Notice of Pre-AIA or AIA Status
1. The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Status of Application, Amendments and/or Claims
2. Applicant’s response dated 12/3/2025 is considered and entered into record. Claims 1-20 are currently pending.
Election/Restriction
3. Applicant’s election of the second culture period condition species a) an absence of fibroblast growth factor and TGFβ1, in the reply filed on 3 December 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
4. The requirement is still deemed proper and is therefore made FINAL.
5. Claims 8, 15 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a non-elected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3 December 2025.
6. Claims 1-7, 9-14, 16-18 and 20 drawn to a method of directed differentiation of human pluripotent stem cells (hPSCs) into neural stem cells, are being considered for examination in the instant application.
Information Disclosure Statement
7. The Information disclosure statements (IDSs) dated 10/25/22 and 3/23/2023 are acknowledged and entered into record. Non-patent literature document number 1 of the IDS dated 3/23/2023 is crossed off, as a copy of the citation is neither provided in the present application, nor in previous related applications.
Claim Rejections - 35 USC § 112
8. 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.
9. 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.
10. Claims 1-2 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
11. The claims are to a method for directed differentiation of human pluripotent stem cells (hPSCs) into neural stem cells (NSCs) comprising: (a) seeding the hPSCs onto a xenogen-free substrate comprising a vitronectin or a synthetic peptide, and culturing in the presence of a Rho kinase inhibitor for about one day (first culture); (b) culturing the cells of step (a) for about 4 to about 6 days on a xenogen-free substrate in a neural differentiation medium to obtain NSCs, wherein at least 90% of the cells are Pax6+ (second culture) (claims 1-2).
12. The specification of the instant application teaches that neural differentiation methods of the invention comprise the use of substrates for the differentiation of hPSCs into neural stem cells, wherein the substrates include an undefined extracellular matrix protein substrate Matrigel®, or defined xenogen-free substrates like vitronectin, a peptide or fragment thereof, or “self-coating substrates” like Synthemax® (para 00015, 00095). Even though the instant specification does not provide an explicit definition of a synthetic peptide, it is known in the relevant field that Synthemax® is a synthetic vitronectin-based peptide substrate, which is xeno-free and provides a more in-vivo like environment for stem cell culture (Synthemax <Synthemax Vitronectin Substrate | Stem Cell Adhesion & Expansion | Corning>, downloaded on 3/5/26, 1 page). However, the brief description in the specification of one example of a synthetic peptide, is not adequate written description of an entire genus of methods encompassing the use of a genus of synthetic peptides as xenogen-free substrate.
13. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. However, in this case, the specification has not shown a relationship between the structure, function or properties of the claimed genus of synthetic peptides. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
14. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (See page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (See Vas-Cath at page 1116).
15. The skilled artisan cannot envision the genus of synthetic peptides of the encompassed methods, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method. Adequate written description requires more than a mere statement that it is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
16. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class.
17. Therefore, the claims do not meet the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 103
18. The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
19. Claims 1-7, 9-14, 16-18 and 20 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Meyer et al (WO 2012/135621, 10/4/2012 and Wilson et al (Stem Cell Rev 2: 67-78, 2006), in view of Shin et al (NeuroReport 15: 1959-1963, 2004), and in further view of Braam et al (Stem Cells 26: 2257-65, 2008).
