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
This Action is in response to the papers filed October 09, 2025.
The examiner has previously acknowledged receiving an executed Declaration under 37 C.F.R. § 1.132 executed by Dr. Nate Manley on December 17, 2024 (“Manley Declaration ”), and filed on 12/18/2024.
Claim 35 has been canceled, claims 47-51 are newly added, and claim 28 has been amended as set forth in the claim set filed October 09, 2025.
Claims 28-29, 31-32, 34, 37-39, and 41-51 are pending in the application and examined on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2017/51677 filed September 14, 2017.
Applicant’s claim for the benefit of a prior-filed parent provisional applications 62/518,591 filed 06/12/2017, 62/449,580 filed 01/23/2017, and 62/394,226 filed 09/14/2016 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is September 14, 2016.
Information Disclosure Statement
The information disclosure statement filed 11/14/2025 fails to comply with the provisions of 37 CFR 1.98(a)(4) because it lacks the appropriate size fee assertion. It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
The information disclosure statement filed 11/14/2025 fails to comply with the provisions of 37 CFR 1.97(a) because it lacks the appropriate size fee set forth in 37 CFR 1.17(v). It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
Response to arguments
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claims 28-29, 31-32, 34, 37-39, 41-45 remain rejected and claims 47-51 are newly rejected under 35 U.S.C. 103 as being unpatentable over Sharp (2010. STEM CELLS 28:152–163; of record) in view of Priest (September 2015. Regen. Med. 10(8), 939–958; of record), Keirstead (2005. The Journal of Neuroscience 25(19): 4694-4705; of record), Ilic (Regenerative Medicine, 9(6), 713–719; Published online: 28 Nov 2014; of record), FirstWord Pharma (2011, Geron Presents Data from GRNOPC1 Trial at International Conferences on Spinal Cord Medicine and Rehabilitation | FirstWord Pharma; Accessed 02/11/2026) and Yocum (2004, Rheumatology, 43:992-999) as evidenced by Franz (The Journal of Spinal Cord Medicine, 39(5), 513–517; of record).
This rejection has been modified as necessitated by Applicant’s amendments filed on October 09, 2025.
Regarding claim 28, Sharp teaches a method of administering oligodendrocyte progenitor cells (OPCs) derived from human embryonic stem cells (i.e. pluripotent stem cells) to mice in order to treat cervical spinal cord contusion injuries (i.e. traumatic spinal cord injury) (Abstract, p. 153). Sharp further teaches that the OPCs transplanted into the mic attenuated lesion pathogenesis and improved the recovery of fore limb motor function (i.e. upper extremity motor function) across multiple forelimb gait parameters (Abstract. p. 162). As the amount is effective in improving the recovery of motor function, it is interpreted as being a therapeutically effective amount. Sharp further teaches that the OPCs express NG2 and PDGF-Ra (Figure 1).
However, Sharp does not teach that the subject to which the OPCs are administered is a human subject.
Priest teaches administering oligodendrocyte progenitor cells derived from human embryonic cells in order to determine their preclinical safety (Abstract). Priest conducted long-term safety and toxicology studies in a rat model of thoracic spinal cord contusion injury. The results of these studies supported clearance by the FDA to initi-ate a Phase I clinical trial to assess safety of AST-OPC1 in human patients with subacute, sensorimotor complete thoracic SCI. (p. 940).
The combined teachings of Sharp and Priest do not teach wherein the OPCs are administered 15-60 days after the subject suffers a traumatic spinal cord injury.
Ilic teaches before the effective filing date of the claimed invention that OPCs administered at days 14-30 post spinal cord injury to human subjects with subacute spinal cord injury in clinical trials (p. 717, 2nd column).
It would be obvious to one of ordinary skill in the art to administer the composition of OPCs utilized to improve upper extremity motor function in a rat model as taught by Sharp to treat a human patient rather than the rat model as taught by Priest and Ilic with a reasonable expectation of success. An artisan would be motivated to administer the OPCs to a human patient as it has been shown that the OPCs derived from hESCs have been cleared for Phase I clinical trial with patients (i.e. humans) by the FDA as taught by Priest and Ilic. Moreover, it would have been obvious to administer 14-30 days post spinal cord injury. A skilled artisan would have had a reasonable expectation of success as controlling spinal cord injury to human subjects using administering OPCs at days 14-30 post spinal cord injury was known in the art before the effective filing date of the claimed invention.
