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
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
2. Applicant’s amendment filed August 27, 2025 is acknowledged. Claims 2, 4-5, 9-13, 15-18, 20-21, 23, 25-29, 32-40, 42-44, 46-51 and 57-61 are canceled. Claims 1, 3 and 63 are amended. Claims 1, 3, 6-8, 14, 19, 22, 24, 30-31, 41, 45, 52-56 and 62-66 are pending in this application. Claims 19, 22, 24, 30-31, 41, 45, 52-56 and 62 are withdrawn with traverse (filed 12/5/2022) from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on December 5, 2022.
3. Claims 1, 3, 6-8, 14 and 63-66 are under examination with respect to a neuronal cell and a glial cell in this office action.
4. Applicant’s arguments filed on August 27, 2025 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Claim Rejections/Objections Maintained
In view of the amendment filed on August 27, 2025, the following rejections are maintained.
Claim Rejections - 35 USC § 102
5. 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)(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.
Claims 1, 3, 6-7, 14, 63 and 65 stand rejected under 35 U.S.C. 102 (a)(2) as anticipated by Fujii et al. (US10865372). The rejection is maintained for the reasons of record and the reasons set forth below.
Claims 1, 3, 6-7, 14, 63 and 65 as amended are drawn to a composition comprising a spheroid of cells comprising human neuronal cell and a human nervous system ganglia; wherein the spheroid of cells is obtained by co-culturing the human neuronal cell with a human Schwann cell, a human oligodendrocyte or a combination thereof, and the spheroid of cells comprises no less than about 40,000 cells or 12,500 cells; wherein the spheroid has a diameter of from about 10-50,000 m or 200-700 m; and wherein a stem cell, if present, is chosen from an embryonic stem cell (ESC), a mesenchymal stem cell (MSC), an induced pluripotent stem cell (iPSC), and combinations thereof; wherein at least some of the human neuronal cells have axons that are myelinated.
Response to Arguments
On p. 13-15 of the response, Applicant argues that i) Fujii fails to disclose myelination with human neuron cells and fails to disclose use of human Schwann cells or human oligodendrocytes. ii) Fujii teaches the use of IMS 32 cell lines (col.14, lines 36-56), which are known to be an immortalized Schwann cell line derived from adult mice, and cites Sango et al. (Exp. Diabetes Res., 2011, Exhibit A) in support of the arguments. iii) Fujii teaches “after the axons were bundled, Schwann cells, cells for myelination, were inoculated” but argues that the Schwann cells are not of human origin. iv) the claimed invention addresses the long-standing difficulties in obtaining in vitro myelination of axon in human systems and cites paragraphs [00226]-[00227] in support of the arguments. v) claims 1 and 63 are novel over Fujii and thus Fujii do not anticipate claims 3, 6-7, 14 and 65 because these claims depend from claims 1 and 63.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2131 -2131.01, Fujii does teach the claimed composition because:
i. The limitation “is obtained by co-culturing the human neuronal cell with a human Schwann cell, a human oligodendrocyte or a combination thereof” is a product-by-process limitation, which is not given patentable weight because if the product set forth in a product-by-process claim appears to be the same as, or an obvious variant of a product of the prior art, the claim is unpatentable even though the prior art product was made by a different process. See In re Marosi, 710 F.2d 799, 218 USPQ 289 (Fed. Cir. 1983) and In re Thorpe, 777 F.2d 695, 227 USPQ 964 (Fed. Cir. 1985). See also MPEP § 2113.
It is noted that the courts have held that when the prior art product reasonably appears to be the same as that claimed, but differs by process in which it is produced, a rejection of this nature is eminently fair and the burden is upon the appellants to prove, by comparative evidence, a patentable difference (In re Brown, 173 USPQ 685 (1972)).
ii. The spheroid of cells disclosed by Fujii comprises human neurons and human glial cells and an aggregation of a plurality of cell bodies derived from human iPSC cells and axons extended from the cell bodies that are myelinated, wherein the spheroid of cells includes human motoneurons, human Schwann cells, human oligodendrocytes and human glial cells, and wherein the spheroid of cells has a diameter of ~100m, ~500m or ~100m to ~2000m (see figures 6, 11 and 18-19; col.6; col. 8; col. 12-col. 14, claims 1-15), which meets the limitations recited in instant claims because the spheroid comprise human neuronal cells derived from human iPSCs and a human nervous system ganglia (i.e. a cluster of cell bodies of neurons in the PNS); and the spheroid has a diameter that is within the claimed range of about 10-50,000 m and the human neuronal cells have axons that are myelinated (see figures 6, 11 and 18-19; col.6; col. 8; col. 12-col. 14, claims 1-15).