20. The claims are to a method for directed differentiation of human pluripotent stem cells (hPSCs) into neural stem cells (NSCs) comprising: (a) seeding the hPSCs onto a xenogen-free substrate comprising a vitronectin or a peptide or fragment thereof, recombinant vitronectin or a synthetic peptide, and culturing in the presence of a Rho kinase inhibitor for about one day (first culture); (b) culturing the cells of step (a) for about 4 to about 6 days on a xenogen-free substrate in a neural differentiation medium to obtain NSCs, wherein at least 90% of the cells are Pax6+ (second culture) (claims 1-3, 10); wherein: the hPSCs are seeded at a cell density of at least about 1x105 cells/cm2 (claims 4, 11); the hPSCs of step (a) are cultured in the presence of ascorbate, transferrin, fibroblast growth factor (FGF2) and TGFβ1 (claims 5, 6, 12-13); the cells of step (b) are cultured in the absence of FGF and TGFβ1 (claims 7, 14); and the cells of step (b) form neural rosettes after about 4 to about 6 days of culture (claims 9, 16). Claim 17 recites a differentiation method of hPSCs to NSCs comprising: (a) seeding hPSCs on recombinant vitronectin at a cell density of about 2x105 cells/cm2 and culturing in a neural differentiation medium comprising a Rho kinase inhibitor, ascorbate, transferrin, FGF (FGF2) and TGFβ1 for about 1 day (first culture); (b) culturing the cells of step (a) for about 4 to about 6 days on a xenogen-free substrate in a neural differentiation medium without FGF and TGFβ1 and optionally without transferrin, to obtain NSCs that are at least 90% Pax6+ (second culture) (claims 17, 18); wherein the cells of step (b) form neural rosettes after about 4 to about 6 days of culture (claim 20).
21. Meyer et al teach neural differentiation methods of PSCs like embryonic stem cells to neural cells (neural precursor or stem cell) (Abstract; para 0060, 0061, 0056), which are Pax6 positive (para 00151) comprising priming (prior to differentiation) in a medium having reduced growth factors (i.e. having a presence of growth factors) (para 0013, 0012) or E8 medium containing FGF2 and TGFβ (para 0099; 00172, lines 6-9), and differentiation in a differentiation medium lacking bFGF and TGFβ (para 0012), wherein the FGF is FGF2 (para 0084, 00138), and the TGFβ includes TGFβ1 (para 00143) (instant claims 5-7, 12-14, 17-18). It is noted that para 0002 of the instant specification teaches that hPSCs can include human embryonic stem cells (ESCs). Meyer et al also teach that the medium comprises transferrin (para 0019) and Rho kinase (ROCK) inhibitor (para 0026, 00102, 00103, 00111); the PSCs can be human (para 0017); the cell density of PSCs is at least or about 105 (1x105) cells/cm2 or “most particularly about” 3x104 to 3x105 cells/cm2 (para 0090); the hPSCs are cultured on a substrate comprising vitronectin (para 0093, 00100, 00130); the priming period is for about 1 day (step (a) of instant claims 1, 10 and 17) (para 0020, 0021, 00111), and further differentiation for about 4 days, about 6 days or “any range derivable therein” (about 4 to about 6 days) (step (b) of instant claims 1, 10 and 17) (para 0021) (instant claims 1-2, 4, 10-11, 17-18). Please note that the clause reciting that the differentiation medium is “optionally without transferrin” (instant claim 17(b)), is interpreted as that the medium: (i) contains transferrin OR (ii) does not contain transferrin. Since Meyer et al teach a differentiation medium comprising transferrin, and lacking bFGF and TGFβ, the reference meets the requirement of claim 17(b). It is also noted that “without (absence of) the FGF, TGFβ1 and transferrin” reads on the non-elected species of the second culture period condition.
22. Even though Meyer et al teach producing neuronal progenitor cells that are Pax6+, the reference does not teach that at least 90% of the cells are positive for Pax6. However, Meyer et al teach or suggest the same culture steps by seeding at about the same cell density using the same medium, and culturing for about the same number of days as in the stated claims.
23. The differences between the claimed method and the prior art method appears to be one of optimization of culture conditions and cell sorting. Therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was made to have optimized the culture conditions as taught in the reference for obtaining at least 90% Pax6+ cells of instant claims. See MPEP 2144.05: A. Optimization Within Prior Art Conditions or Through Routine Experimentation.