Regarding claims 28, 37 and 38, the limitation of the amount of cells administered, Sharp teaches that 1,500,000 cells (1.5 x 106 cells) are administered to the location of the spinal injury (p. 153).
However, Sharp does not teach that the composition contains amounts of cells which are between 2 x 106 cells and 50 x 106 cells, more specifically 10 x 106 and 20 x 106 cells.
Priest teaches administering oligodendrocyte progenitor cells derived from human embryonic cells at an amount of 2.4 × 106 cells per rat in order to determine the starting dose of 2 x 106- cells in human patients (p. 941, 955). Priest further discloses that the highest planned dose for clinical testing is 2 x 107 cells/patient (p. 955).
It would have been obvious to one of ordinary skill in the art to modify and optimize the number of cells administered to the mice in Sharp to have a range between 2 x 106 and 2 x 107 cells when administered to humans as taught by Priest with a reasonable expectation of success. An artisan would be motivated to utilize OPCs between the range of 2 x 106 and 2 x 107 cells as Priest states that due to the administration of the highest feasible dose in rats (2.4 x 106) it was determined to be the starting value in the clinical trial for humans and additionally, the highest planned dose for the clinical test would be 2 x 107 cells per patient (p. 955). Priest further states that it is important to identify the optimal cell administration parameters for SCI including injection volume and injection rate when administering a certain amount of cells (p. 955). Therefore the amount of cells is a case of routine optimization. Although 10 x 106 cells is not explicitly taught, it is within the range of optimization described by Priest et al of starting doses and highest planned dose for clinical testing (p. 955).
Regarding claim, 34, the combined teachings of Sharp, Priest and Ilic as discussed above delivery of OPCs 14-30 days post injury.
It would be obvious to administer the OPCs via the method taught by Sharp at 20-40 days post injury which falls in the subacute/intermediate phase with a reasonable expectation of success.
Regarding the limitation in claim 28, that the upper extremity motor level function improves by at least two motor levels in 1-12 months after administration according to ISNCSCI scale is not explicitly taught by the combined references above. However, as each and every method step has been taught by the combination of references, it would be inherent that the same method steps would yield the same results. As evidenced by Franz, the step of measuring of motor levels by ISNCSCI would be obvious to one of ordinary skill in the art when assessing spinal cord injury as it is the most frequently used clinical neurological assessment to determine the location and severity of SCI (p. 513). It would be obvious to one of ordinary skill in the art to routinely optimize the parameters of treatment to achieve a desired effect.
Regarding the issue of inherency, see Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination. Id. See also Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1329-32, 2020 USPQ2d 6227 (Fed. Cir. 2020). (see MPEP 2112 (IV)).in
Regarding claims 28 and 31, the combined teachings of Sharp and Priest as discussed above do not explicitly teach the distance from the injury epicenter wherein the composition is administered, nor that it is 2-10mm, or approximately 5mm caudal of the injury.
Keirstead teaches a method of treating traumatic spinal cord injury via administering human oligodendrocyte progenitor cells (Abstract). Keirstead further states that the method enhances remyelination and promotes improvement of motor function in rats which received transplantations to spinal cord injury sites 7 days post injury (Abstract, p. 4794). The OPCs, which are differentiated by the same protocols as Sharp are administered to the spinal cord injury site at a depth of 1.2 mm at one site 4mm caudal to the spinal cord injury epicenter. And thus, are administered approximately 5mm caudal to the spinal injury epicenter.
It would have been obvious to one of ordinary skill in the art to administer the OPCs 4mm caudal to the spinal cord injury epicenter as taught by Keirstead in the method of administering OPCs to a human spinal cord injury as taught by Sharp with a reasonable expectation of success. An artisan would be motivated to inject the OPCs 4mm caudal to the injury site as it has been shown that the OPCs are capable of migrating and engrafting over short distances in the spinal cord up to 11 mm cranially and 3mm caudally (p. 4698). Furthermore, although the exact distance of injection from the epicenter is not specified in Sharp, Sharp teaches that most of the transplanted hESC-derived OPCs localized to the lesion epicenter and the cervical lesion itself emanated a distance of 2mm (p. 161).
Regarding the new limitation of claim 28, wherein tacrolimus 0.3 mg/kg/day is administered for one or more days, Sharp teaches that cyclosporine A is administered to the subject prior to treatment at a dose of 20 mg/kg/day (p. 153). Cyclosporine A is utilized in the instant specification (para. 0079) as an exemplary immunosuppressive drug. Moreover, Ilic teaches that it is known in the art to utilize an immunosuppressive regimen with AST-OPC1 cells (p. 717, 2nd column). However, none of the references explicitly teach the utilization of tacrolimus of about 0.3 mg/kg/day administered for one or more days.