The spheroid disclosed by Fujii also comprises one or a plurality of cells including a human glial cell, a human motor neuron, a human oligodendrocyte or a human Schwann cell as in claim 3 because human iPSCs differentiate into human motor neurons, human glial cells, human Schwann cells and/or human oligodendrocytes (see col. 13, lines 63-67; col.14, lines 36-56; claims 1-15), which is also evidenced by Kanton et al. (p. 420; 1st col., last paragraph; p. 422, figure 4; Nature, 2019; 574:418-422. doi.org/10.1038/s41586-019-1654-9) and Horner et al. (; p. 1, abstract; Cells, 2022; 11:3753. doi.org/10.3390/cells11233753).
The neuronal cell encompassed within the spheroid disclosed by Fujii is derived from a stem cell including human iPSC and/or any or plurality of cells are differentiated from human iPSC as in claim 6 (see col.14, lines 36-56; claims 1-15).
The spheroid disclosed by Fujii is also free of iPSCs or undifferentiated stem cells and/or immune cells as in claims 14 and 65 (see col.14, lines 36-56; claims 1-15).
Since the diameter of the spheroid disclosed by Fujii is within the claimed diameter range of the spheroid, the cell number within the spheroid of cells disclosed by Fujii also meet the claimed range of no less than about 40,000 cells or 12,500 cells. The plurality of neuronal cells encompassed within the spheroid disclosed by Fujii also comprise axon bundles with a width of 100mm (see col.6, lines 45-48), which meets the limitation “at least one parallel fasciculated axon with a width of from about 100-500mm in claim 63. Thus, claims 1, 3, 6-7, 14, 63 and 65 are anticipated by Fujii et al. (US10865372).
Accordingly, the rejection of claims 1, 3, 6-7, 14, 63 and 65 under 35 U.S.C. 102 (a)(2) as anticipated by Fujii is maintained.
Claim Rejections - 35 USC § 103
6. 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 3, 6-7, 14, 63 and 65 stand rejected under 35 U.S.C. 103 as obvious over by Fujii et al. (US10865372) in view of Dingle et al. (Tissue Engi.. 2015; 21: DOI:10.1089/ten.tec.2015.0135, as in IDS) and Knoblich’260 (US2021/0095260). The rejection is maintained for the reasons of record and the reasons set forth below.
Claims 8 and 64 stand rejected under 35 U.S.C. 103 as being unpatentable over Fujii et al. (US10865372) in view of Dingle et al. (2015), Knoblich’260 (US2021/0095260) as applied to claims 1, 3, 6-7, 14, 63 and 65 above, and further in view of De Simone et al. (Intl. J. Toxicol., 2017; 36:463-477) and Ohshiro et al. (J. Neurosci. Methods, 2007; 165:49-54). The rejection is maintained for the reasons of record and the reasons set forth below.
Claim 66 stands rejected under 35 U.S.C. 103 as being unpatentable over Fujii et al. (US10865372) in view of Dingle et al. (2015), Knoblich’260 (US2021/0095260), De Simone et al. (2017) and Ohshiro et al. (2007) as applied to claims 1, 3, 6-8, 14 and 63-65 above, and further in view of Gupta et al. (US2017/0267970). The rejection is maintained for the reasons of record and the reasons set forth below.
