DETAILED ACTION
Applicant’s response filed October 15, 2025 has been received and entered into the application file. All arguments have been fully considered. Claims 1, 4, 8-10, 15-16, 19-22, 24 and 26-27 are currently pending. Claims 2-3, 5-7, 11-14, 17-18, 23, 25 and 28-29 are cancelled. Claim 1 is currently amended.
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
REJECTION(S) MAINTAINED
Claim(s) 1, 4, 8-10, 15, 19-22, 24 and 26-27 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Chen et al., (Journal of Neuroscience Research 73:778-786 (2003); previously cited) (“Chen”), in view of Gronthos et al., (J Dent Res 81(8): 531-535, 2002; previously cited) (“Gronthos”), Arthur et al., (STEM CELLS 2008; 26: 1787-1795; previously cited) (“Arthur”), and Pierdomenico et al., (Transplantation 2005; 80:836-842, previously cited) (“Pierdomenico”), as evidenced by Osman et al., (Arterioscler Thromb Vasc Biol. 2020; 40:1231-1238; previously cited (“Osman”).
The rejection has been updated in view of Applicant’s amendment submitted 10/15/2025.
Chen is directed to bone marrow stromal cell therapy (MSCs) after stroke. Chen specifically investigates induction of neurogenesis, reduction of apoptosis, and promotion of basic fibroblast growth factor (bFGF) expression as mechanisms that improve neurological functional recovery (Abstract).
Regarding claim 1, Chen specifically teaches administering 3 x 106 male rat bone marrow stromal cells (MSCs) (i.e., administering a therapeutically effective dose) to female rats that had been subjected to 2 hours of middle cerebral artery occlusion (MCAO), wherein the cells were administered 24 hours post-stroke (Abstract; Transplantation Procedures, page 779). Chen teaches the MSCs survived and were distributed throughout the cortex, striatum, vessel walls of the damaged brain, and in the ischemic boundary zone (IBZ) (Histology, right column, first paragraph, page 781).
As to the limitation that the method of “treating a human subject who has suffered a stroke”, although Chen discloses administration of the therapeutic MSCs to female rats, it is noted that Chen teaches administering the therapeutic MSCs to the rodent subjects that were subjected to MCAO which is used as a representative human stroke model. Chen does not disclose administering the MSCs to human subjects, however Chen employs the identical MCAO model as disclosed in the instant specification at Example 4 (page 48, lines 10-17), which represents the most common human model of ischemic stroke and movement disorder as a result of the stroke (Fig. 1). Therefore, Chen’s rodent MCAO model represents administration of the therapeutic cells to humans for treating a human subject who has suffered a stroke and has a movement disorder as a result of the stroke, absent evidence to the contrary, thus meeting the limitation of claim 1.
Chen teaches that neurogenesis within the adult brain is mediated via trophic influences (Discussion, left col, last paragraph, page 783), and in combination with the neurological functional recovery, the treatment method resulted in newly formed cells expressing proteins phenotypic of progenitor-like neurons (TUJ1) and astrocytes (GFAP) which are consistent with neurogenic cell identity (Discussion, right col, first paragraph, page 783 and Figure 3). The MSC treatment promotes endogenous cell proliferation in the subventricular zone (SVZ), decreased apoptosis and increased endogenous bFGF expression in the ischemic boundary area (Discussion, right col, second paragraph, page 783 and Discussion, left col, last paragraph, page 785). Chen teaches that bFGF stimulates nerve regeneration. (Discussion, right col, second paragraph, page 783). Chen indicates that the interaction of MSCs with the ischemic brain microenvironment leads to production of trophic factors which reduce apoptosis and promote proliferation of endogenous stem and progenitor cells, thus enhancing neuronal functional recovery (Discussion, right col., last paragraph at page 783 to left col., first paragraph, page 784).
As to the limitation that the population of cells are human dental pulp stem cells (hDPSCs), it is noted that although Chen recognizes that mesenchymal stem and progenitor cells are multipotent and capable of differentiating into various cell types, including neurons, when cued by the appropriate microenvironment (page 778, right column, first paragraph), Chen does not further teach the population of therapeutic MSCs are derived from human dental pulp tissue.