FirstWord Pharma teaches a trial using OPCs to treat spinal cord injury comprising administering their GRNOPC1 cells which are derived from ESCs with a low-dose tacrolimus immunosuppressant from injection to 46 days and then tapered until 60 days before withdrawn completely (p. 2; 1st paragraph). Moreover, Yocum teaches that low doses known in the art for administration of tacrolimus to prevent transplant rejection are 0.1-0.2 mg/kg/day (p. 998, 2nd column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to substitute FirstWord Pharma and Yocum’s low dose of tacrolimus of 0.1-0.2 mg/kg/day for the Sharp’s cyclosporine A at a dose of 20 mg/kg/day in the method of spinal cord injury treatment through OPC administration as taught by Sharp, Priest, Keirstead and Ilic with a reasonable expectation of success. An artisan would be motivated to do so as Ilic teaches OPC administration is accompanied by tacrolimus regimens, First Word Pharma teaches low-dose tacrolimus is utilized in OPC administration for spinal cord injury, and Yocum teaches that low dose for transplantation purposes are 0.1-0.2 mg/kg/day.
Regarding claim 29, Sharp teaches that the OPCs are transplanted via injection into the spinal cord injury site at one site cranial and one site caudal of the lesion epicenter at a depth of 1.2 mm (p. 153).
Regarding claim 32, Sharp teaches that the OPCs localized mostly to the lesion epicenter (i.e. capable of engrafting to the injury site). (p. 156, 161).
Regarding claim 39, Sharp teaches that the injury is a cervical spinal cord injury (Abstract).
Regarding claims 41-42, Sharp teaches that the transplant group had an increase of stride length, proximal forelimb range of motion, specifically in the step lift-off, and a relative increase in frequency of passed-perpendicular steps. Thus, the improvement in forelimb function in the transplant group was observed across multiple forelimb gait parameters relevant to the level of injury (p. 161) Additionally, Sharp teaches that bilateral improvement was present (p. 157). Thus, if bilateral improvement is achieved one of ordinary skill in the art would find unilateral improvement obvious.
Regarding claims 43-44, regarding the limitations that the upper extremity motor level function improves by at least two levels in 3 and 12 months after administration according to ISNCSCI scale is not explicitly taught by the combined references above. However, as each and every method step has been taught by the combination of references, it would be obvious to one of ordinary skill in the art that the same method steps would yield the same results with a reasonable expectation of success. As evidenced by Franz, the step of measuring of motor levels by ISNCSCI would be obvious to one of ordinary skill in the art when assessing spinal cord injury as it is the most frequently used clinical neurological assessment to determine the location and severity of SCI (p. 513). It would be obvious to one of ordinary skill in the art to routinely optimize the parameters of treatment to achieve a desired effect.
Regarding claim 45, Sharp teaches that the oligodendrocyte progenitor cells are derived from human embryonic stem cells (Abstract).
Regarding claim 47, Sharp, Priest, Kierstead, Ilic, First Word Pharma, and Yocum make obvious the method of claim 28. Moreover, Yocum teaches tacrolimus is an orally available drug (p. 993, 1st column).
Regarding claims 48-51, Sharp, Priest, Kierstead, Ilic, First Word Pharma, and Yocum make obvious the method of claim 28. Moreover, FirstWord Pharma teaches that the low dose immunosuppression comprising tacrolimus is administered at OPC injection, continued and then tapered at day 46 (after 45 days reduced) to be discontinued at day 60 (p. 2; 1st paragraph).
Therefore, the invention would have been obvious to one of ordinary skill in the art.
Response to Arguments regarding the rejection of claims 28-29, 31-32, 34, 35, 37-39, 41-45 under 35 USC 103
Applicant's arguments filed 10/09/2025 have been fully considered and are persuasive regarding the new limitation recited involving tacrolimus in the independent claim, however, in light of the amendments made, a new ground of rejection is set forth involving the previous rejection and the addition of FirstWord Pharma and Yocum.
Moreover, applicants’ arguments with respect to the treatment of spinal cord injuries in rats, and not a human subject (pages 6-7 of the remarks filed on 10/9/2025) is not persuasive because Ilic discloses a Phase I clinical trial of AST-OPCl. Applicant’s repetitive arguments that the individual prior art does not teach the entire claim, are spurious. It is already acknowledged that the claims, when cited under 103, are not anticipatory. The teachings of Sharp, Priest, Keirstead, Ilic, FirstWord Pharma,Yocum and Franz are relevant for the reasons stated in the new rejection of record.
