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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application 17/909,263, filed 09/20/2022, is a 371 national stage entry of International Application No. PCT/US2021/021124, filed 03/05/2021, and claims priority to U.S. Provisional Patent Application No. 62/986,116, filed 03/06/2020.
Status of Application and Claims
Claims 1-3,5, 7, 9, 12, 14-16, 19, 21, 23, 26-27, 29-30 and 40 are currently pending. Claims 26-27,29-30 and 40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction requirement in the reply filed on 06/25/2025..
In the reply filed 06/25/2025, Applicant elected dental pulp stem cell as a single species of stem cell, and glial cell derived neurotrophic factor (GDNF) as a single species of neurotrophic factor. These species elections are fully acknowledged.
The restriction and election requirements have been deemed proper and previously made FINAL.
Claims 26-27, 29-30 and 40 are withdrawn
Claims 1-3,5, 7, 9, 12, 14-16,19, 21 and 23 are examined on the merits herein.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
The rejection of claims 1-4, 7, 12, 14-16, 18, and 21 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments clarifying the claims.
Claims 12 and 16, continue to recite the phrase “and/or” and will be interpreted as being optional limitations recited in the alternative, and not required for the claimed invention.
Claim 5 is newly rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 depends from canceled claim 4, which is unclear. Claim 5, if interpreted to depend from claim 1, is unclear in reference to “the one or more neurotrophic factors” because claim 1 only refers to “a neurotrophic factor”.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The rejection of claims 4 and 18 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is rendered moot by the cancelation of the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
The rejection of claims 1-5, 7, 9, and 12 under 35 U.S.C. 103 as being unpatentable over Dailey, M. T. et al. (2018). Journal of Oral and Maxillofacial Surgery, 76(10), Supplement, E74 (cited in PTO-892) in view of Sharma, A. D. et al. (2016). J. Biosci. Bioeng., 121(3), 325-335 (cited in PTO-892), Rutowski, G. E. et al. (2004). J. Neural Eng., 1, 151 (cited in PTO-892), and Fan, et al. (2020). Acta Biomaterialia, 101, 304-313 (cited in IDS 10/20/2022), as evidenced by Pourlak, T. et al. (2021). J. Stomatol. Oral Maxillofac. Surg., 122, 441-452 (cited in PTO-892) is withdrawn.
Applicant’s remarks have been fully considered and are persuasive. Applicant explains that Dailey is a precursor to the instant invention and relates to a cell sheet, not a cylindrical conduit with axons regenerated and oriented in a defined orientation. The uses for the two are distinct as outlined at pages 7-8 of the Remarks dates 11/04/2025. The secondary references, Sharma and Rutkowski, use scaffold systems to orient axons, which does not read on the claims, as amended. With regard to Fan, there is a gap between use of microgrooves to orient cells and formation of a conduit from the sheet. The teachings of Fan lead one to wrap a cell sheet around a PTFE mold, not form a conduit from the sheet by rolling it as depicted in Fig. 1A of the Specification and recited in the claims.
Claims 14, 16, 19 and 23 remain rejected under 35 U.S.C. 103 as being unpatentable over Dailey, M. T. et al. (2018). 76(10), Supplement, E74 (cited in PTO-892) in view of Syed-Picard, F. N. et al. (2014J. Dent. Res, 93(3), 250-255 (cited in PTO-892), as evidenced by Pourlak, T. et al. (2021). J. Stomatol. Oral Maxillofac. Surg., 122, 441-452 (cited in PTO-892).
Applicant does not appear to have presented arguments specific to this rejection or relating to Syed-Picard and therefore, the rejection is maintained. Applicant has added that the claimed conduit is scaffold-freed, which is met by the teachings of Dailey and Syed-Picard.
Dailey teaches dental pulp cells (DPCs) are emerging as a promising source of stem cells in nerve regeneration mainly due to their neural crest cell origin; as derivatives of neural crest, DPCs produce neurotrophic factors (NTF) that may have a paracrine modulatory effect on damaged axons, ultimately enhancing axon regeneration and extension (“Purpose” L. Col. lines 11-17). Dailey teaches a method to direct DPCs to form manipulatable NTF secreting cell sheets that are capable of inducing axon extension (“Conclusion”). DPCs read on the “population of cells comprising a stem cell” in instant claim 14, as well as the cells recited in instant claim 16. As evidenced by Pourlak, dental pulp stem cells (DPSCs, Applicant’s elected species of stem cell) are mesenchymal stem cells (MSCs) (“2.1.1. Dental Pulp Stem Cells (DPSCs)”). Therefore, the stem cells of the DPCs taught by Dailey are being interpreted as a species of mesenchymal stem cells; thus, claim 23 is read upon by the stem cells of Dailey’s DPC sheet.
