DETAILED ACTION
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 .
Applicant's reply filed on 10/23/2025 has been entered.
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.
Claim(s) ) 53-54,56-58,60-62,64 remain rejected under 35 U.S.C. 103 as being unpatentable over USPGPUB 20160331786 (‘786) in view of Stylianou (Cytotherapy (2006) Vol. 8, No. 1, 57-61 ).
Claim 53 is drawn to a method for treating spinal cord injury comprising administering composition comprising a cell population comprising oligodendrocyte progenitor cells (OPCs) expressing one or markers selected from NG2, PDGFRa, GD3 and a cryopreservation media, subsequent to thawing without further processing. Claim 53 now requires the cryopreservation media comprise HEPES, adenosine, L-glutathione and DMSO at 1-20% and an injection volume of 50-100 microliters.
‘786 teaches at para 158, administering AST-OPCs, derived from pluripotent embryonic stem cells (Claim 56) or iPSCs (see para 006, claim 57), between 2.4 X 105 cells per rat (efficacy dose, 2.4 ml single injection, which equates to a stock concentration of cells of 1,000,000 cells per mL), as claimed (claim 54). ‘786 teaches more cells can be administered by delivering 4, 6mL injections, which is 24 mL to rat spinal cord. At paragraph 13, ‘786 also teaches administration to human spinal cord 4x107 to 2X108cells (see para 88), including a volume of 50-100ml (para 89). ‘786 states, “… cryopreserved AST-OPC1 cells were thawed and injected into the spinal cord of immunodeficient Rag2-/-γc-/-/shi-/- (Shiverer) mice …” which meets the limitation of injection subsequent to thawing, without processing (para 0178) as well as the limitations of claim 58 (ready for administration upon thawing). With regard to claims 60-61, use of low dose immunosuppressants is taught, including tacrolimus and cyclosporine at para 0095.
‘786 does not teach use of any specific cryoprotectant. However, Stylianou taught a cryoprotectant that had significantly improved post-thaw recovery and quality of cells. Stylianou taught, “The product CryoStorTM (Biolife Solutions, Owego, NY, USA), is composed of dextran-40, sodium, potassium, calcium, magnesium, phosphate, HEPES, lactobionate, sucrose, mannitol, glucose, adenosine and glutathione. It has a pH of 7.6 and an osmolarity of 360. It is protein and serum free.” (page 58, left column, para 2, claim 62). Stylianou taught DMSO was included at with 5% or 10% (claim 64). Stylianou teaches that the manufacturers evaluated the use of CryostorTM on a variety of cell types and was found to improve post-thaw survival and more rapid recovery, among other benefits. Stylianou teaches that DMSO is effective at lower concentrations in CryostorTM which leads to introduction of less DMSO into patients.
It would have been obvious at the time of filing to carry out the method of ‘786 of administering AST-OPCs, derived from pluripotent embryonic stem cells to treat spinal cord injury using the cryoprotecting media taught by Stylianou to arrive at the invention as claimed. One would have been motivated to use the cryopreservation media of Stylianou as it taught numerous improved cryopreservation features over other cryopreservation media and a reduced DMSO amount which would lead to transfer of this toxic substance when cells are administered in vivo. One would have had a reasonable expectation of success in using the CryostorTM media in freezing the AST-OPCs because Stylianou taught CryostorTM was effective on many different cell types and one of ordinary skill would know how to carry out cryopreservation.
Applicant argues that Stylianou does not teaches use of Cryostor with OPCs, which are the celltype used in the claimed method. Stylianou teaches the used of Cryostor with HSCs, RBCs, muscle cells, kidney cells, ovarian cells, among others. There is no indication whatsoever, in Stylianou or any art of record, that there is a cell type Cryostor would not work with. It appears superior cryopreservation results were found
on a diverse set of cells types and thus it would have been obvious to use Cryostor with OPCs as set forth above. There is no evidence of any unexpected results for cryopreservation of OPCs with Cryostor
Double Patenting
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 53-54,56-62 and 64 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 of U.S. Patent No. 10,286,009 in view of Stylianou (Cytotherapy (2006) Vol. 8, No. 1, 57-61).