Response to Arguments
On p. 15-16 of the response, Applicant argues that i) for the reasons set forth above, Fujii does not anticipate, teach or suggest claims 1, 3, 6-7, 14, 63 or 65 and Dingle or Knoblich’260 does not overcome the deficiencies of Fujii; ii) for the reasons set forth above, claims 1 and 63 are patentable over Fujii in view of Dingle and Knoblich’260, and De Simone or Ohshiro does not overcome the deficiencies of Fujii, Dingle or Knoblish’260; iii) since claims 8 and 64 depend from claims 1 and 63, claims 6 and 64 are also patentable over the combination of Fujii, Dingle, Knoblich’260 with De Simone and Ohshiro; iv) for the reasons set forth above, claim 63 is patentable over the combination of Fujii in view of Dingle, Knoblich’260, De Simone and Ohshiro, and Gupta does not overcome the deficiencies of Fujii, Dingle, Knoblich’260, De Simone and Ohshiro, claim 66 depending from claim 63 is also patentable over the combination of Dingle, Knoblich’260, De Simone, Ohshiro, and Gupta.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2141, MPEP2141-I, rationales identified by the Court in KSR (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, 82 USPQ2d 1385 (2007)), MPEP2141-II, the basic factual inquires of Graham v. John Deere Co.(Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966)),and MPEP §2141.01-2147.03, the cited references do render the claimed invention obvious because:
i. For the reasons set forth above, Fujii does teach the composition recited in claims 1, 3, 6-7, 14, 63 and 65.
ii. Even if Fujii does not teach the diameter range of the spheroid that is exactly identical to the claimed ranges of 10-50,000m or 200-700m or the cell number ranges that are not exactly identical to the claimed ranges of no less than about 40,000 cells or no less than about 12,500 cells recited in claims 1, 7 and 63, Dingle teaches that spheroid sizes are controlled by initial seeding densities and can reach a stable size by 14 DIV (p. 1279, 2nd col., 2nd paragraph).
Dingle teaches a composition comprising a 3D-cortical spheroid comprising neurons, glia, astrocytes, oligodendrocytes and microglia and neural stem/progenitor cells, wherein the spheroid has a diameter of about 100-300m and has a density of 2x106 cells/mm3 or 2-4 x105/mm3, wherein the neurons and glia in spheroids formed 3D structures and neurons formed synaptic connections and were electrically active (see p.1276, 2nd col., Results-Cortical cells self-assembled into 3D spheroids to p.1277; p. 1277-1278, figures 1a-c and 2; p. 1280, in vivo-like cell morphology and structure, Supplementary Fig. S1 (a)-(b)). Dingle teaches that initial seeding densities for 3D-cortical spheroid cultures were 1K, 2K, 4K or 8K cortical cells/spheroid, spheroid diameters at 7-21 DIV ranged from 180m-300m (see Figure 1b); and that based on seeded at 8k cells/spheroid, the cell density at 1 DIV spheroid is 2x106 cells/mm3 and that at 7-21 DIV is 2-4 x105/mm (p.1276-1278, Results-Cortical cells self-assembled into 3D spheroids, Figures 1a-c; p. 1279-1281, Discussion). Dingle also teaches that spheroid sizes are controlled by initial seeding densities and can reach a stable size by 14 DIV (p. 1279, 2nd col., 2nd paragraph).
Knoblich’260 (US2021/0095260) teaches a composition comprising multi-differentiated cerebral spheroids/organoids/tissue having a size of at least 100mm-10mm; 100mm….2mm or volume of 1x106…10x106mm3 to 1x106mm….60mm3, wherein the multi-differentiated cerebral spheroids/organoids comprise neuronal tissue comprising radial glia, neurons neural progenitor cells, pluripotent stem cells (paragraphs [0012]; [0033]-[0039]; [0056]).
A person of ordinary skill in the art would have recognized that selecting and applying the known size range and cell number ranges and the known technique disclosed by Dingle and Knoblich’260 to the Fujii’s composition comprising a spheroid of cells comprising a human neuronal cell and a human nervous ganglia comprising human motor neurons, human Schwann cells, human oligodendrocytes and human glial cells would have yielded the predictable result of the claimed composition comprising a spheroid comprising a human neuronal cell and a human nervous ganglia and wherein at least some of the human neuronal cells have axons that are myelinated and the spheroid has a diameter size of the claimed diameter ranges and the claimed cell number ranges, and resulted in an improved product.