Dailey teaches DPCs were cultured in wells of a 6 well plate in growth medium for 8-10 days to form a cell sheet; the expression of NTF genes including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and neurotrophin-3 (NT-3) were assessed using real-time quantitative reverse transcriptase polymerase chain reaction (“Materials and Methods” lines 2-9). Dailey teaches that the DPCs formed a robust cell sheet that could be easily detached from the culture dish and handled, and the DPCs in the cell sheets expressed the genes for BDNF, GDNF, and NT-3 (“Results” lines 1-4). Based on these teachings, the DPCs of Dailey’s cell sheet read on cells which produce one or more neurotrophic factors, particularly BDFN, GDNF (Applicant’s elected species for neurotrophic factor), and NT-3, as recited in the “wherein” clause of instant claim 14 and instant claims 18 and 19. Dailey teaches the scaffold-free cell sheet capable of producing NTFs can be wrapped around facial nerve defects to accelerate facial nerve healing and enhance functional recovery (“Purpose” R. Col. lines 1-4).
The teachings of Dailey differ from the instantly claimed invention in that they fail to address that the cells are cultured to confluence on a substrate to produce the sheet of cells; the sheet of cells is separated from the substrate; and the cells are cultured anchored at two or more points to substantially align the cells in the sheet of cells, as recited in instant claim 14.
Syed-Picard teaches self-assembled, scaffoldless, three-dimensional (3D) tissues engineered from DPCs and assessed as a device for pulp regeneration (Abstract). Syed-Picard teaches that if cells regenerate a 3D tissue without the use of exogenous materials, the cells would potentially be able to recapitulate native tissue more closely in regenerative therapies and generate their own preferred 3D microenvironment; the DPC cell sheets formed in this method assemble into a cylindrical 3D tissue that is highly cellular and solid (p. 250 final para through p. 251 1st and 2nd paras). Syed-Picard teaches samples prepared by plating DPCs onto sample dishes and allowing them to culture to confluence, after which 2 minutien pins are placed in the center of each dish approximately 7 mm apart and culture medium is changed to include growth factors; the tissue sheets are contracted by the cells to pull away from the edges of the dishes and roll toward the pins to form 3D scaffoldless cylindrical tissues (p. 251 Fig. 1 (D) and (E); “Formation and Delivery of DPCs in 3d Scaffoldless Engineered Tissues in/to Tooth Roots”). This contraction of the cells to pull away from the dishes and roll towards the pins reads on separation of a cell sheet from the substrate (dish) and aligning the cells in the sheet during culturing.
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to apply two pins to the culturing cell sheet generated by Dailey, in the method taught by Syed-Picard, after confluence; this would then result in the formation of a cultured and rolled 3D scaffoldless tissue which is naturally separated from the substrate and can be applied as a nerve regenerative therapeutic. The ordinarily skilled artisan would have been motivated to perform this step while culturing the cell sheet in order to generate a 3D tissue without the use of exogenous materials, wherein the cells are able to recapitulate native tissue more closely in regenerative therapies and generate their own preferred 3D microenvironment; these qualities would naturally enhance the regenerative therapeutic effects of a resulting NTF-producing DPC cell sheet, and this natural cylindrical/curved structure to the cell sheet would additionally facilitate easier wrapping of the cell sheet around facial nerve defects and accelerate facial nerve healing, as is the intended use of the DPC cell sheet taught by Dailey. The ordinarily skilled artisan would have a reasonable expectation of success performing this step when culturing the DPC cell sheet because both Dailey and Syed-Picard teach highly similar methods of forming DPC cell sheets for use as regenerative therapeutics.
2’) Claim 15 remains rejected under 35 U.S.C. 103 as being unpatentable over Dailey, M. T. et al. (2018). “Scaffold-Free Dental Pulp Cell Sheets to Enhance Facial Nerve Regeneration.” Journal of Oral and Maxillofacial Surgery, 76(10), Supplement, E74 (cited in PTO-892) and Syed-Picard, F. N. et al. (2014). "Scaffoldless tissue-engineered dental pulp cell constructs for endodontic therapy." J. Dent. Res, 93(3), 250-255 (cited in PTO-892), as applied to claims 14, 16, 18-19 and 23 above, and further in view of Fan, et al. (2020). “A prevascularized nerve conduit based on a stem cell sheet effectively promotes the repair of transected spinal cord injury.” Acta Biomaterialia, 101, 304-313 (cited in IDS 10/20/2022), as evidenced by Pourlak, T. et al. (2021). “Usage of stem cells in oral and maxillofacial region.” J. Stomatol. Oral Maxillofac. Surg., 122, 441-452 (cited in PTO-892).