***
Claim 46 remains rejected under 35 U.S.C. 103 as being unpatentable over Sharp (supra) in view of Priest (supra), Keirstead (supra), Ilic (supra), FirstWord Pharma (supra) and Yocum (supra) as evidenced by Franz (supra) as applied to independent claim 28, and in further view of Wang (2013. Cell Stem Cell 12: 252–264; previously cited).
This rejection has been modified as necessitated by Applicant’s amendments filed on October 09, 2025.
Regarding claim 46, the combined teachings of Sharp, Priest, Keirstead, Ilic, FirstWord Pharma and Yocum as discussed in the above 103 rejection of claim 28 render obvious a method of improving upper extremity motor function via administering a composition of OPCs derived from ESCs to a human patient, as iterated above in the 103 rejection the content of which is incorporated herein, in its entirety.
However, these references do not teach that the OPCs are derived from iPSCs.
Wang teaches that OPCs can be derived from iPSCs and hESCs in order to establish an autologous source of the cells (Abstract, p. 253). These cells exhibited high myelination efficiency to the same level as tissue derived OPCs when implanted (p. 261).
It would have been obvious to one of ordinary skill in the art to derive the OPCs utilized in the method made obvious by Sharp, Priest, Keirstead, and Ilic from induced pluripotent stem cells as taught by Wang et al. with a reasonable expectation of success. As demonstrated by Wang OPCs can be derived efficiently from ESCs or iPSCs (p. 253), thus utilizing iPSCs as described by Wang instead of the ESCs described by Sharp and Priest would be substituting known types of pluripotent stem cells for the same purpose of deriving OPCs.
Therefore, it would have been obvious to one of ordinary skill in the art.
Response to Arguments regarding the rejection of claim 46 under 35 USC 103
As Applicant’s arguments against Claim 46 is based on the arguments against the references of the 103 rejection of independent claim 28 above, the rejection of claim 46 regarding Wang is maintained.
Double Patenting
Claims 28, 29, 31, 32, 34, 35, 37-38, 41-46, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 10,286,009 in view of Ilic (2014, Regen Medicine) and Franz (The Journal of Spinal Cord Medicine, 39(5), 513-517).
Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claim 28, Patent ‘009 recites a method of reducing spinal cord injury-induced parenchymal cavitation (i.e. treating spinal cord injury) in a human subject with an acute spinal cord injury, the method comprising directly injecting into the spinal cord injury site approximately 5 mm caudal of the spinal cord injury epicenter of said subject a composition comprising a population of human pluripotent stem cell-derived oligodendrocyte progenitor cells (OPCs) that are capable of engrafting at the spinal cord injury site and remaining within the spinal cord injury site of said subject for a period of 180 days or longer following the injection. (Claim 1).
Patent ‘009 teaches additionally that low dose immunosuppression is also administered such as tacrolimus which is administered 0.03 mg/kg/day (Claim 2 and 3).
Regarding the limitation wherein the cells express NG2 and PDGF-Ra, Patent ‘009 teaches that OPCs obtained from pluripotent stem cells suitable for treating spinal cord injury inherently have PDGF-Ra and NG2 expression (Patent ‘009; Column 5, lines 9-11).
Regarding the limitation wherein the upper extremity motor level function improves by at least two levels in 1-12 months after administration according to ISNCSCI scale, the limitation is not explicitly taught by Claim 1.
However, as the steps taught by Claim 1 of Patent ‘009 are essentially the same as in the instant claim 1, the effect would have been obvious as evidenced by Franz, the step of measuring of motor levels by ISNCSCI would be obvious to one of ordinary skill in the art when assessing spinal cord injury as it is the most frequently used clinical neurological assessment to determine the location and severity of SCI (p. 513). It would be obvious to one of ordinary skill in the art to routinely optimize the parameters of treatment to achieve a desired effect.
Therefore, the invention is rejected on the grounds of non statutory obviousness type double patenting.
Response to arguments against the Obviousness Double Patenting Rejection
As Applicant’s arguments against the Double Patenting rejection previously set forth is based on the arguments against the references of the 103 rejection of independent claim 28 above in that the claims do not teach the newly amended limitations, the rejection has been modified to address the newly amended limitations which are present in Patent ‘009 as claims 2 and 3.
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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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634