However, Gronthos teaches methods of isolating human dental pulp stem cells (hDPSCs) since they represent an adult stem cell population possessing the properties of high proliferative potential, capacity for self-renewal, and multi-lineage differentiation (Introduction, page 531). Gronthos specifically teaches comparing adipogenic and neural differentiation potential between human DPSCs and bone marrow-derived MSCs (BMMSCs). Figure 3 of Gronthos shows that DPSCs have high levels of expression for both Nestin (neural marker) and GFAP (glial marker, e.g., astrocytes), whereas BMMSCs only stained positive for Nestin and did not stain positive for GFAP.
It is additionally noted that Osman evidences that GFAP is also expressed in neural stem cells that give rise to neurons and glial cells in the brain and spinal cord. Therefore, the GFAP expression disclosed by Gronthos is further considered a neural marker.
Arthur is directed to studies of the neurogenic potential of human adult dental pulp stem cells (hDPSCs) and teaches that the hDPSCs respond to neuronal inductive conditions both in vitro and in vivo, and expressed neuronal-specific markers at both the gene and protein levels. When exposed to neuronal inductive media, the hDPCSs exhibited the capacity to produce sodium current consistent with functional neuronal cells. Arthur teaches that hDPSCs have the potential for use in cell-based therapies for treating neurological diseases (Abstract; Functional Analysis of the Neuronal Properties of DPSCs In Vitro, page 1791; Neural Induction of DPSCs In Vivo, pages 1791-1792). Arthur further teaches that, even under non-neural conditions, the DPSCs expressed the neural progenitor marker Nestin, as well as the glial marker GFAP, and when cultured under neural inductive conditions the DPSCs expressed the neuron-specific marker NeuN. Arthur’s findings demonstrated that the human DPSCs were predisposed to a neuronal fate, and when subjected to neuronal differentiation environment, the neuronal fate was further enhanced (Introduction, page 1788, left col, second and third paragraphs; Neural Induction Assay, page 1788).
Arthur specifically notes:
“Collectively, these data suggest that in response to the neuronal inductive stimuli, a greater proportion of DPSCs had stopped proliferating and had acquired a phenotype resembling mature neurons.” (page 1790, right col, last sentence).
Arthur further conducted in vivo neural induction of the DPSCs using an avian embryo model for investigating neuronal differentiation capacity, wherein 48 hours after exposure to in vivo neuronal conditions, the DPSCs displayed the morphology of biopolar cells and neurons with multiple neurites (Fig 3B, 3D) (page 1792, left col, first full paragraph).
Therefore, given that Gronthos has established hDPSCs have neural differentiation potential and Arthur further teaches that hDPSCs have neurogenic potential and Arthur specifically investigates both in vivo and in vitro conditions wherein the hDPSCs respond to neuronal induction, specifically acquiring a phenotype indicative of mature neurons, one of ordinary skill in the art would find it prima facie obvious to substitute human mesenchymal stem cells derived from dental pulp, i.e., dental pulp stem cells (hDPSCs), for Chen’s bone marrow-derived mesenchymal stem cells in order to promote regeneration of neurons in the treatment of stroke in a human subject.
The person of ordinary skill in the art would have been motivated to use human dental pulp stem cells (hDPSCs), as taught by Gronthos and Arthur, for the predictable result of providing a species compatible cell type that has demonstrated neural differentiation potential and responds to neuronal inductive conditions both in vitro and in vivo.
The skilled artisan would have had a reasonable expectation of success in substituting the human dental pulp stem cells because Gronthos and Arthur have shown that dental pulp stem cells are an effective therapeutic cell type. Substitution of one element (i.e., neural regenerative cell type) for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Further regarding claim 1 and the limitation the administered stem cells are allogeneic, it is noted that Gronthos administers human cells to mice (xenogenic) and does not further teach allogeneic transplant. However, Pierdomenico teaches that dental pulp stem cells have immunosuppressive activity and are an easily accessible and efficient source of MSCs (mesenchymal stem cells) (Abstract: Conclusions; Immunological Modulation, page 839). Figure 5 of Pierdomenico illustrates the dental pulps stem cells imparted 91% T-cell inhibition as compared to a 75% inhibitory effect for the bone marrow stem cells (Effect on T-cell Proliferation, page 841).
