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 .
Status of the Claims
Applicant’s submission filed 27 January 2026 has been entered. Claims 1-5, 7-17, 19, and 21 are pending. Claims 1-5, 7-9, 11, 14, 16-17, 19, and 21 have been amended, while claim 6 has been cancelled without prejudice or disclaimer. Therefore, prosecution on the merits continues for claims 1-5, 7-17, 19, and 21. All arguments have been fully considered with the status of each prior ground of rejection set forth below.
Status of Prior Rejections/Response to Arguments
RE: Objection to the Specification
The substitute Specification filed 27 January 2026 is acknowledged and entered into the application file. With that, the substitute Specification removes the shading from Table 2.
Therefore, the objection is withdrawn.
RE: Objection to claims 2, 6-7, 9, 14, and 19
The cancellation of claim 6 renders the objection moot for that claim. For the remaining claims, Applicant’s amendments to each of instant claims 2, 7, 9, 14, and 19 obviate the objections of record.
Therefore, the objections are withdrawn.
RE: Rejection of claims 2-4, 6-9, 11, 14, 19, and 21 under 35 USC 112(b)
The cancellation of claim 6 renders the rejection moot for that claim. For the remaining claims, Applicant has failed to remove the trademarks/trade names from each of instant claims 2, 4, 9, and 11. However, Applicant’s amendments to each of instant claims 2-4, 7-9, 11, 14, 19, and 21 otherwise obviate the remaining rejections of record.
Therefore, the rejections are maintained for claims 2, 4, 9, and 11 and are withdrawn for claims 3, 7-8, 14, 19, and 21.
RE: Rejection of claims 16-17 under 35 USC 101
Applicant has amended independent claim 16 to require at least 80% of the neural progenitor cells to express FOXG1. With that, Applicant has traversed the rejection, asserting in Page 11 of the Remarks filed 27 January 2026 that the recitation of this additional element is substantial to obviate the rejection of record. In response, the Examiner respectfully submits that neural progenitor cells naturally express FOXG1. See, for example, Page 3 and Figure 1 of Hou et al (Front Cell Neurosci, 2020). Accordingly, the purported additional elements do not amount to more than the judicial exception.
Therefore, the rejection is maintained and amended to encompass the claims as written.
RE: Rejection of claims 1-3, 5, 8, 10, 14-17, and 19 under 35 USC 102 over Muotri et al
Applicant has amended independent claim 1 to require the EB medium to comprise (i) a basal medium selected from the group consisting of a) to c): a) KnockOut DMEM/F12 medium alone, b) DMEM/F12 in combination with Neurobasal Medium, c) KnockOut DMEM/F12 medium in combination with Neurobasal Medium; and (ii) supplements comprising or consisting of d) or e): d) N-2 Supplement and GlutaMAX-I Supplement, e) N-2 Supplement, GlutaMAX-I Supplement and B-27 Supplement, minus vitamin A; wherein the EB medium further comprises inhibitors, wherein the inhibitors comprise or consist of a BMP inhibitor, an AMPK inhibitor and an ALK inhibitor. As these limitations were previously presented in instant claims 6-7, these amendments obviate the rejection of record.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1-5, 8, 10, 14-17, and 19 under 35 USC 103 over Muotri et al in view of Lim et al
Applicant has amended independent claim 1 to require the EB medium to comprise (i) a basal medium selected from the group consisting of a) to c): a) KnockOut DMEM/F12 medium alone, b) DMEM/F12 in combination with Neurobasal Medium, c) KnockOut DMEM/F12 medium in combination with Neurobasal Medium; and (ii) supplements comprising or consisting of d) or e): d) N-2 Supplement and GlutaMAX-I Supplement, e) N-2 Supplement, GlutaMAX-I Supplement and B-27 Supplement, minus vitamin A; wherein the EB medium further comprises inhibitors, wherein the inhibitors comprise or consist of a BMP inhibitor, an AMPK inhibitor and an ALK inhibitor. As these limitations were previously presented in instant claims 6-7, these amendments obviate the rejection of record.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1-3, 5-8, 10, 14-17, 19, and 21 under 35 USC 103 over Muotri et al in view of Tan et al and Matsumoto et al
The cancellation of claim 6 renders the rejection moot for that claim. For the remaining claims, Applicant’s arguments filed 27 January 2026 have been fully considered but they are not persuasive.
Applicant has traversed the rejection, asserting in Pages 12-13 of the Remarks filed 27 January 2026 that the technical problem of Muotri et al and Tan et al differ from that of the instant disclosure, as the instant disclosure is concerned with the generation of NPCs with forebrain fate. In response, the Examiner respectfully submits that the features upon which Applicant relies (i.e., forebrain-fated NPCs) are not recited in the rejected claims. 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). Accordingly, the cited references read on the instantly claimed method, which is broadly directed to a method of generating NPCs from ESCs or iPSCs.
Applicant has further traversed the rejection, asserting in Pages 13-17 that Muotri et al and Tan et al fail to individually disclose the recited embryoid body medium and supplements. In response, the Examiner respectfully submits that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Tan et al was a secondary reference utilized to teach an embryoid body medium that has a basal medium comprising DMEM/F12 and Neurobasal media.