Spheroid sizes are controlled by initial seeding densities and can reach a stable size by 14 DIV and the spheroid having a diameter of about 100-300m and a density of 2x106 cells/mm3 or 2-4 x105/mm3 can allow the neurons, Schwann cells and glia to form a 3D spheroid structure comprising a human neuronal cell and a human nervous ganglia and wherein at least some of the human neuronal cells have axons that are myelinated, and with synaptic connections and synaptic activities in the spheroid.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply known size range and cell number ranges and the known technique disclosed by Dingle and Knoblich’260 to the Fujii’s composition. and yield the predictable result of the claimed composition comprising a spheroid comprising a human neuronal cell and a human nervous system ganglia with a size of the claimed diameter ranges and the claimed cell number ranges.
Further, the claimed spheroid requires a diameter of spheroids at 10-50,000m or 200-700m or no less than about 40,000 cells or no less than about 30,000 cells, which overlaps with the ranges of Fujii, Dingle or Knoblich’260 because Fujii teaches a composition comprising a spheroid comprising human motor neurons, human Schwann cells, human oligodendrocytes, and human glia and clusters of cell bodies of a plurality of human motor neurons, human Schwann cells, human oligodendrocytes and human glia having a diameter of ~100m, ~500m or ~100m to ~2000m, Dingle teaches that the spheroid has a diameter of about 100-300m and has a density of 2x106 cells/mm3 or 2-4 x105 cells /mm3 and Knoblich’260 teaches a composition comprising multi-differentiated cerebral spheroids/organoids/tissue having a size of at least 100mm-10mm; 100mm….2mm. Because the claimed range overlaps with the range disclosed by the prior art, a prima facie case of obviousness exists. Note that
“In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. See MPEP §2144.05-I. In addition, “a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985)” See MPEP §2144.05-I.
Moreover, routine optimization of the spheroid sizes and cell numbers of Fujii, Dingle and Knoblich’260 would have led to the claimed range of a spheroid diameter of 10-50,000m or 200-700m or comprising no less than about 40,000 cells or no less than about 30,000 cells because Fujii teaches the claimed composition comprising a spheroid of cells having a diameter of ~100m, ~500m or ~100m to ~2000m; Dingle teaches that the spheroid has a diameter of about 100-300m and has a density of 2x106 cells/mm3 or 2-4 x105 cells/mm3 for making 3D-cortical spheroid cultures and forming synaptic connections and activities; and Knoblich’260 teaches a composition comprising multi-differentiated cerebral spheroids/organoids/tissue having a size of at least 100mm-10mm; 100mm….2mm. The person of ordinary skill in the art would have found it obvious to optimize within the range taught by Fujii, Dingle and Knoblich’260 because Fujii, Dingle and Knoblich’260 teach that the entire range, and also teach how to optimize the size and number of 3D spheroids comprising different neurons, glial cells, oligodendrocytes, microglia, astrocytes and neural progenitor cells. Note that
“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”; “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969); Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert.denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP § 2144.05.
Accordingly, the rejection of claims 1, 3, 6-7, 14, 63 and 65 under 35 U.S.C. 103 as obvious over by Fujii in view of Dingle and Knoblich’260 is maintained.
iii. For the reasons set forth above, Fujii, Dingle and Knoblich’260 do teach the limitations and composition recited in claims 1, 3, 6-7, 14, 63 and 65, and render the claims 1, 3, 6-7, 14, 63 and 65 obvious.
While Fujii, Dingle and Knoblich’260 do not teach the claimed ratio for neuronal cells and Schwann cells/astrocytes/glial cells in spheroid including neuronal cells to astrocytes at a ratio of 1:1 recited in claims 8 and 64, De Simone and Ohshiro teach these limitations and provide motivation and an expectation of success in using the claimed ratio for neuronal cells and Schwann cells/astrocytes/glial cells in spheroid including neuronal cells to astrocytes at a ratio of 1:1 in the composition of Fujii, Dingle and Knoblich’260 because De Simone and Ohshiro teachesa ratio of 1:1 to 5:1 for neurons (2.5x105 cells) and glial cells/astrocytes in co-culture to form a spheroid.
De Simone teaches a neuron-astrocyte coculture model comprising a ratio of 1:1 for neurons (2.5x105 cells) and glial cells/astrocytes (2.5x105 cells) in a 6-well transwell system to investigate neuroprotection and cytotoxicity and for high throughput screening platforms (see p. 464-465, Cell Coculture Model in a Transwell plate System, Figures 1-2). Ohshiro teaches a dorsal root ganglion (DRG)-dorsal horn neuron (DHN)- co-culture comprising 4000 DRG cells (including Schwann cells and glial cells) and 20,000 DHNs, which is equal to a ratio of 5:1 of neurons to Schwann cells/glial cells) (see p. 50, 2nd col.).