As set forth above, Applicant does not appear to have specifically addressed this rejection or the teachings of Syed-Picard.
The teachings of Dailey and Syed-Picard, with evidence from Pourlak, as they apply to claims 14, 16, 19, and 23, are addressed supra. It is reiterated that the combined teachings render obvious the steps of instant claim 14, and the natural rolling of the sheet of cells as a result from the anchoring of the cell sheet using the two pins is an inherent property of the cell sheet resulting from these method steps. Thus, the step recited in instant claim 15 wherein the roll of cells is generated prior to further culturing of the anchored sheet of cells is read upon by the collective teachings of Dailey and Syed-Picard.
The collective teachings differ from the instantly claimed invention in that they fail to teach that the rolled sheet of cells is cultured further for the purpose of fusing the rolled sheet of cells to form a cylindrical cell structure, e.g., by adhesion and/or remodeling of adjacent layers of cells in the cylindrical roll of cells, and to substantially align the cells in the rolled sheet of cells lengthwise in the rolled sheet of cells.
Fan teaches that, with cell sheet technology, an intact and contiguous cell sheet composed of cells and extracellular matrix (ECM), can be obtained with a high adhesive ability depending on fibronectin, which can be trans-planted or grafted to the host tissues without using any sutures (p. 305 L. Col. 3rd para). Fan teaches culturing an MSC cell sheet in a culture dish for 14 days, until formation of a dense and contiguous cell sheet, implied removal of the sheet from the dish/media by cutting the sheet into strips, rolling the sheet into a nerve conduit by using PTFE tube as a model, and culturing the conduit in a different culture media for another 7 days during which the cell sheets fuse into a cylindrical conduit and the resulting conduit can stand on a flat surface independently when the PTFE tube is removed prior to implantation into spinal cord injured rats (Fig. 1; “2.2 MSC cell sheet preparation;” “2.4 Nerve conduit based on MSC cell sheet and prevascularized MSC cell sheet”). Fan demonstrates healing benefits of the fused nerve conduit when transplanted into rat spinal cord injuries (p. 308, 1st and 2nd paras). Fan teaches the conduits formed with this method not only provide a new therapeutic method for spinal cord injury, but also expand the application range of the cell sheet (“4. Conclusions”).
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to culture the naturally-rolled 3D scaffoldless cylindrical DPC structure, while being anchored to continue to provide the 3D shape, for another 7 days to allow the cell sheet to fuse into the cylindrical conduit which can stand on a flat surface independently, and arrive at the instantly claimed invention. In doing so, the cells of the cell sheet would be substantially aligned in the rolled sheet of cells lengthwise, because this is an inherent property of the effect of culturing the DSC cell sheet when anchored at two points (see instant specification [0087]: “due to stresses placed on the cell sheet from culturing while anchored, the cells will align, forming an aligned construct”). Per MPEP 2112.01, where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). The ordinarily skilled artisan would have been motivated to allow the cell sheet to continue to culture while being anchored to fuse into the cylindrical conduit in order to mimic the fused cylindrical nerve conduit of Fan, which demonstrates healing benefits of the fused nerve conduit when transplanted into rat spinal cord injuries. The ordinarily skilled artisan would seek to apply these benefits for the intended purpose of the nerve conduit (facial nerve regeneration), as discussed by Dailey. The ordinarily skilled artisan would have a reasonable expectation of success culturing the cylindrical nerve conduit to fuse the cells into the cylindrical structure because Fan teaches this to be an appropriate method of fusing a MSC cell sheet into a cylindrical shape, thanks to the adhesion ability of the fibronectin secreted by the cells; the ordinarily skilled artisan would expect the DPC cell sheet (which also contains MSCs) to operate in a similar manner.
2”) Claim 21 remains rejected under 35 U.S.C. 103 as being unpatentable over Dailey, M. T. et al. (2018). “Scaffold-Free Dental Pulp Cell Sheets to Enhance Facial Nerve Regeneration.” Journal of Oral and Maxillofacial Surgery, 76(10), Supplement, E74 (cited in PTO-892) and Syed-Picard, F. N. et al. (2014). "Scaffoldless tissue-engineered dental pulp cell constructs for endodontic therapy." J. Dent. Res, 93(3), 250-255 (cited in PTO-892), as applied to claims 14, 16, 19 and 23 above, and further in view of Sharma, A. D. et al. (2016). “Oriented growth and transdifferentiation of mesenchymal stem cells towards a Schwann cell fate on micropatterned substrates.” J. Biosci. Bioeng., 121(3), 325-335 (cited in PTO-892), as evidenced by Pourlak, T. et al. (2021). “Usage of stem cells in oral and maxillofacial region.” J. Stomatol. Oral Maxillofac. Surg., 122, 441-452 (cited in PTO-892).