Therefore, one of ordinary skill in the art would find it prima facie obvious to substitute allogeneic stem cells, for the prior art xenogenic cells, thus meeting the limitation of claim 1.
The person of ordinary skill in the art would have been motivated to use allogeneic dental pulp stem cells (hDPSCs), as taught by Pierdomenico, for the predictable result of providing a species compatible cell type that has demonstrated reduced immunoreactivity and are an easily accessible and efficient source of therapeutic MSCs.
Substitution of one element for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Regarding claim 4, the movement disorders imparted by Chen’s stroke model are considered to be uncoordinated movement as illustrated by the movement tests of Fig. 1, thus meeting the limitation of claim 4.
Regarding claims 8-9, Chen teaches middle cerebral artery occlusion (MCAO), thus meeting the limitation of claims 8 and 9.
Regarding claim 10, Chen teaches administration 24 hours after the stroke, thus meeting the limitation of claim 10.
Regarding claim 15, Chen teaches administering the stem cells by injection to the tail vein, which reads on administered systemically, thus meeting the limitation of claim 15.
Regarding claims 21-22 and 24 and the limitations directed to the cell concentration, the only difference between Chen’s teaching and the claimed method is Chen teaches administering 3 x 106 male rat bone marrow stromal cells (MSCs) to female rats, wherein the female rats weighed about 270-300 grams (correlates to 0.27 to 0.3 kg) (Animal Middle Cerebral Artery Occlusion Model, left col. page 779), thus Chen’s concentration of cells ranges from 10-11.1 x 106 per kg.
The claimed limitation comprises only the routine optimization of the concentration of cells for use in the claimed method. Said optimization would have been obvious and well-within the purview of the ordinarily skilled artisan at the time of filing.
Note that the optimization of doses/concentrations would have been prima facie obvious to one of ordinary skill in the art at the time of filing:
“[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. “ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05).
As set forth at MPEP 2144.05 II. A:
“Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”
Regarding claims 19 and 20, the combined prior art does not disclose administering the cells a plurality of times (claim 19) or once every four or more weeks (claim 20). However, Chen has shown that a single dose, administered 24 hours after occlusion, was effective for improving neural regeneration and motor function. Therefore, it would have been obvious to one having ordinary skill in the art at the time of the invention to optimize the dosing regimen as a matter of routine experimentation as it is a recognized result effective variable which achieves the recognized result of improving neural regeneration and motor function. Moreover, at the time of the claimed invention, one of ordinary skill in the art would have been motivated by routine practice to optimize the dosing regimen with a reasonable expectation for successfully regenerating neuron and improving motor function; thus, meeting the limitation of claims 19 and 20.
Absent any teaching of criticality by the Applicant concerning the dosing regimen, it would be prima facie obvious that one of ordinary skill in the art would recognize this as a result effective variable whose dosing regimen is a matter of routine optimization. Differences in dosing parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such parameter is critical. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05).
Regarding claim 26, Chen (Cell Culture, page 779), and Gronthos (Subjects and Cell Culture, page 531), each teach the stem cells can be culture expanded prior to administration, thus meeting the limitation of claim 26.
Regarding claim 27, it is noted that limitations to cells being cryopreserved prior to thawing and administration are product-by-process limitations and are merely describing the administered cells by the manner in which the cells were prepared.
Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, the method by which the administered cells have been produced by cryopreservation prior to thawing and administration is not sufficiently detailed so as to impart any unique structural/chemical properties to the administered cells, rather any non-frozen, thawed hDPSCs are considered to read on the mixture.
As set forth at the rejection of claim 1, the cited prior art teaches the claimed hDPSC, thus claim 27 is included in the rejection of claim 1.
Claim 16 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Chen, in view of Gronthos, Arthur and Pierdomenico, as evidenced by Osman, as applied to claims 1-2, 4, 7-10, 15, 19-22, 24 and 26-27 above, and further in view of Chen et al., (Journal of the Neurological Sciences 189 (2001) 49-57; previously cited) (“Chen 2001”).
The teaching of Chen, in view of Gronthos, Arthur and Pierdomenico, as evidenced by Osman is set forth above.