A person of ordinary skill in the art would have recognized that applying the known ratio of 1:1 for neuron-astrocyte co-cultures or the known ratio of 5:1 of neuron-Schwann cell co-cultures and the known technique disclosed by De Simone and Ohshiro to the composition of Fujii, Dingle and Knoblich’260 would have yielded the predictable result of the claimed composition comprising a spheroid comprising human neuronal cells or stem cells or human nervous system ganglia with a size of the claimed diameter ranges and the claimed cell number ranges and resulted in an improved product for investigating neuroprotection and cytotoxicity and for high throughput screening platforms. Using the ratio of neurons to astrocytes at 1:1 for neuron-astrocyte co-cultures or 5:1 of neuron-Schwann cell co-cultures in the composition of Fujii, Dingle and Knoblich’260 would expand application of the composition of Fujii, Dingle and Knoblich’260 for use of investigating neuroprotection and cytotoxicity and for high throughput screening platforms and for therapeutic purposes.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply the known ratio of 1:1 for neuron-astrocyte co-cultures or the known ratio of 5:1 of neuron-Schwann cell co-cultures and the known technique disclosed by De Simone and Ohshiro to the composition of Fujii, Dingle and Knoblich’260, and yield the predictable result of the claimed composition comprising a spheroid comprising human neurons, human astrocytes, and human radial glial cells or comprising human neurons, astrocytes, glial cells, oligodendrocytes and microglia and neural progenitor cells with a size of the claimed diameter ranges and the claimed cell number ranges.
Further, routine optimization of the ratio of 5:1 for neurons to Schwann cells/astrocytes/glia cells in neuron-Schwann cell/astrocyte/glia cell co-culture in the composition of Fujii, Dingle and Knoblich’260 would have led to the claimed range of 4:1 for neurons to Schwann cells/glial cells/astrocytes or 10:1 for neurons to Schwann cells because De Simone teaches a ratio of 1:1 for neuron-astrocyte co-cultures and Ohshiro a ratio of 5:1 for neuron-Schwann cell co-cultures. The person of ordinary skill in the art would have found it obvious to optimize within the range taught by De Simone and Ohshiro because De Simone and Ohshiro teach that the entire range, and also teach how to optimize the size and number of 3D spheroids comprising different neurons, Schwann cells, glial cells and astrocytes. Note that
“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”; “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969); Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert.denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP § 2144.05.
Accordingly, the rejection of claims 8 and 64 under 35 U.S.C. 103 as being unpatentable over Fujii in view of Dingle and Knoblich’260 as applied to claims 1, 3, 6-7, 14, 63 and 65 above, and further in view of De Simone and Ohshiro is maintained.
iv. For the reasons set forth above, Fujii in view of Dingle, Knoblich’260, De Simone and Ohshiro do teach the limitations and composition recited in claims 1, 3, 6-8, 14 and 63- 65, and render the claims 1, 3, 6-8, 14 and 63- 65 obvious.
While Fujii, Dingle, Knoblich’260, De Simone and Ohshiro do not explicitly teach that the spheroid has an elastic modulus of from 100-4800 Pascals in claim 66, Gupta teaches this limitation and provides motivation and an expectation of success because Gupta teaches a 3D spheroid culture composition comprising a spheroid of cells in a 3D hydrogel, wherein the spheroid of cells include a co-culture of neurons ang glial cells (see paragraphs [0117]-[0118] ; [0155]-[0156]; [0208]; [0226]), wherein the spheroid (i.e. cluster) comprises 10,000-100,000 cells or 100,000-1million cells or 1-10 million cells or 10-100 million cells (see [0157]) and wherein the spheroid has an elastic modulus of from about 100-4800 Pascals as in claim 66 (see paragraphs [0167]-[0169]).