As set forth above, Applicant does not appear to have specifically addressed this rejection or the teachings of Syed-Picard.
The teachings of Dailey and Syed-Picard, with evidence from Pourlak, as they apply to claims 14, 16, 18-19, and 23, are addressed supra.
The collective teachings differ from the instantly claimed invention in that they fail to teach that the method further comprises, after producing the cell sheet, differentiating the cells to a cell type that produces one or more neurotrophic factors, such as a Schwann cell-line phenotype.
Sharma teaches Schwann cells (SCs) secrete trophic and growth factors which promote neural regeneration, and it has been shown that implantation of SCs supports axonal elongation and regeneration; these properties enable SCs to be one of the most attractive cell-based therapies for peripheral nervous system (PNS) and central nervous system (CNS) regeneration (p. 325 L. Col. 1st para). Sharma teaches multipotent MSCs are a versatile cell source for neural repair strategies which can be transdifferentiated into SC-like phenotypes (p. 325 R. Col. 1st para). Sharma investigates transdifferentiation of MSCs seeded on micropatterned substrates to SC-like phenotypes and investigation of topographical cues on transdifferentiation, alignment and morphology of the MSCs (p. 326 L. Col. final para). Sharma provides a method of in vitro transdifferentiation of rat MSCs into SC-like phenotypes by simply replacing the culturing media of the growing cells with that of trans-differentiation media and further incubation (p. 326 “In vitro transdifferentiation of rat MSCs into SC-like phenotypes”).
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to transdifferentiate the MSC cells of the DPC cell sheet, after growth of the cells to generate the cell sheet, into SC-like phenotypes using the method taught by Sharma, and arrive at the instantly claimed invention. The ordinarily skilled artisan would have been motivated to perform this transdifferentiation because SCs secrete trophic and growth factors which promote neural regeneration, and it has been shown that implantation of SCs supports axonal elongation and regeneration; these properties enable SCs to be one of the most attractive cell-based therapies for peripheral nervous system (PNS) regeneration, which is the purpose of the DPC cell sheet taught by Dailey. The ordinarily skilled artisan would have a reasonable expectation of success transdifferentiating the MSCs on the DPC cell sheet, after culturing to confluence, based on Sharma’s demonstration that the orientation of MSC cells pose no threat to the success of the transdifferentiation of these MSCs to SC-like phenotypes; thus, transdifferentiation of MSCs to SC-like phenotypes by simply following Sharma’s method and replacing the culture media of the cells with a transdifferentiation media during growth is expected to be successful regardless of whether or not the MSC cells are formed within an oriented cell sheet structure.
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.
1) Claims 1-3,5, 7, 9 and 12 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2 and 10 of copending Application No. 16/976,821 in view of Sharma, A. D. et al. (2016). “Oriented growth and transdifferentiation of mesenchymal stem cells towards a Schwann cell fate on micropatterned substrates.” J. Biosci. Bioeng., 121(3), 325-335 (cited in PTO-892), Rutowski, G. E. et al. (2004). “Synergistic effects of micropatterned biodegradable conduits and Schwann cells on sciatic nerve regeneration.” J. Neural Eng., 1, 151 (cited in PTO-892), and Fan, et al. (2020). “A prevascularized nerve conduit based on a stem cell sheet effectively promotes the repair of transected spinal cord injury.” Acta Biomaterialia, 101, 304-313 (cited in IDS 10/20/2022), as evidenced by Dailey, M. T. et al. (2018). “Scaffold-Free Dental Pulp Cell Sheets to Enhance Facial Nerve Regeneration.” Journal of Oral and Maxillofacial Surgery, 76(10), Supplement, E74 (cited in PTO-892) and Pourlak, T. et al. (2021). “Usage of stem cells in oral and maxillofacial region.” J. Stomatol. Oral Maxillofac. Surg., 122, 441-452 (cited in PTO-892).
Applicant does not appear to have provided any arguments to this rejection and it is maintained for reasons of record.
