra. Eckelt et al. and Hatt et al. differ from the instant invention in failing to teach an epithelial marker which is epithelial cell adhesion molecule (EpCAM).
Chuang et al. teach that epithelial cell adhesion molecule (EpCAM) is an epithelial marker that is expressed in human fetal gonads (i.e. fetal cell marker) found in pregnant subjects. Chuang et al. further teach using anti-EpCAM antibodies that bind to and detect EpCAM in fluorescence activated cell sorting (FACS) (Abstract; p. 14390, right col. 1st 2nd & 4th full ¶s).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have incorporated EpCAM as taught by Chuang into the method of Eckelt and Hatt as an epithelial marker and further use anti-EpCAM antibodies to capture and isolate fetal cells from samples obtained from maternal pregnant subjects because Chuang taught that EpCAM is expressed on fetal gonads and can be used as a selective marker for enrichment of fetal cells. One of ordinary skill would have had reasonable expectation of success in incorporating the teaching of Chuang into the fetal cell enrichment and isolation method of Eckelt and Hatt because all of Eckelt, Hatt, and Chuang teach analogous art in fetal cell selection, enrichment, and isolation from maternal blood samples.
Response to Arguments
9. Applicant’s arguments with respect to claims 278-290 and 292-299 have been considered but are moot in light of the new grounds of rejection necessitated by Applicant’s amendment and because the new grounds of rejection do not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
10. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GAILENE R. GABEL whose telephone number is (571)272-0820. The examiner can normally be reached Monday, Tuesday, and Thursday 5:30 AM to 4:00 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory S. Emch can be reached at (571) 272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GAILENE GABEL/Primary Examiner, Art Unit 1678
February 12, 2026