An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical but an examined application is not patentably distinct from the reference claims because the examined claim is either anticipate by, or would have been obvious over, the reference claims. See, e.e., 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). Although the conflicting claims are not identical, they are not patentably distinct from each other because claim 53 is generic to all that is recited in claims 1 and 8 of US 10,286,009 with exception of the now recited cryopreservation media components. That is, claim 1 ‘009 falls entirely within the scope of claim 53 of the instant application. Specifically, claim 1 of ‘009 is identical to the instant claim 53 with the exception that claim 1 of ‘009 is limited to the timing and placement of the cells within the spinal cord.‘009 is also limited to carrying out the method in humans. Claim 8 of ‘009 encompasses the number of cells delivered by claims 54-55.
‘009 does not teach or suggest cryopreservation medium or immediately injecting the cells as recited in the present claims. However, Stylianou taught a cryoprotectant that had significantly improved post-thaw recovery and quality of cells. Stylianou taught, “The product CryoStorTM (Biolife Solutions, Owego, NY, USA), is composed of dextran-40, sodium, potassium, calcium, magnesium, phosphate, HEPES, lactobionate, sucrose, mannitol, glucose, adenosine and glutathione. It has a pH of 7.6 and an osmolarity of 360. It is protein and serum free.” (page 58, left column, para 2, claim 62). Stylianou taught DMSO was included at with 5% or 10% (claim 64). Stylianou teaches that the manufacturers evaluated the use of CryostorTM on a variety of cell types and was found to improve post-thaw survival and more rapid recovery, among other benefits. Stylianou teaches that DMSO is effective at lower concentrations in CryostorTM which leads to introduction of less DMSO into patients.
It would have been obvious at the time of filing to carry out the method of ‘786 of administering AST-OPCs, derived from pluripotent embryonic stem cells to treat spinal cord injury using the cryoprotecting media taught by Stylianou to arrive at the invention as claimed. One would have been motivated to use the cryopreservation media of Stylianou as it taught numerous improved cryopreservation features over other cryopreservation media and a reduced DMSO amount which would lead to transfer of this toxic substance when cells are administered in vivo. One would have had a reasonable expectation of success in using the CryostorTM media in freezing the AST-OPCs because Stylianou taught CryostorTM was effective on many different cell types and one of ordinary skill would know how to carry out cryopreservation.
With regard to the now-recited markers, page 4 of the Specification states, “The Day 42 OPCs produced in accordance with the present disclosure are comparable (in terms of their overall marker expression profile) to OPCs generated using an alternative method that are currently in clinical testing to treat spinal cord injury (Priest et al., 2015 Regen Med. 10(8):939-58; Manley et al., 2017 Stem Cells Transl Med. 6(10):1917-1929),” Page 18 states, “The day 42 OPCs produced in accordance with the present disclosure express canonical OPC markers NG2 and PDGFRa and are comparable (in terms of their overall marker expression profile) to OPCs generated using an alternative method that are currently in clinical testing to treat spinal cord injury.”
2) Claims 53-54,56-62 and 64 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,10 and 12 of co-pending Application No. 18/262,909 (reference application) in view of Stylianou (Cytotherapy (2006) Vol. 8, No. 1, 57-61).
An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical but an examined application is not patentably distinct from the reference claims because the examined claim is either anticipate by, or would have been obvious over, the reference claims. See, e.e., 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). Although the conflicting claims are not identical, they are not patentably distinct from each other because claim 1 is generic to all that is recited in claim 1 of US ‘909. That is, claim 1 ‘909 falls entirely within the scope of claim 53 of the instant application. Specifically, claim 1 of ‘909 is identical to the instant claim 53 with the exception that claim 1 of ‘909 is limited to administration of human OPCs. Claims 9,10 and 12 encompasses the number of cells delivered by claims 54-55.
‘909 does not teach or suggest cryopreservation medium or immediately injecting the cells as recited in the present claims. However, Stylianou taught a cryoprotectant that had significantly improved post-thaw recovery and quality of cells. Stylianou taught, “The product CryoStorTM (Biolife Solutions, Owego, NY, USA), is composed of dextran-40, sodium, potassium, calcium, magnesium, phosphate, HEPES, lactobionate, sucrose, mannitol, glucose, adenosine and glutathione. It has a pH of 7.6 and an osmolarity of 360. It is protein and serum free.” (page 58, left column, para 2, claim 62). Stylianou taught DMSO was included at with 5% or 10% (claim 64). Stylianou teaches that the manufacturers evaluated the use of CryostorTM on a variety of cell types and was found to improve post-thaw survival and more rapid recovery, among other benefits. Stylianou teaches that DMSO is effective at lower concentrations in CryostorTM which leads to introduction of less DMSO into patients.