App ‘821 claims a method of producing neurite outgrowth in a neuron, comprising culturing neural crest-derived stem cells in the presence of a growth factor without a scaffold to produce a scaffold-free tissue structure, wherein the neural crest-derived stem cells of the scaffold-free tissue structure produce one or more neurotrophic factors (claim 1). App’821 claims the tissue structure comprises a tissue sheet (claim 2). App’821 claims the neural crest-derived stem cells are dental pulp cells (claim 10). Thus, these cells read on the limitations of the cells in claims 2 and 3. As evidenced by Pourlak, dental pulp stem cells are mesenchymal stem cells (MSCs) (“2.1.1. Dental Pulp Stem Cells (DPSCs)”). Thus, claim 9 is read upon. Additionally, as evidenced by Dailey, dental pulp cells express neurotrophic factor (NTF) genes including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and neurotrophin-3 (NT-3) (“Materials and Methods” lines 2-9). Thus, the dental pulp cells read on the limitations of instant claim 5.
App ’821 differs from the instant invention in that it fails to claim the specific method steps recited in instant claims 1 and 7. Therefore, App ’821 fails to claim the limitations of the microgrooved substrate recited in instant claim 12.
Sharma teaches Schwann cells (SCs) secrete trophic and growth factors which promote neural regeneration, and it has been shown that implantation of SCs supports axonal elongation and regeneration; these properties enable SCs to be one of the most attractive cell-based therapies for peripheral nervous system (PNS) and central nervous system (CNS) regeneration (p. 325 L. Col. 1st para). Sharma teaches multipotent MSCs are a versatile cell source for neural repair strategies which can be transdifferentiated into SC-like phenotypes (p. 325 R. Col. 1st para). Sharma teaches enhanced neuronal regeneration should be supported with directionality; an oriented axonal cell alignment will be superior compared to randomized cellular therapies for nerve regeneration (p. 325 R. Col. 3rd para). Sharma provides a method of in vitro transdifferentiation of rat MSCs into SC-like phenotypes by simply replacing the culturing media of the growing cells with that of a trans-differentiation media and further incubation (p. 326 “In vitro transdifferentiation of rat MSCs into SC-like phenotypes”).
Sharma investigates transdifferentiation of MSCs seeded on micropatterned substrates to SC-like phenotypes and investigation of topographical cues on transdifferentiation, alignment and morphology of the MSCs (p. 326 L. Col. final para). Sharma teaches the grooves of the micropatterned polymeric films of the substrates to be 11-13 µm (microns) (Fig. 1). Sharma demonstrates the micropatterned polymeric substrates act as very useful tools in providing orientation to growing MSCs; MSCs grown on patterned substrates grew in the direction of the microgrooves, were highly oriented and showed elongation along the grooves, compared to cells grown on smooth substrates (p. 330 R. Col. 1st para). Sharma additionally observed no obvious deleterious effects of patterning on the proliferation and transdifferentiation of the MSC cells to SC-like phenotypes (p. 221 L. Col. 1st para).
Sharma refers to a previous work wherein their research group demonstrated nerve regeneration conduits with rolled biodegradable micropatterned PLA films in the inner lumens, after seeding with SCs, significantly improve the sciatic nerve regeneration in a rodent model of peripheral nerve injury (p. 333 R. Col. final para). Sharma proposes rolling the resulting films of the present study to fabricate a nerve conduit along with transdifferentiated MSCs transplantation to test the synergistic potential of physical and biological cues on peripheral nerve repair in a rat model (p. 334 L. Col. 1st para).
Rutowski, the previous work referenced by Sharma, teaches rolling of the micropatterned film wherein the lengths of the grooves of the film are oriented parallel to the longitudinal axis of the cylindrical nerve conduit (Fig. 1).
Fan teaches that, with cell sheet technology, an intact and contiguous cell sheet composed of cells and extracellular matrix (ECM), can be obtained with a high adhesive ability depending on fibronectin, which can be trans-planted or grafted to the host tissues without using any sutures (p. 305 L. Col. 3rd para). Fan teaches culturing an MSC cell sheet in a culture dish for 14 days, until formation of a dense and contiguous cell sheet, implied removal of the sheet from the dish/media by cutting the sheet into strips, rolling the sheet into a nerve conduit by using PTFE tube as a model, and culturing the conduit in a different culture media for another 7 days during which the cell sheets fuse into a cylindrical conduit and the resulting conduit can stand on a flat surface independently when the PTFE tube is removed prior to implantation into spinal cord injured rats (Fig. 1; “2.2 MSC cell sheet preparation;” “2.4 Nerve conduit based on MSC cell sheet and prevascularized MSC cell sheet”). The Examiner notes that the MSC contiguous cell sheet covers 100% of the culture dish in Fig. 1; therefore, in order to result in a contiguous cell sheet, the MSC cell sheet grown in the dish is grown to confluence. Fan demonstrates healing benefits of the nerve conduit when transplanted into rat spinal cord injuries (p. 308, 1st and 2nd paras). Fan teaches the conduits formed with this method not only provide a new therapeutic method for spinal cord injury, but also expand the application range of the cell sheet (“4. Conclusions”).
