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 .
Claim Status
Claims 1, 3-12, and 14-17 are currently pending in this application.
Election/Restrictions
Applicant’s election with traverse of Group I, claims 3-11, in the reply filed on Nov. 27, 2025 is acknowledged. Upon further consideration, the restriction requirement as set forth in the Office action mailed on Oct. 2, 2025 is hereby withdrawn. Claims 1, 3-12, and 14-17 have been considered on the merits and all arguments have been fully considered.
Claim Objections
Claims 1, 4-7, 9-12 and 14-17 are objected to because of the following informalities: The amendments to claims 1, 4-7, 9-12 and 14-17 are nearly illegible due to scanning of a submission with colored text, i.e., colored MS Word tracked changes, particularly parts of claims 5-6 and 11-12. See 37 CFR 1.52. Appropriate correction is required.
Status of Rejections
Status of the rejections: the previous claim rejections under 35 USC §§ 101, 112(b) and 112(d) are withdrawn in view of the claim amendments.
Claim Interpretation
In the claims, the term “chemical culture system” is interpreted as a single composition product comprising a defined mixture of the specifically recited components (e.g., medium and additives) while the term “characterized” is considered non-limiting and merely redundant with comprising. However the preamble phrase “for the nervous system” is not defined by the claims or instant specification and, thus, is considered non-limiting beyond meaning the medium is generally suitable for use with neuronal cell types generally, i.e., neuronal cells and glial cells in vitro. Furthermore, if the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states a purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation. MPEP 2111.02(II).
The term “culture medium” viewed in light of the specification has implied broad limitations to encompass any composition comprising capable of comprising a living cell, at least for a short duration (e.g., 1 millisecond) but may also comprise essential nutrients suitable for growth and/or proliferation of at least one mammalian neuronal or glial cell type. However the term “basic” regarding a culture medium is not defined by the claims or instant specification and, thus, is considered non-limiting beyond meaning the medium is generally suitable for use with many diverse neuronal/glial cell types, such as by comprising minimum essential ingredients. For example, the basic culture medium need not comprises non-essential amino acids as noted as optional at instant pg. 5, ¶ 7.
In claim 1, the phrase “at least one of D(+)-galactose, recombinant human transferrin” is interpreted as requiring either D(+)-galactose or recombinant human transferrin but not necessarily both. It is noted that the term “recombinant human transferrin” when viewed in light of the specification means a human transferrin protein obtained via genetic engineering, and having no relationship to a recombinant human.
35 USC § 112(a), Scope of Enablement, (new)
Claims 14-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, while being enabled for inducing neural directed differentiation of stem cells, the specification does not enable any person, skilled in the art to which it pertains or with which it is most nearly connected to, to direct neural differentiation of already differentiated cells. It is noted that there are enabled embodiments wherein the cells are undifferentiated neural progenitor cells, such as ReNcell VM cells. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
The claims are directed to methods of using cell culture conditions to intentionally induce neural differentiation of either stem cells or differentiated cells. While the prior art teaches how to direct neural differentiation of stem cells in culture, the prior art is silent as to starting with differentiated cells. Thus, these aspects of using must be shown to a reasonable extent so that one of the ordinary skills in the art would be able to practice the invention without any undue or unreasonable burden on such artisan: such as in claim 14 using merely exposing differentiated cells with a chemical culture system according to claim 1. However there are no working examples provided, and instead the instant application is silent to accomplish this method. The dependent claims, such as claim 17, fail to add any enabling active step to accomplish the aforementioned.
Nowhere does the instant specification show how to induce differentiation of an already differentiated cells, regardless of using the chemical culture system recited in claim 1 or regardless of whether directed toward neuronal fates/lineage. Thus, there is no evidence in the instant application or the prior art that the scope of the claims could predictably result in one of the recited results and undue experimentation would be required to fill these gaps in the application and prior art. In summary, the claims are rejected under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement to a person skilled in the art to which it pertains or with which it is most nearly connected to perform the method of any of claims 14-17 wherein the cells are differentiated cells instead of stem cells. Given the lack of working examples, the limited guidance provided in the specification, and the lack of guidance in the prior art, undue and/or unreasonable experimentation would have been required for one skilled in the art to produce the recited differentiation over the full scope of the cells of claims 14-17.