It would have been obvious at the time of filing to carry out the method of ‘909 of administering AST-OPCs, derived from pluripotent embryonic stem cells to treat spinal cord injury using the cryoprotecting media taught by Stylianou to arrive at the invention as claimed. One would have been motivated to use the cryopreservation media of Stylianou as it taught numerous improved cryopreservation features over other cryopreservation media and a reduced DMSO amount which would lead to transfer of this toxic substance when cells are administered in vivo. One would have had a reasonable expectation of success in using the CryostorTM media in freezing the AST-OPCs because Stylianou taught CryostorTM was effective on many different cell types and one of ordinary skill would know how to carry out cryopreservation.
With regard to the now-recited markers, page 4 of the Specification states, “The Day 42 OPCs produced in accordance with the present disclosure are comparable (in terms of their overall marker expression profile) to OPCs generated using an alternative method that are currently in clinical testing to treat spinal cord injury (Priest et al., 2015 Regen Med. 10(8):939-58; Manley et al., 2017 Stem Cells Transl Med. 6(10):1917-1929),” Page 18 states, “The day 42 OPCs produced in accordance with the present disclosure express canonical OPC markers NG2 and PDGFRa and are comparable (in terms of their overall marker expression profile) to OPCs generated using an alternative method that are currently in clinical testing to treat spinal cord injury.”
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
3) Claims 53-54,56-62 and 64 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26-28 and 31-32 of co-pending Application No. 18/548472 (reference application) in view of Stylianou (Cytotherapy (2006) Vol. 8, No. 1, 57-61).
An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical but an examined application is not patentably distinct from the reference claims because the examined claim is either anticipate by, or would have been obvious over, the reference claims. See, e.e., 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). Although the conflicting claims are not identical, they are not patentably distinct from each other because claim 1 is generic to all that is recited in claim 1 of US ‘472 with exception of the cryopreservation media composition. That is, claim 26 of ‘472 falls entirely within the scope of claim 53 of the instant application. Specifically, claim 26 of ‘472 is identical to the instant claim 53 with the exception that claim 26 of ‘472 depends from claim 24, which recites the inclusion of cryopreservation media. Instant claim 53 depends from claim 50, which also adds cryopreservation to the method of formulating the cells. Claims 31-32 encompasses the number of cells delivered by claims 54-55.
‘472 does not teach or suggest cryopreservation medium or immediately injecting the cells as recited in the present claims. However, Stylianou taught a cryoprotectant that had significantly improved post-thaw recovery and quality of cells. Stylianou taught, “The product CryoStorTM (Biolife Solutions, Owego, NY, USA), is composed of dextran-40, sodium, potassium, calcium, magnesium, phosphate, HEPES, lactobionate, sucrose, mannitol, glucose, adenosine and glutathione. It has a pH of 7.6 and an osmolarity of 360. It is protein and serum free.” (page 58, left column, para 2, claim 62). Stylianou taught DMSO was included at with 5% or 10% (claim 64). Stylianou teaches that the manufacturers evaluated the use of CryostorTM on a variety of cell types and was found to improve post-thaw survival and more rapid recovery, among other benefits. Stylianou teaches that DMSO is effective at lower concentrations in CryostorTM which leads to introduction of less DMSO into patients.
It would have been obvious at the time of filing to carry out the method of ‘786 of administering AST-OPCs, derived from pluripotent embryonic stem cells to treat spinal cord injury using the cryoprotecting media taught by Stylianou to arrive at the invention as claimed. One would have been motivated to use the cryopreservation media of Stylianou as it taught numerous improved cryopreservation features over other cryopreservation media and a reduced DMSO amount which would lead to transfer of this toxic substance when cells are administered in vivo. One would have had a reasonable expectation of success in using the CryostorTM media in freezing the AST-OPCs because Stylianou taught CryostorTM was effective on many different cell types and one of ordinary skill would know how to carry out cryopreservation.
With regard to the now-recited markers, page 4 of the Specification states, “The Day 42 OPCs produced in accordance with the present disclosure are comparable (in terms of their overall marker expression profile) to OPCs generated using an alternative method that are currently in clinical testing to treat spinal cord injury (Priest et al., 2015 Regen Med. 10(8):939-58; Manley et al., 2017 Stem Cells Transl Med. 6(10):1917-1929),” Page 18 states, “The day 42 OPCs produced in accordance with the present disclosure express canonical OPC markers NG2 and PDGFRa and are comparable (in terms of their overall marker expression profile) to OPCs generated using an alternative method that are currently in clinical testing to treat spinal cord injury.”