Regarding claims 1 and 12, it would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of App‘821, Sharma, Rutowski, and Fan, and perform the following steps: (1) culture App‘821’s DPCs (which contain DPSCs, aka MSCs) on a micropatterned substrate with a groove size between 11-13 µm (which reads on the “less than 25 microns” of claim 12), as taught by Sharma, and generate a separatable DPC cell sheet with the cells aligned along the grooves of the substrate; (2) separate the resulting DPC cell sheet from the substrate and roll onto a PTFE tube to generate a cylindrical conduit, as shown by Fan, so that the cells are aligned parallel to the longitudinal axis of the cylindrical conduit, as shown by the combined teachings of Sharma and Rutowski; and (3) culture the resulting conduit in another culture media to fuse the cells together and form a cylindrical conduit which can stand on a flat surface independently when the PTFE tube is removed, as taught by Fan, and arrive at the instantly claimed invention.
The ordinarily skilled artisan would have been motivated to perform step (1) in order to provide oriented cell alignment in the scaffold-free tissue structure of App ‘821, which is taught by Sharma to be superior for axonal growth compared to randomized cellular therapies for nerve regeneration. The ordinarily skilled artisan would find reasonable expectation of success performing step (1) based on the fact that the DPCs contain MSCs, which are the cells that successfully align along the microgrooves during growth on microgrooved substrate, as shown by Sharma.
The ordinarily skilled artisan would have been motivated to perform step (2) in order to experience the regenerative benefits, taught by Sharma and Rutowski, that result from specific cell alignment in a cylindrical nerve conduit wherein the cells are aligned parallel to the longitudinal axis of the resulting cylinder (similarly to the aligned MSC and SC cells taught within the rolled micropatterned nerve conduit of the combined teachings of Sharma and Rutowki). The ordinarily skilled artisan would have a reasonable expectation of success performing step (2) because Fan demonstrates rolling of a MSC cell sheet onto PTFE successfully generates a cylindrical nerve conduit; thus, one would expect the aligned cell sheet grown on microgrooved substrate to also exhibit these separatable and manipulatable characteristics during rolling.
The ordinarily skilled artisan would have been motivated to perform step (3) in order to experience nerve regeneration enhancement capabilities of the resulting nerve conduit by mimicking the spinal cord nerve conduit taught by Fan, which is shown to help improve spinal cord nerve injury recovery, without the use of sutures, upon transplantation. The ordinarily skilled artisan would find reasonable expectation of success performing step (3) based on the fact that the resulting nerve conduit, which contains MSCs in the form of DPSCs, has a substantially similar makeup to the nerve conduit of Fan (a sheet of MSC cells), and is formed in the same cylindrical structure; thus, it would be expected that further culturing of the cylindrical conduit after rolling on PTFE would naturally promote fusion of the cells into one cylindrical conduit which exhibits the high adhesion capabilities of the conduit of Fan.
Regarding claim 7, it would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to transdifferentiate the MSC cells of the DPC cell sheet, after growth of the cells on the micropatterned substrate, into SC-like phenotypes using the method taught by Sharma, and arrive at the instantly claimed invention. The ordinarily skilled artisan would have been motivated to perform this transdifferentiation because SCs secrete trophic and growth factors which promote neural regeneration, and it has been shown that implantation of SCs supports axonal elongation and regeneration; these properties enable SCs to be one of the most attractive cell-based therapies for peripheral nervous system (PNS) regeneration, which is the purpose of the DPC cell sheet taught by Dailey. The ordinarily skilled artisan would have a reasonable expectation of success transdifferentiating the MSCs on the DPC cell sheet, after culturing on the microgrooved substrate, based on Sharma’s demonstration that the presence of the microgrooves on the substrate and the orientation of the cells on the sheet pose no threat to the success of the transdifferentiation of MSCs to SC-like phenotypes.
This is a provisional nonstatutory double patenting rejection.