Claim Rejections - 35 USC § 112(b), (new)
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.
Claims 12 and 14-17 are 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 pre-AIA the applicant regards as the invention.
Claims 12 and 14 each recites “the chemical culture system described in claim 1,” which is ambiguous and unclear as to what “description” in claim 1 is being referred to and whether this wording limits the chemical culture system to being ‘a chemical culture system of claim 1’ or a ‘chemical culture system according to claim 1.’ Claims 15-17 are also included in this rejection for depending from indefinite claim 14.
Claims 12 and 14-17 are generally narrative and indefinite, failing to conform with current U.S. practice. They appear to be a literal translation into English from a foreign document and are replete with grammatical and idiomatic errors. For example, claim 12 recites conditions sufficient “to induce the pluripotent stem cells differentiate into neural stem cells or brain organoids”; and claims 15-17 recite a method of inducing neural directed differentiation comprising “DRG neuron differentiation culture” or “cortical neuron differentiation culture.” (But not astrocyte differentiation “culture”). Claim 14 recites “neural directed differentiation” of already “differentiated cells,” which is incoherent. Claims 15-17 are also included in this rejection for depending from indefinite claim 14.
Claims 12 and 14-17 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. For claim 12, the omitted steps for inducing differentiation of pluripotent stem cells into neural stem cells or brain organoids are a step of contacting the cells with an inhibitor such as 10 μM SB-431542 and/or 100 nM LDN-193189. For claim 14, the omitted steps for inducing differentiation of stem cells into neural cells is a step of contacting the cells with an effective amount of a TGF-β pathway inhibitor and a BMP inhibitor, such as 10 μM SB-431542 and/or 100 nM LDN-193189 (see instant Examples 3-5). For claim 15, the omitted steps for inducing differentiation into astrocytes is a step of contacting the cells made by claim 14 with an effective amount of LIF, EGF and FGF (Example 4); for inducing differentiation into cortical neurons is a step of contacting the cells of claim 14 with an effective amount of a chemical Wnt inhibitor, e.g., CHIR99021 (Example 4); and for inducing differentiation into DRG neurons is a step of contacting the cells of claim 14 with effective amounts of chemical activator/inhibitor of specific signaling pathways (e.g., Wnt, FGF, and/or neurotrophic factors) (Example 4 uses 3 M CHIR99021, 10 µM SU5402 and 10 µM DAPT).
Claim 17 recites the method further comprising adding “chemical small molecule inhibitors” during the “cortical neuron differentiation culture,” which is ambiguous and unclear as to the precise scope of the additional method step when the method comprises culturing the cells “in the chemical culture system described in claim 1 [comprising small molecular compounds] under conditions sufficient to induce neural directed differentiation comprising cortical neuron differentiation culture.” The term “chemical small molecule inhibitors” is not defined in the instant claims, the instant specification or the prior art and potentially encompasses any inhibitor of any biological process or property without limit. Moreover usage of the relative term “small” is indefinite here as neither the prior art nor the specification provides a definition or standard for a “small” versus non-small molecule, and thus, a person of ordinary skill in the art would not understand the metes and bounds of “small” in claim 17.
Claim Rejections - 35 USC § 103, (modified)
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 12, and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Lu (CN106244548A) in view of Zhang (Zhang et al., Free Radic Biol Med 24: 66-75 (1998)).
The claims are interpreted as provided in a previous section.
Lu teaches a cell culture medium comprising a medium (e.g., DMEM or DMEM/F12,) and the additive luteolin at an amount of 35 µM (preferably 10 µg/mL) (pg. 2, last para., to pg. 3; claim 7). Lu teaches using such a medium for inducing stem cells into neural progenitor cells and differentiated neural cells.
Lu does not expressly teach the medium comprises piperidinol oxide.