A person of ordinary skill in the art would have recognized that selecting and applying the known spheroid in a 3D hydrogel having an elastic modulus of from about 100-4800 Pascals and the known culture technique disclosed by Gupta to the composition of Fujii, Dingle, Knoblich’260, De Simone and Ohshiro would have yielded the predictable result of the claimed composition comprising a spheroid of cells that comprises a human neuronal cells and a human nervous system ganglia, and wherein the spheroid has a diameter of the claimed diameter range and the claimed cell number, and with at least one parallel fasciculated axon with the claimed width of 100-500um, and has an elastic modulus of from 100-4800 Pascals, and resulted in an improved product for investigating neuroprotection and cytotoxicity and for high throughput screening platforms. Using the known spheroid in a 3D hydrogel having an elastic modulus of from about 100-4800 Pascals and the known culture technique disclosed by Gupta in the composition of Fujii, Dingle, Knoblich’260, De Simone and Ohshiro would expand application of the composition of Gupta to the composition of Fujii, Dingle, Knoblich’260, De Simone and Ohshiro for use of investigating neuroprotection and cytotoxicity and for high throughput screening platforms and for therapeutic purposes.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known spheroid in a 3D hydrogel having an elastic modulus of from about 100-4800 Pascals and the known culture technique disclosed by Gupta to the composition of Fujii, Dingle, Knoblich’260, De Simone and Ohshiro, and yield the predictable result of the claimed composition comprising a spheroid of cells comprising a human neuronal cell and a human nervous system ganglia, wherein the spheroid has a diameter of the claimed diameter range and the claimed cell number, and with at least one parallel fasciculated axon with the claimed width of 100-500um, and has an elastic modulus of from 100-4800 Pascals. See MPEP § 2143. 01-I, MPEP § 2144.06 and MPEP §2144.07.
Further, routine optimization of the spheroid in 3D hydrogel in the composition of Fujii, Dingle, Knoblich’260, De Simone, Ohshiro and Gupta would have led to a spheroid in 3D hydrogel having an elastic modulus of from about 100-4800 Pascals because Gupta teaches a spheroid of cells in a 3D hydrogel, wherein the spheroid of cells include a co-culture of neurons ang glial cells, wherein the spheroid (i.e. cluster) comprises 10,000-100,000 cells or 100,000-1million cells or 1-10 million cells or 10-100 million cells and has an elastic modulus of from about 100-4800 Pascals. The person of ordinary skill in the art would have found it obvious to optimize within the range taught by Gupta because Gupta teach that the entire range, and also teach how to optimize the elastic modulus of a spheroid of cells in a 3D hydrogel. Note that
“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”; “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969); Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert.denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP § 2144.05.
Accordingly, the rejection of claim 66 under 35 U.S.C. 103 as being unpatentable over Fujii in view of Dingle, Knoblich’260, De Simone and Ohshiro as applied to claims 1, 3, 6-8, 14 and 63-65 above, and further in view of Gupta is maintained.
Double Patenting
7. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 6-8, 14 and 63-65 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10-13, 15, 35, 39-42, 48-50, 67-68 of copending Application No. 18/687179 in view of Fujii et al. (US10865372), Dingle et al. (2015), Knoblich’260 (US2021/0095260), De Simone et al. (2017), Ohshiro et al. (2007) and Gupta et al. (US2017/0267970). The rejection is maintained for the reasons of record and the reasons set forth below.
Response to Arguments
On p. 16 of the response, Applicant argues that the rejection is moot in view of amendment to the claims and remarks set forth above.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §804, MPEP §2141, MPEP2141-I, rationales identified by the Court in KSR (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, 82 USPQ2d 1385 (2007)), MPEP2141-II, the basic factual inquires of Graham v. John Deere Co.(Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966)),and MPEP §2141.01-2147.03, the cited references do render the claimed invention obvious because:
i. The claims of the ‘179 Application claim a composition comprising a first spheroid of cells comprising one or a combination of cells and/or tissue chosen from a neuronal cell, an astrocyte and a glial cell (independent claim 1) and further comprising a second spheroid of cells comprising one or a combination of cells chosen from a glial cell, an embryonic cell….and combination as recited in instant claim 3, and wherein the cells include cells that are derived from human spinal cord tissue (i.e. human origin) as recited in instant claim 1.