2)Claims 14-16, 18-19, 21 and 23 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2 and 10 of copending Application No. 16/976,821 in view of Syed-Picard, F. N. et al. (2014). "Scaffoldless tissue-engineered dental pulp cell constructs for endodontic therapy." J. Dent. Res, 93(3), 250-255 (cited in PTO-892), Fan, et al. (2020). “A prevascularized nerve conduit based on a stem cell sheet effectively promotes the repair of transected spinal cord injury.” Acta Biomaterialia, 101, 304-313 (cited in IDS 10/20/2022), and Sharma, A. D. et al. (2016). “Oriented growth and transdifferentiation of mesenchymal stem cells towards a Schwann cell fate on micropatterned substrates.” J. Biosci. Bioeng., 121(3), 325-335 (cited in PTO-892), as evidenced by Dailey, M. T. et al. (2018). “Scaffold-Free Dental Pulp Cell Sheets to Enhance Facial Nerve Regeneration.” Journal of Oral and Maxillofacial Surgery, 76(10), Supplement, E74 (cited in PTO-892) and Pourlak, T. et al. (2021). “Usage of stem cells in oral and maxillofacial region.” J. Stomatol. Oral Maxillofac. Surg., 122, 441-452 (cited in PTO-892).
Applicant does not appear to have provided any arguments to this rejection and it is maintained for reasons of record.
App‘821 claims a method of producing neurite outgrowth in a neuron, comprising culturing neural crest-derived stem cells in the presence of a growth factor without a scaffold to produce a scaffold-free tissue structure, wherein the neural crest-derived stem cells of the scaffold-free tissue structure produce one or more neurotrophic factors (claim 1). App’821 claims the tissue structure comprises a tissue sheet (claim 2). App’821 claims the neural crest-derived stem cells are dental pulp cells (claim 10). Thus, these cells read on the limitations of the cells in claim 16. As evidenced by Pourlak, dental pulp stem cells are mesenchymal stem cells (MSCs) (“2.1.1. Dental Pulp Stem Cells (DPSCs)”). Thus, claim 23 is read upon. Additionally, as evidenced by Dailey, dental pulp cells express neurotrophic factor (NTF) genes including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and neurotrophin-3 (NT-3) (“Materials and Methods” lines 2-9). Thus, the dental pulp cells read on the limitations of instant claims 18 and 19.
App’821 differs from the instant invention in that it fails to claim the specific method steps recited in instant claims 14 and 15. Additionally, App’821 fails to claim the additional method step recited in instant claim 21.
Syed-Picard teaches self-assembled, scaffoldless, three-dimensional (3D) tissues engineered from DPCs and assessed as a device for pulp regeneration (Abstract). Syed-Picard teaches that if cells regenerate a 3D tissue without the use of exogenous materials, the cells would potentially be able to recapitulate native tissue more closely in regenerative therapies and generate their own preferred 3D microenvironment; the DPC cell sheets formed in this method assemble into a cylindrical 3D tissue that is highly cellular and solid (p. 250 final para through p. 251 1st and 2nd paras). Syed-Picard teaches samples prepared by plating DPCs onto sample dishes and allowing them to culture to confluence, after which 2 minutien pins are placed in the center of each dish approximately 7 mm apart and culture medium is changed to include growth factors; the tissue sheets are contracted by the cells to pull away from the edges of the dishes and roll toward the pins to form 3D scaffoldless cylindrical tissues (p. 251 Fig. 1 (D) and (E); “Formation and Delivery of DPCs in 3d Scaffoldless Engineered Tissues in/to Tooth Roots”). This contraction of the cells to pull away from the dishes and roll towards the pins reads on separation of a cell sheet from the substrate (dish) and aligning the cells in the sheet during culturing.
Fan teaches that, with cell sheet technology, an intact and contiguous cell sheet composed of cells and extracellular matrix (ECM), can be obtained with a high adhesive ability depending on fibronectin, which can be trans-planted or grafted to the host tissues without using any sutures (p. 305 L. Col. 3rd para). Fan teaches culturing an MSC cell sheet in a culture dish for 14 days, until formation of a dense and contiguous cell sheet, implied removal of the sheet from the dish/media by cutting the sheet into strips, rolling the sheet into a nerve conduit by using PTFE tube as a model, and culturing the conduit in a different culture media for another 7 days during which the cell sheets fuse into a cylindrical conduit and the resulting conduit can stand on a flat surface independently when the PTFE tube is removed prior to implantation into spinal cord injured rats (Fig. 1; “2.2 MSC cell sheet preparation;” “2.4 Nerve conduit based on MSC cell sheet and prevascularized MSC cell sheet”). Fan demonstrates healing benefits of the fused nerve conduit when transplanted into rat spinal cord injuries (p. 308, 1st and 2nd paras). Fan teaches the conduits formed with this method not only provide a new therapeutic method for spinal cord injury, but also expand the application range of the cell sheet (“4. Conclusions”).