24. Generally, differences in culture parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such condition is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Additionally, with regard to the culture conditions for obtaining at least 90% of the cells to be Pax6+ (instant claims 1, 10 and 17), said conditions are results-effective variables which can be optimized. In the case of obtaining at least 90% Pax6+ cells, one of skill in the art would clearly recognize that culture conditions of hPSCs to NSCs (including medium composition, cell density, days of culture, etc.) must be sufficiently adjusted to obtain at least 90% of Pax6+ cells, and that said conditions can be variable and could easily be optimized by a cell culture scientist. As such, obtaining at least 90% Pax6+ cells by culturing hPSCs would amount to nothing more than routine experimentation and cell sorting that can be optimized (see In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977); and In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980)).
25. Meyer et al do not teach neural rosette formation of instant claims 9, 16 and 20.
26. Wilson et al teach that neural rosette formation is a “developmental signature” of neuroprogenitors (neural stem cells) in cultures comprising differentiating ESCs (PSCs) (Abstract; page 71, col 1, para 2). Even though, the formation of neural rosettes during the process of differentiation of PSCs is taught by Wilson et al, it is to be noted that the “wherein the cells of step (b) form neural rosettes” clause of instant claims 9, 16 and 20 do not recite a step, rather recites an intended outcome of culturing the cells in a differentiation medium as claimed, and as taught by the cited art.
27. Meyer et al or Wilson et al do not teach the culture medium comprises ascorbate. Meyer et al however, teach the addition of vitamins to the culture medium of the invention (para 0088).
28. Shin et al teach that ascorbic acid enhances differentiation of embryonic stem cells (pluripotent stem cells) (including formation of neural or CNS stem cells) into neurons (Abstract; Materials and Methods, para 1). The reference teaches that brain has a specific ascorbic acid transporter and that ascorbate increases differentiation to neurons like dopaminergic neurons from CNS precursors as compared to untreated cultures (Introduction, para 1, 3; Discussion, para 1).
29. Meyer et al, Wilson et al or Shin et al do not teach using recombinant vitronectin recited in instant claims 3, 10 and 17.
30. Braam et al teach defined growth conditions for hESC culture. The reference teaches that cells attached efficiently to natural vitronectin and both, natural and recombinant vitronectin effectively supported growth in culture (Abstract). Braam et al teach that for addressing basic biology and clinical applications with regards to hESCs, “it is clearly beneficial to culture with fully defined culture substrates and media based on recombinant (or clinical grade) proteins” (page 2263 - Discussion, para 1). Please note that vitronectin is a xenogen-free substrate as stated in para 00095 of instant specification.
31. It would have therefore, been obvious to the person of ordinary skill in the art at the time the claimed invention was made to modify the method of differentiation of PSCs to NSCs that are Pax6+ by plating cells on vitronectin, wherein the cells of step (b) (neural stem cells) form neural rosettes in view of the combined teachings of Meyer et al and Wilson et al by including ascorbate to the medium in view of the teachings of Shin et al, and using recombinant vitronectin as the substrate for culturing the PSCs or hESCs based upon the teachings of Braam et al. The person of ordinary skill would have been motivated to add ascorbic acid as this is a known vitamin having antioxidant properties that enhances differentiation of ES cells (Shin et al, Introduction, para 3; Discussion, para 1). The person of ordinary skill would have been motivated to use recombinant vitronectin as this effectively supported growth of ESCs in culture, and it is advantageous “to culture with fully defined culture substrates and media based on recombinant (or clinical grade) proteins” to understand the basic biology as well as clinical applications of ESCs (Braam et al). The person of ordinary skill would have expected success because differentiation of hPSCs to neural stem cells using similar culture conditions, was well understood and successfully implemented in the relevant field, at the time the invention was made.
32. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
33. Claims 1-4, 9-11 and 16 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Vanderhaeghen et al US PGPB 20100166720, 7/1/2010 and Wilson et al (2006), in view of Chang et al (PLoS one 5: 1-9, 2010), and in further view of Braam et al (2008).