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
4) Claims 53-54,56-62 and 64 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28, 37-39 and 45 of co-pending Application No. 16/333,566 (reference application) in view of Stylianou (Cytotherapy (2006) Vol. 8, No. 1, 57-61).
An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical but an examined application is not patentably distinct from the reference claims because the examined claim is either anticipate by, or would have been obvious over, the reference claims. See, e.e., 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). Although the conflicting claims are not identical, they are not patentably distinct from each other because claim 1 is generic to all that is recited in claim 1 of US ‘566 with exception of the cryopreservation media composition. That is, claim 28 of ‘566 falls entirely within the scope of claim 53 of the instant application. Specifically, claim 26 of ‘566 is identical to the instant claim 53 with the exception that claim 53 recites the inclusion of cryopreservation media. Reference claims 37-38 encompasses the number of cells delivered by claims 54-55.
‘566 does not teach or suggest cryopreservation medium or immediately injecting the cells as recited in the present claims. However, Stylianou taught a cryoprotectant that had significantly improved post-thaw recovery and quality of cells. Stylianou taught, “The product CryoStorTM (Biolife Solutions, Owego, NY, USA), is composed of dextran-40, sodium, potassium, calcium, magnesium, phosphate, HEPES, lactobionate, sucrose, mannitol, glucose, adenosine and glutathione. It has a pH of 7.6 and an osmolarity of 360. It is protein and serum free.” (page 58, left column, para 2, claim 62). Stylianou taught DMSO was included at with 5% or 10% (claim 64). Stylianou teaches that the manufacturers evaluated the use of CryostorTM on a variety of cell types and was found to improve post-thaw survival and more rapid recovery, among other benefits. Stylianou teaches that DMSO is effective at lower concentrations in CryostorTM which leads to introduction of less DMSO into patients.
It would have been obvious at the time of filing to carry out the method of ‘566 of administering AST-OPCs, derived from pluripotent embryonic stem cells to treat spinal cord injury using the cryoprotecting media taught by Stylianou to arrive at the invention as claimed. One would have been motivated to use the cryopreservation media of Stylianou as it taught numerous improved cryopreservation features over other cryopreservation media and a reduced DMSO amount which would lead to transfer of this toxic substance when cells are administered in vivo. One would have had a reasonable expectation of success in using the CryostorTM media in freezing the AST-OPCs because Stylianou taught CryostorTM was effective on many different cell types and one of ordinary skill would know how to carry out cryopreservation.
With regard to the now-recited markers, page 4 of the Specification states, “The Day 42 OPCs produced in accordance with the present disclosure are comparable (in terms of their overall marker expression profile) to OPCs generated using an alternative method that are currently in clinical testing to treat spinal cord injury (Priest et al., 2015 Regen Med. 10(8):939-58; Manley et al., 2017 Stem Cells Transl Med. 6(10):1917-1929),” Page 18 states, “The day 42 OPCs produced in accordance with the present disclosure express canonical OPC markers NG2 and PDGFRa and are comparable (in terms of their overall marker expression profile) to OPCs generated using an alternative method that are currently in clinical testing to treat spinal cord injury.”
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant references the arguments posed for the rejection under 35 USC 103 for these double patenting rejections. Those arguments are not persuasive for reasons set forth above, under 35 USC 103.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 53-62 and 64 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The invention relates to a method of treating spinal cord injury using oligodendrocyte progenitor cells (OPCs). The claims are directed to such treatment but are aimed at an embodiment that appears to be attempting to differ from the method carried out in the prior art in that the cells are administered in cryopreservation media directly post-thaw.
The specification points to the prior-art method. At page 18, the Specification states, “The day 42 OPCs produced in accordance with the present disclosure express canonical OPC markers NG2 and PDGFRa and are comparable (in terms of their overall marker expression profile) to OPCs generated using an alternative method that are currently in clinical testing to treat spinal cord injury” and also references Manley (at page 4) as the cells that are in clinical testing. Thus, it appears what Applicant has contributed to the prior art is a method of obtaining the OPCs. What Applicant is claiming appears to be cells that can be administered immediately post-thaw in cryopreservation medium. The cells appear to not need to be washed, cultured to increase cell number, purified, or concentrated and resuspended. Applicant argues in the Remarks dated 04/15/2025 and Remarks dated 01/15/2025 that the prior art does not meet the limitation of administering the cells “without further processing” and that the cryopreservation would have been expected to decrease cell numbers and administration of the cells in cryopreservation media would be expected to be toxic. However, the cells of Manley are not processed post-thaw to increase cell numbers in any way. The cryopreservation media is not replaced to remove DMSO or any other components that one would not want administered in vivo.