Sharma teaches Schwann cells (SCs) secrete trophic and growth factors which promote neural regeneration, and it has been shown that implantation of SCs supports axonal elongation and regeneration; these properties enable SCs to be one of the most attractive cell-based therapies for peripheral nervous system (PNS) and central nervous system (CNS) regeneration (p. 325 L. Col. 1st para). Sharma teaches multipotent MSCs are a versatile cell source for neural repair strategies which can be transdifferentiated into SC-like phenotypes (p. 325 R. Col. 1st para). Sharma investigates transdifferentiation of MSCs seeded on micropatterned substrates to SC-like phenotypes and investigation of topographical cues on transdifferentiation, alignment and morphology of the MSCs (p. 326 L. Col. final para). Sharma provides a method of in vitro transdifferentiation of rat MSCs into SC-like phenotypes by simply replacing the culturing media of the growing cells with that of trans-differentiation media and further incubation (p. 326 “In vitro transdifferentiation of rat MSCs into SC-like phenotypes”).
Regarding the method steps recited in claim 14, it would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to apply the culturing method of DPCs taught by Syed-Picard and include the step of anchoring the produced cell sheet with pins after confluence; this would then result in the formation of a cultured and rolled 3D scaffoldless tissue which is naturally separated from the substrate and can be applied as a nerve regenerative therapeutic. The ordinarily skilled artisan would have been motivated to perform this step while culturing the tissue sheet in order to generate a 3D tissue without the use of exogenous materials, wherein the cells are able to recapitulate native tissue more closely in regenerative therapies and generate their own preferred 3D microenvironment; these qualities would naturally enhance the regenerative therapeutic effects of a resulting NTF-producing DPC tissue sheet, and this natural cylindrical/curved structure to the tissue sheet would additionally facilitate easier application of the cell sheet around facial nerve defects and accelerate facial nerve healing, as is the intended use of the DPC tissue sheet claimed by App’821. The ordinarily skilled artisan would have a reasonable expectation of success performing this step when culturing the DPC cell sheet because both App’821 and Syed-Picard teach similar methods of forming 3D DPC tissue sheets for use as regenerative therapeutics.
Regarding the additional method step of claim 15, it would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to culture the naturally-rolled 3D scaffoldless cylindrical DPC structure, while being anchored to continue to provide the 3D shape, for another 7 days to allow the cell sheet to fuse into the cylindrical conduit which can stand on a flat surface independently, and arrive at the instantly claimed invention. In doing so, the cells of the cell sheet would be substantially aligned in the rolled sheet of cells lengthwise, because this is an inherent property of the effect of culturing the DSC cell sheet when anchored at two points (see instant specification [0087]: “due to stresses placed on the cell sheet from culturing while anchored, the cells will align, forming an aligned construct”). Per MPEP 2112.01, where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). The ordinarily skilled artisan would have been motivated to allow the cell sheet to continue to culture while being anchored to fuse into the cylindrical conduit in order to mimic the fused cylindrical nerve conduit of Fan, which demonstrates healing benefits of the fused nerve conduit when transplanted into rat spinal cord injuries. The ordinarily skilled artisan would seek to apply these benefits for the intended purpose of the nerve conduit (nerve regeneration), as discussed by App’821. The ordinarily skilled artisan would have a reasonable expectation of success culturing the cylindrical nerve conduit to fuse the cells into the cylindrical structure because Fan teaches this to be an appropriate method of fusing a MSC cell sheet into a cylindrical shape, thanks to the adhesion ability of the fibronectin secreted by the cells; the ordinarily skilled artisan would expect the DPC cell sheet (which also contains MSCs) to operate in a similar manner.
Regarding the step recited in instant claim 21, it would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to transdifferentiate the MSC cells of the DPC tissue sheet, after growth of the cells to generate the cell sheet, into SC-like phenotypes using the method taught by Sharma, and arrive at the instantly claimed invention. The ordinarily skilled artisan would have been motivated to perform this transdifferentiation because SCs secrete trophic and growth factors which promote neural regeneration, and it has been shown that implantation of SCs supports axonal elongation and regeneration; these properties enable SCs to be one of the most attractive cell-based therapies for peripheral nervous system (PNS) regeneration, which is the purpose of the DPC cell sheet of App’821. The ordinarily skilled artisan would have a reasonable expectation of success transdifferentiating the MSCs on the DPC cell sheet, after culturing to confluence, based on Sharma’s demonstration that the orientation of MSC cells pose no threat to the success of the transdifferentiation of these MSCs to SC-like phenotypes; thus, transdifferentiation of MSCs to SC-like phenotypes by simply following Sharma’s method and replacing the culture media of the cells with a transdifferentiation media during growth is expected to be successful regardless of whether or not the MSC cells are formed within an oriented cell sheet structure.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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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/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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