34. Vanderhaeghen et al teach in vitro methods for differentiation of mammalian pluripotent stem cells (mPS) to neuronal progenitor cells that are paired box protein PAX6 positive (PAX6+) (Abstract; claims 1, 22), wherein the differentiation involves an adherent culture by plating or seeding the mPS cells onto a substrate for promoting growth and survival of the cells, and thereafter culturing the cells in a differentiation medium (para 0010, 0011, 0080, 0081, 0086); and wherein the mPS cells comprise human cells (para 0069). The reference teaches contacting the mPS cells (plating or seeding) with the adherent surface comprising vitronectin substrate for about 24 hours (about 1 day) (para 0087, 0090); and culturing the mPS cells between 3 and 21 days (including about 4 to about 6 days of culture as recited in instant claims 1, 10), (para 0019) (instant claims 1, 10). The reference also teaches that the plating or seeding cell density can be up to about 1x105 cells/cm2 (para 0085) (instant claims 4, 11); and that the substrate comprises vitronectin (para 0087) (instant claim 2).
35. Even though Vanderhaeghen et al teach producing neuronal progenitor cells that are Pax6+, the reference does not teach that at least 90% of the cells are positive for Pax6. However, Vanderhaeghen et al teach or suggest the same culture steps for about the same number of days by seeding a similar PS cell density as in the stated claims.
36. The differences between the claimed method and the prior art method appears to be one of optimization of culture conditions and cell sorting. Therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was made to have optimized the culture conditions as taught in the reference for obtaining at least 90% Pax6+ cells of instant claims. See MPEP 2144.05: A. Optimization Within Prior Art Conditions or Through Routine Experimentation.
37. Generally, differences in culture parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such condition is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) Additionally, with regard to the culture conditions and cell sorting for obtaining at least 90% of the cells are Pax6+ (instant claims 1, and 10), said conditions are results-effective variables which can be optimized. In the case of obtaining at least 90% Pax6+ cells, one of skill in the art would clearly recognize that culture conditions of hPSCs to NSCs (including days of culture, cell density, etc.) must be sufficiently adjusted to obtain at least 90% of Pax6+ cells, and that said conditions can be variable and could easily be optimized by a cell culture scientist. As such, obtaining at least 90% Pax6+ cells by culturing hPSCs would amount to nothing more than routine experimentation and cell sorting that can be optimized (see In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977); and In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980)).
38. Vanderhaeghen et al do not teach neural rosette formation of instant claims 9 and 16.
39. The teachings of Wilson et al are set forth above.
40. Vanderhaeghen et al or Wilson et al do not teach a Rho kinase inhibitor as recited in instant claims 1 and 10.
41. Chang et al teach the use of Rho kinase (ROCK) inhibitors in a culture of seeded murine ESCs (PSCs) to neural stem cells (neural progenitor cells) (Abstract). The reference teaches that ROCKs maintained ES cell in an undifferentiated state, while ROCK inhibitors (Y-27632) prevented ES colony formation and induced ES differentiation to neural progenitor cells (Abstract – Conclusions; page 4, col 2, last para; page 5, col 1, paras 1, 3; page 6, Discussion, para 1). The reference concludes that Rho kinase inhibition represents a strategy for neural differentiation and “preparing large numbers of neural progenitor cells” for therapeutic application (Abstract – Background, Conclusions/Significance; page 8, last para).
42. Vanderhaeghen et al, Wilson et al or Chang et al do not teach recombinant vitronectin recited in instant claims 3 and 10.
43. The teachings of Braam et al are set forth above.
44. It would have therefore, been obvious to the person of ordinary skill in the art at the time the claimed invention was made to modify the method of differentiation of PSCs to NSCs that are Pax6+ by plating cells on vitronectin, wherein the cells of step (b) (neural stem cells) form neural rosettes in view of the combined teachings of Vanderhaeghen et al and Wilson et al by culturing in the presence of a Rho kinase inhibitor in view of the teachings of Chang et al, and using recombinant vitronectin as the substrate for culturing the PSCs or hESCs based upon the teachings of Braam et al. The person of ordinary skill would have been motivated to add a Rho kinase inhibitor as ROCK inhibition represents a strategy for neural differentiation and “preparing large numbers of neural progenitor cells” for therapeutic application (Chang et al). The person of ordinary skill would have been motivated to use recombinant vitronectin as this effectively supported growth of ESCs in culture, and it is advantageous “to culture with fully defined culture substrates and media based on recombinant (or clinical grade) proteins” to understand the basic biology as well as clinical applications of ESCs (Braam et al). The person of ordinary skill would have expected success because differentiation of hPSCs to neural stem cells using similar culture conditions, was well understood and successfully implemented in the relevant field, at the time the invention was made.
45. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
Double Patenting
Non-Statutory
46. 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).
47. 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).
48. 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.
49. 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.
50. Claims 1-7, 9-14, 16-18 and 20, are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 5, 8, 13-14 of US Patent 10,920,193 in view of Meyer et al (2012), Chang et al (2010), Braam et al (2008) and Wilson et al (2006). Although the conflicting claims are not identical, they are not patentably distinct from each other because in each case the claims are directed to a method of culturing hPSCs as an adherent monolayer (seeding) to generate neuron progenitor cells in a medium comprising FGF, wherein the neural differentiation medium is E6 (i.e. lacks FGF2 and TGFβ1 – see instant specification para 000101), to obtain at least 95% Pax6+ neuron progenitor cells.
The only differences between the 2 sets of claims are:
i) Instant claims recite the use of Rho kinase inhibitor, while the ‘193 claims do not mention this limitation. However, this would be obvious in view of Meyer et al. and Chang et al for reasons stated above.
(ii) Instant claims recite a xenogen-free substrate vitronectin, while the ‘193 are silent on this limitation. However, as stated above, the use of vitronectin in PSC culture would be obvious in view of Meyer et al and Braam et al.
(iii) Instant claims recite the formation of neural rosettes, while the ‘193 claims do not recite this limitation. However, this would be obvious in view of Wilson et al teaching that the formation of rosettes is a “developmental signature” of neural stem cells in cultures (see para 26 of this office action).
(iv) Instant claims recite a cell density of hPSCs, which is absent in the ‘193 claims. However, this would be obvious in view of the teachings of Meyer et al. Moreover, the ‘193 disclosure teaches a “conventional” seeding density of hPSCs at about 1.5x105 cells/cm2 (col 3, lines 11-15).
51. Therefore, the instant claims are not patentably distinct over the issued claims in U.S. patent 10,920,193.
52. Claims 1-6, 9-13, 16 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claim 6, of US Patent 12,084,680 in view of Meyer et al (2012), Chang et al (2010), Braam et al (2008) and Wilson et al (2006). Although the conflicting claims are not identical, they are not patentably distinct from each other because in each case the claims are directed to a method of culturing hPSCs in an adherent monolayer (seeding) to generate neuromesodermal progenitor cells (neural stem cells) in a medium comprising FGF.
The only differences between the 2 sets of claims are:
i) Instant claims recite the use of Rho kinase inhibitor, while the ‘680 claims do not mention this limitation. However, this would be obvious in view of Chang et al for reasons stated above.
(ii) Instant claims recite a xenogen-free substrate comprising recombinant vitronectin, while the ‘680 claims are silent on this limitation. However, the use of this vitronectin for PSC culture would be obvious in view of Braam et al.
(iii) Instant claims recite formation of neural rosettes, while the ‘680 claims do not recite this limitation. However, this would be obvious in view of Wilson et al teaching that the formation of rosettes is a “developmental signature” of neural stem cells in cultures (see para 26 of this office action).
(iv) Instant claims recite a cell density of hPSCs, which is absent in the ‘680 claims. However, this would be obvious in view of the teachings of Meyer et al. Moreover,
the ‘680 disclosure teaches a “conventional” seeding density of hPSCs at about 1.5x105 cells/cm2 (col 3, lines 13-17).