With regard to toxicity of DMSO-containing cryopreservation media, the art supports that DMSO is cytotoxic at room temperature and is harmful when introduced in vivo.
Marcantonini (Molecules, 2022 May 19;27(10):3254) teaches that DMSO remains the cryoprotecting agent of choice in the cryopreservation of mammalian cell lines but that it can be dangerous by causing alterations of the mitochondrial membranes, thus increasing electron leakage and the production of reactive oxygen species (ROS). Marcantonini teaches that to avoid these adverse effects, the agent has to be removed as soon as possible, particularly after the cells are thawed. DMSO toxicity is also a concern in cell therapy protocols. In patients receiving infusions of cells frozen using DMSO, significant side effects have been reported, including cardiovascular, neurological, gastrointestinal, and allergic reactions, and DMSO has been associated with hematological disturbances as an altered expression of natural killer (NK) and T-cell markers in circulating leukocytes and their in vivo function.
Likewise, Raju (BBA - General Subjects 1865 (2021) 12974, PAGES 1-11) teaches the following:
The two most commonly used CPAs are glycerol and dimethyl sulfoxide (DMSO). Glycerol was first identified as a CPA in 1949 [8] while DMSO was identified in 1959 [9]. Unfortunately, both have levels of toxicity making them unsuitable for many applications, and often require extensive washing during thawing to prevent cell death or subsequent adverse reactions if used in medical treatments.
Paragraph 14 of the Specification reads as follows:
[0014] In another embodiment, the OPCs produced according to the invention are prepared as a ready to administer (RTA) OPC cell therapy composition for the treatment of a patient. A method of formulating human OPCs for administration to a subject directly after thawing and of formulating OPC cell therapy compositions for cryopreservation and the administration of the cryopreserved composition to a subject subsequent to thawing are also presented. In another aspect, the RTA composition may be formulated as a thaw and inject (TAI) composition, whereby the composition is administered by injection subsequent to thawing, without further processing of the OPCs.
Thus, given Applicant’s Remarks and paragraph 14, the claimed “without further processing” is interpreted to include not removing the cryopreservation media.
With this in mind, the skilled artisan would look to the specification for guidance as to what cryopreservation media should be used that can be administered in vivo and not be toxic as argued by Applicant and as is taught by the art. At paragraph 116, the Specification states, “OPCs formulated in cryopreservation media appropriate for post thaw ready to administer (RTA) applications may comprise OPCs suspended in adenosine, dextran-40, lactobionic acid, HEPES (N-(2-Hydroxyethyl) piperazine-N’- (2- ethanesulfonic acid)), sodium hydroxide, L-glutathione, potassium chloride, potassium bicarbonate, potassium phosphate, dextrose, sucrose, mannitol, calcium chloride, magnesium chloride, potassium hydroxide, sodium hydroxide, dimethyl sulfoxide (DMSO), and water.” No claim is limited to this. Claim 59 recites some of these components but lists them as optional further components and uses the term “or”. The working examples teaches that the trademarked Cryostor10TM was used. There are no working examples, however, that support whether this media overcomes the negative impacts of cryopreservation in a manner that would support the cells for treatment of any spinal injury. There are no in vivo examples supporting treatment.
Thus, it is not clear what Applicant is attempting to capture in the claims. Given the claims, the Specification and Applicant’s arguments dated 01/15/2025, it cannot be determined what breadth of the claims may be free of the art and enabled by the Specification. For this reason, a total lack of enablement is found in the interest of compact prosecution because the scope of what is enabled outside what is already taught in the art cannot be determined.
Applicant previously remarked that the amendments to claim 53 address the rejection as previously made. These amendments were not sufficient as the recited media components list does not include all of the components used to freeze the cells in the working examples and it is not discussed in the specification which components are responsible for the improved characteristics and ability to be administered in vivo without toxicity, as is argued by Applicant as being surprising.
Applicant has amended claim 53 to limit the volume administered and the location (spinal cord). While it is possible that these smaller volumes do not cause DMSO-induced damage to cells in the spinal cord, there is no evidence in support of this and no evidence that leaving the DMSO in the thawed cells, at room temperature, is not toxic to the cells.
Conclusion
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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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632