While the claims of the ‘179 Application do not recite that the spheroid has a specific diameter or cell number or neuronal cells having axons that are myelinated, Fujii, Dingle, Knoblich’260, De Simone, Ohshiro and Gupta teach these limitations and provide motivation and an expectation of success for the reasons set forth above under the 103 rejections. Accordingly, the provisional rejection of claims 1, 3, 6-8, 14 and 63-65 on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10-13, 15, 35, 39-42, 48-50, 67-68 of copending Application No. 18/687179 in view of Fujii, Dingle, Knoblich’260, De Simone, Ohshiro and Gupta is maintained.
Conclusion
8. NO CLAIM IS ALLOWED.
9. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Hyung et al. (Sci. Rep., 2015; 5:15122. DOI:10.1038/srep15122) teach a motor neuron-Schwann cell coculture comprising a ratio of 1:3 for motor neurons (1x104 cells/coverslip) and Schwann cells (3x104 cells/coverslip) (see p. 8-9 Cell Preparation).
Vadivelu et al. (Sci. Rep. 2015; 5:15083. DOI:10.1038/srep15083. published Oct 14, 2015) teach a composition comprising 3D co-culture comprising spheroids comprising olfactory ensheathing cells (OECs) co-cultured with Schwann cells and astrocytes (see abstract).
Krencik et al. (Stem Cell Rep. 2017; doi.org/10.1016/j.stemcr.2017.1.026) teach a 3D organoid-like spheres comprising hPSC-derived astrocytes and neurons generated from hPSC-derived neural stem cells (hNeurons) or induced via Neurogenin 2 overexpression (iNeurons) (see abstract).
Lancaster et al. (Nature, 2013; 501:373-379) teach a composition comprising 3D cerebral organoid/spheroid cultures comprising neurons, glia, astrocytes, oligodendrocytes, radial glial progenitor cells microglia derived from human H9 embryonic stem cells (H9 hESCs), or human induced pluripotent stem cells (hiPSCs) or mouse A9 embryonic stem cells (A9 mESCs), wherein the organoid/spheroid has a diameter of about 100-1000m (see Day 22 in Extended Data Figure 7a-g, p. 14, Extended data Figure 5), wherein the neurons and glia in spheroids formed 3D structures and neurons formed synaptic connections and were electrically active (see p. 16-17, Extended Data Figure 7).
Knoblich et al. (US10407664; also published as US2015/0330970) teaches a 3D neuronal tissue culture or cerebral organoid culture comprising outer radial glia cells and cortical cells of a cortical inner fiber layer in an inner fiber layer; and a 3D matrix that is a hydrogel; wherein the radial glial cells and cortical cells are derived from pluripotent stem cells including induced pluripotent stem cells and wherein the outer radial glia cells are in an outer or extra cortical subventricular zone (see Figures 1, 6 and 9; col. 2-5; col. 17; col. 20; col. 21-29, Examples 2-8; col. 37-38, claims 1-18).
Rossen et al. (US11324779) teaches an injectable 3D spheroid microtissue comprising: a plurality of spheroids, each comprising a plurality of cells of a first cell type and a plurality of cells of a second cell type, wherein the first cell type are endothelial cells that are concentrated in an interior core region of each spheroid and the second cell type is mesenchymal stem cells (MSCs); and wherein the plurality of spheroids are free of vascular interconnections; and the spheroids have diameters of 100 um, 200 um or 400μm or less than 1000um and the ratio of endothelial cells to MSCs is 3:1or 1:1 or 1:3, wherein the endothelial cells concentrated in an interior region define a distinct structure with discernable boundaries and consisting essentially of said endothelial cells, and wherein the endothelial cells are vascular endothelial cells and the distinct structure is a blood vessel precursor (see abstract; co.2; col. 42; col. 45-47; col. 49, lines 11-35).
10. This application contains claims 19, 22, 24, 30-31, 41, 45, 52-56 and 62 drawn to an invention nonelected with traverse in the reply filed on 12/05/2022. A complete reply to the final rejection must include cancellation of nonelected claims or other appropriate action (37 CFR 1.144) See MPEP § 821.01.
11. THIS ACTION IS MADE FINAL. 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.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chang-Yu Wang whose telephone number is (571)272-4521. The examiner can normally be reached on Monday-Thursday, 7:00am-5:30pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker, can be reached on 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Chang-Yu Wang
December 29, 2025
/CHANG-YU WANG/Primary Examiner, Art Unit 1675