However Zhang teaches including in a cell culture medium the additive piperidinol oxide (TPL-H, 4-OH-2,2,6,6-tetramethyl-1-hydroxypiperidine) at 20 µM to act as an antioxidant to protect cells from oxidative stress and injury (Fig. 5, pg. 66, right col., last para.). Thus, it would have been prima facie obvious to one of ordinary skill in the art at the effective time of filing to modify a medium taught by Lu by including an additive of piperidinol oxide TPL-H at 20 µM as taught by Zhang. One of ordinary skill in the art would be motivated to protect any cells in the medium from oxidative damage to help maintain optimal viability, including using the medium for culturing neural progenitor cells and differentiated neural cells as taught by Lu.
Regarding claims 12 and 14-15, Lu teaches using a cell culture medium comprising a medium (e.g., DMEM or DMEM/F12,) and the additive luteolin at an amount of 35 µM (preferably 10 µg/mL) (pg. 2, last para., to pg. 3; claim 7). Lu teaches using such a medium for inducing stem cells into neural progenitor cells and differentiated neural cells, such as GFAP+ astrocytes or NEFH+ DRG neurons (pg. 6, Table 2), even in the absence of any piperidinol oxide component.
Claims 1, 4-5, 12, and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Lu in view of Zhang as applied above, and further in view of Arora (Arora, M., Mater methods 3(175): 24 (2013)).
Regarding claim 5, the combination of Lu and Zhang does not teach wherein luteolin is present at 10 or 50 µM. However Arora teaches cell culture media can be optimized for specific concentrations of components using routine experimentation (pg. 7, last para.).
It would have been prima facie obvious to one of ordinary skill in the art at the effective time of filing to modify a medium taught by Lu and Zhang by further optimizing the luteolin concentration for use in inducing stem cells toward neural differentiation as taught by Lu. One of ordinary skill in the art would be motivated to do so because Lu teaches the purpose of adding luteolin is to improve neural differentiation as a results-effective variable and it can be optimized using routine experimentation within the skills of one of ordinary skill in the art as taught by Arora to arrive at concentration of either 10 or 50 µM, such as starting from dosage of 35 µM. One of ordinary skill in the art would be motivated to do so to improve differentiation efficiency and obtain more neural-differentiated cells as is the goal of Lu. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Claims 1, 4, 6, 9-10, 12, and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Lu in view of Zhang as applied above, and further in view of Yan (CN104694475A).
Regarding claims 1 and 6, the combination of Lu and Zhang does not teach wherein the medium comprises D-galactose at an amount of 5-25 µg/mL or 7.5 µg/mL.
However Yan teaches a neural stem cell medium comprising D(+)-galactose as an additive at 7.5 µg/mL and DMEM with DMEM/F12 as the base/basic culture medium ([0046]; [0051]; Abstract; ([0013], [0003], [0052]-[0054]; claims 1 and 3).
It would have been prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing to modify the medium taught by Lu and Zhang by including D(+)-galactose taught by Yan at the concentration taught by Yan. One of ordinary skill in the art with the goal of culturing neural stem cells and/or differentiating stem cells into neural cells in cultures as taught by Lu would be motived by Yan to include the respective additives at already validated concentrations for neural stem cell culture. Regarding claim 6, Yan teaches wherein the galactose is at 7.5 µg/mL (Abstract). Regarding claims 9-10, Yan teaches wherein neural stem cell media additives include growth factors (e.g., epidermal growth factor, bFGF, progesterone, insulin, and/or putrescine) and inorganic salts (iron and sodium selenite) ([0015]; [0020]; [0035]; [0055]; [0005]; claims 1 and 3).
Claims 1, 4, 8, 12, and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Lu in view of Zhang as applied above, and further in view of Choi (Choi et al., Korean Journal of Chemical Engineering 24: 1058-63 (2007)).
Regarding claim 8, Lu teaches wherein the foundation of the cell culture medium is DMEM (pg. 3, para. 1-2), i.e., a basic culture medium; however, the combination of Lu and Zhang does not expressly teach wherein the medium comprises medium non-essential amino acids.