53. Therefore, the instant claims are not patentably distinct over the issued claims in U.S. patent 12,084,680.
54. Claims 1-4 and 10-11 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 15-21 of co-pending application number 17/343,647 in view of Meyer et al (2012), Chang et al (2010), Braam et al (2008) and Wilson et al (2006). Although the conflicting claims are not identical, they are not patentably distinct from each other because in each case the claims are directed to obtaining Pax6+ neuroepithelium from hPSCs comprising culturing for 1-5 days in a monolayer (seeded).
The only differences between the two sets of claims are:
i) Instant claims recite the use of Rho kinase inhibitor, while the ‘647 claims do not mention this limitation. However, this would be obvious in view of Chang et al for reasons stated above.
(ii) Instant claims recite a xenogen-free substrate comprising recombinant vitronectin, while the ‘647 claims are silent on this limitation. However, the use of vitronectin in PSC culture would be obvious in view of Braam et al.
(iii) Instant claims recite formation of rosettes, while the ‘647 claims do not recite this limitation. However, this would be obvious in view of Wilson et al teaching that the formation of rosettes is a “developmental signature” of neural stem cells in cultures (see para 26 of this office action).
(iv) Instant claims recite a cell density of hPSCs, which is absent in the ‘647 claims. However, this would be obvious in view of the teachings of Meyer et al for reasons stated above.
55. This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
56. Claims 1-7, 9-14, 16-18 and 20 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-5, 11 and 15-17 of US Patent 11,767,508, in view of Meyer et al (2012) and Braam et al (2008).
Although the conflicting claims are not identical, they are not patentably distinct from each other because in each case the claims are to a method of directed differentiation of human PSCs (hPSCs) into neural stem cells (neuroepithelial cells), comprising seeding hPSCs at a density between about 75x103 and about 1x105 cells/cm2 (of about 1x105 cells/cm2 or about 2x105 cells/cm2) on a substrate in the presence of Rho kinase inhibitor for about 1-2 days using a medium comprising ascorbic acid (ascorbate), transferrin, FGF2 and TGFβ1 (E8); culturing the cells for about 2 to about 6 days in a neural differentiation medium (E6) comprising ascorbate, transferrin (absence of FGF2 and TGFβ1); and forming polarized rosette structure having at least 80% (can include at least 90%) that are Pax6+ cells (Pax6+/N-cadherin).
The only difference between the two sets of claims is:
Instant claims recite a xenogen-free substrate comprising vitronectin, while ‘508 claims do not have this limitation. However, the use of vitronectin in PSC culture would be obvious in view of Meyer et al and Braam et al for reasons stated above.
57. Therefore, the instant claims are not patentably distinct over the issued claims in U.S. patent 11,767,508.
58. Claims 1-7, 9-14, 16-18 and 20 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 5-8 of US Patent 12,529,032, in view of Meyer et al (2012) and Braam et al (2008).
Although the conflicting claims are not identical, they are not patentably distinct from each other because in each case the claims are directed to a method comprising culturing cells on a substrate to generate neuroepithelial cells (neural stem cells) that are at least 80% (can include at least 90%) of Pax6+ cells having a rosette structure; wherein the method comprises seeding cells onto a substrate at a density between about 75 x103 cells/cm2 to about 2.5 x105 cells/cm2 (i.e. includes about 1x105 cells/cm2 and 2x105 cells/cm2 ); the seeding is done using a medium comprising a Rho kinase inhibitor; the total culturing duration is for about 5 days; and the neural differentiation medium is E6 (i.e. lacks FGF2 and TGFβ1.
The only differences between the two sets of claims are:
i) Instant claims recite differentiation of hPSCs while the ‘032 patent claims do not have this limitation. However, this would be obvious in view of Meyer et al. for reasons stated in para 21 of this Office action.
(ii) Instant claims recite a xenogen-free substrate vitronectin, while the ‘032 claims do not recite this limitation. However, the use of vitronectin or recombinant vitronectin would be obvious in view of Braam et al for reasons stated above.
59. Therefore, the instant claims are not patentably distinct over the issued claims in U.S. patent 12,529,032.
Conclusion
60. No claims are allowed.
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/A. D./
Examiner, Art Unit 1675
5 March 2026
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