Regarding claim 16 and the limitation that the population of cells are administered locally to the brain of the human subject, it is noted that the combined prior art does not further teach local administration of the stem cells to the brain.
However, Chen 2001 is directed to treating cerebral ischemia (MCAO, stroke) by intracerebral transplantation of bone marrow stromal cells (MSCs). Chen 2001 teaches the intracerebral transplantation of the MSCs provided significant improvement in motor and somatosensory function (Abstract).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute local administration of the MSCs to the brain for the systemic administration of the stem cells since both types of dosing are known for treating stroke. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of MSCs for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Response to Arguments
Rejections under 35 USC 103(a):
As to Applicant’s remarks regarding the amended limitation directed to treating a human subject, as discussed at Applicant’s remarks (page 8), it is noted that Applicant’s remarks have been considered, but are not found persuasive in view of the updated rejection set forth above, specifically addressing the newly amended limitation.
Applicant has asserted that the therapeutic potential of hDPSCs is not tied to their comparative neurogenic differentiation potential.
However, Applicant’s argument is not found persuasive since Chen is directed to stem cell-based therapy for treating stroke, wherein the stem cell-based therapy includes inducing neurogenesis, in addition to reducing apoptosis and promoting expression of basic fibroblast growth factor (bFGF).
Therefore, given that Gronthos has established hDPSCs have neural differentiation potential and Arthur further teaches that hDPSCs have neurogenic potential, and Arthur specifically investigates both in vivo and in vitro conditions wherein the hDPSCs respond to neuronal induction, specifically acquiring a phenotype indicative of mature neurons, one of ordinary skill in the art would find it prima facie obvious to substitute human mesenchymal stem cells derived from dental pulp, i.e., dental pulp stem cells (hDPSCs), for Chen’s bone marrow-derived mesenchymal stem cells in order to induce neurogenesis in the treatment of stroke in a human subject.
As to Applicant’s remarks regarding Chen’s teaching at Discussion page 783 (left col, lines 30-38), as discussed at Applicant’s remarks (page 8), it is noted that Applicant’s remarks have been considered, but are not found persuasive in teaching away from using MSCs derived from dental pulp.
In response to Applicant’s argument, it is noted that previously cited Nosrat et al evidences that dental pulp stem cells produce neurotrophic factors (Abstract) and Chen’s next paragraph of the Discussion notes that the MSCs secrete factors having trophic influences that mediate neurogenesis, and thus the result in improvement in neurological function after these functions were impaired by the ischemic insult. Chen (Discussion, right col, last paragraph, page 783 to left col, first paragraph, page 784) further teaches the therapeutic effect arising from MSC treatment is in part due to the interaction of the MSCs with the brain microenvironment leads to the production of the trophic factors which additionally reduce apoptosis and promote proliferation of endogenous stem and progenitor cells.
As to Applicant’s remarks that one of ordinary skill in the art would not consider DPSCs equivalent to BMSCs for the treatment of stroke, as discussed at Applicant’s remarks (page 9), Applicant’s remarks have been carefully considered, but are not found persuasive for the reasons set forth immediately above.
As to Applicant’s remarks directed to Exhibit A and the post-filing showing that hDPSCs showed greater reduction in infarct volume compared to hBMSCs, as well as reduced gliosis, and superior neuroprotective, migratory and in vitro angiogenic effects, as discussed at Applicant’s remarks (pages 9-10), Applicant’s remarks have been fully considered, but are not found persuasive since Applicant’s arguments are not commensurate in scope with the claimed invention.
The claims as currently written do not recite any limitations requiring any specific reduction in infarct volume, or any limitations regarding neuroprotective, migratory or in vitro angiogenic effects.
The showing of unexpected results must be commensurate in scope with the invention as claimed. MPEP 716.02(d).
As to Applicant’s remarks regarding the rejection of claim 16, Applicant’s remarks have been fully considered. Applicants rely on the arguments used in traversing the above rejection of claim 1 to also traverse this rejection without additional arguments. However, as explained above, the previous rejection stands. Therefore, the response set forth above to arguments also applies to this rejection.
Conclusion
No claim is allowed. No claim is free of the prior art.
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.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633