Choi teaches a medium for culturing and differentiating stem cells based on DMEM and supplemented with non-essential amino acids (NEAs) (pg. 1059, left col., last para., to right col., 1st para.; Table 1). Further, Choi teaches exogenously added amino acids affect mammalian cells in culture, often beneficially, and can alter proliferation and differentiation rates with EAs but not NEAs preferred for both (pg. 1058, left col., last para., to right col., 3rd para.; abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing with the goal of making a medium for stem cell culture to add non-essential amino acids to a medium based on DMEM . One of ordinary skill in the art would be motivated by Choi demonstrating media for proliferating stem cells using these components, such as for proliferation and/or differentiation.
Claims 1, 4, 12, and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Lu in view of Zhang as applied above, and further in view of Alshawaf (Alshawaf et al., Sci Rep 8: 603 (2018)).
Regarding claim 16, the combination of Lu and Zhang does not specifically teach a method of dorsal root ganglion (DRG) neuron differentiation, such as using cytokines added in a cell culture medium. However Alshawaf teaches methods of DRG neuron differentiation using a medium comprising the cytokines NGF (10 ng/mL), NT3 (10 ng/mL), and BDNF (10 ng/mL) (pg. 2, 4th para.).
It would have been prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing with the goal of performing a process for directing stem cells to differentiate into DRG neurons to add NGF (at 10 ng/mL), NT3 (at 10 ng/mL), and/or BDNF (at 10 ng/mL) to a cell culture medium. One of ordinary skill in the art would be motivated by Alshawaf’s protocol demonstrating media comprising these cytokines for differentiating cells into mature DRG neurons (pg. 9, 4th para.; Fig. 2-6).
Claims 1, 4, 12, 14-15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Lu in view of Zhang as applied above, and further in view of Shi (Shi et al., Nat Protoc 7: 1836-46 (2012)).
Regarding claim 17, the combination of Lu and Zhang does not specifically teach a method of cortical neuron differentiation, such as using a small chemical inhibitor in a cell culturing step. However Shi teaches methods of cortical neuron differentiation using media comprising the chemical inhibitors SB431542 (at 10 M) and noggin (at 500 ng/mL) or dorsomorphin (at 1 µM) (e.g., a neural induction medium) (pg. 1839, left col.).
It would have been prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing with the goal of making a medium for directing stem cells to differentiate into cortical neurons to add SB431542 (at 10 M). One of ordinary skill in the art would be motivated by Shi’s protocol demonstrating media comprising SB431542 for differentiating cells into mature cortical neurons (Fig. 1 and 3-4).
Response to Arguments
Applicant’s remarks filed regarding the 103 rejections have been fully considered but not found persuasive.
Applicant argues, if even the prior art teaches a culture medium comprising luteolin and piperidinol oxide to protect cardiomyocytes, the prior art does not teach such a medium “for cells of the nervous system” or further “achieving neural cell culture without serum and animalderived growth factors." However as noted above, when the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states a purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation. MPEP 2111.02(II). Here, patentable over the art cannot rely on language solely recited in the preamble of claim 1 because “for the nervous system” is both unclear as a limitation to a cell culture system and not limiting because the body of the claim describes a complete invention and the language recited solely in the preamble does not provide any distinct definition of any of the claimed invention’s limitations. Thus, the preamble of the claim(s) is not considered a limitation and is of no significance to claim construction. See Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See MPEP § 2111.02.
In addition applicant argues that this ability to achieve neural cell culture without serum and animalderived growth factors is an unexpected technical effect rendering the claimed invention obvious over the prior art. However In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a lack of animal serum growth factors) are not recited in the rejected claim(s). Instead, the claims are open-ended with the wordings the chemical culture system comprising and the additives comprise. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Allowable Subject Matter
Claims 3 and 6-7 are objected above and also here as being dependent upon a rejected base claim, however these claims appear to be directed to allowable subject matter if both the informalities noted above are overcome and if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The reasons for indicating allowable subject matter is a search of the prior arts does not reveal any disclosures, alone or in combination, that teaches or reasonably suggests a cell culture medium comprising piperidinol oxide at 10-200 µM and recombinant human transferrin at 50-200 ng/mL.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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