Applicant has further traversed the rejection, asserting in Page 18 of the Remarks filed 27 January 2026 that the ordinary artisan would not have been motivated to combine Muotri et al and Tan et al because of their differing objectives, which respectively are the formation of cortical organoids and dopaminergic neurons. In response, the Examiner respectfully submits that the one of ordinary skill in the art before the effective filing date of the invention would have been motivated to utilize an embryoid body culture medium that supports the formation of dopaminergic neurons, as Muotri et al disclose the testing of drugs that affect dopamine levels within the cortical organoids, and would have had a reasonable expectation of success since the disclosures of both Muotri et al and Tan et al are concerned with the intermediate generation of NPCs via the formation of embryoid bodies derived from iPSCs. Furthermore, the ordinary artisan would have recognized that the combination of DMEM/F12 and Neurobasal medias as disclosed in Tan et al are serum-free medias (Muotri et al: Paragraphs [0008], [0049]), and can be supplemented with GlutaMAX, N2, and B27 as serum replacements using principles and techniques well-known in the art (Matsumoto et al: Paragraphs [0140]). See Page 20 of the Office action filed 04 November 2025.
Applicant has lastly traversed the rejection, asserting in Pages 18-19 of the Remarks filed 27 January 2026 that the mediums in Muotri et al are not considered clinical grade. In response, the Examiner respectfully submits that Muotri et al disclose that the intermediate NPCs are cultured in the mediums and formed into cortical organoids, which are utilized for preclinical use. See Paragraphs [0007], [0047], [0052], [0066], [0069], [0140]-[0141] of Muotri et al. As this adheres to Applicant’s definition of “clinical grade” within Paragraph [0053] of the instant Specification, the mediums of Muotri et al are considered to be “clinical grade”.
Therefore, the rejection is maintained and amended to encompass the claims as written.
RE: Rejection of claims 1-3, 5, 8-10, 14-17, and 19 under 35 USC 103 over Muotri et al in view of Lee et al
Applicant has amended independent claim 1 to require the EB medium to comprise (i) a basal medium selected from the group consisting of a) to c): a) KnockOut DMEM/F12 medium alone, b) DMEM/F12 in combination with Neurobasal Medium, c) KnockOut DMEM/F12 medium in combination with Neurobasal Medium; and (ii) supplements comprising or consisting of d) or e): d) N-2 Supplement and GlutaMAX-I Supplement, e) N-2 Supplement, GlutaMAX-I Supplement and B-27 Supplement, minus vitamin A; wherein the EB medium further comprises inhibitors, wherein the inhibitors comprise or consist of a BMP inhibitor, an AMPK inhibitor and an ALK inhibitor. As these limitations were previously presented in instant claims 6-7, these amendments obviate the rejection of record.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1-3, 5, 8, 10-17, and 19 under 35 USC 103 over Muotri et al in view of Gibco
Applicant has amended independent claim 1 to require the EB medium to comprise (i) a basal medium selected from the group consisting of a) to c): a) KnockOut DMEM/F12 medium alone, b) DMEM/F12 in combination with Neurobasal Medium, c) KnockOut DMEM/F12 medium in combination with Neurobasal Medium; and (ii) supplements comprising or consisting of d) or e): d) N-2 Supplement and GlutaMAX-I Supplement, e) N-2 Supplement, GlutaMAX-I Supplement and B-27 Supplement, minus vitamin A; wherein the EB medium further comprises inhibitors, wherein the inhibitors comprise or consist of a BMP inhibitor, an AMPK inhibitor and an ALK inhibitor. As these limitations were previously presented in instant claims 6-7, these amendments obviate the rejection of record.
Therefore, the rejection is withdrawn.
New/Maintained Grounds of Rejection
Claim Objections
Claims 1 and 12 are objected to because of the following informalities:
Regarding claim 1: The instant claim is objected to for having a semicolon following part d) instead of a comma.
Appropriate correction is required.
Regarding claim 12: Each claim should begin with a capital letter and end with a period. Periods may not be used elsewhere in the claims except for abbreviations. See MPEP § 608.01(m). Therefore, the extraneous periods within “N.sup.6, O.sup.2'-Dibutyryl Adenosine 3',5' cyclic- monophosphate sodium salt” in Line 3 need to be removed, and the recitation needs to be reverted back to its “N6, O2'-Dibutyryl Adenosine 3',5' cyclic- monophosphate sodium salt” form.
Appropriate correction is required.
Claim Interpretation
The transitional term “including” recited in instant claim 1 is defined by Applicant to be
synonymous with “comprising”. See Paragraph [0052] of the instant Specification. Therefore, the claim language is inclusive or open-ended and may include additional, unrecited elements or method steps. See MPEP § 2111.03(I).
The term “clinical grade” as recited in instant claims 1, 3, 8, and 21 is defined by Applicant to indicate that “such an agent, medium, or cell-derived material is suitable for clinical use per se, and/or allows directed differentiation of stem cells, in particular embryonic stem cells or induced pluripotent stem cells so as to generate safe and stable cells, especially hNPCs suitable for clinical use.” See Paragraph [0053] of the instant Specification.
Instant claim 16 is directed to NPCs generated by the method of claim 1, or cells derived therefrom, wherein at least 80% of the NPCs are FOXG1+. With that, instant claim 19 is directed to a method of generating neurons, astrocyte progenitor cells, astrocytes, oligodendrocyte progenitor cells, oligodendrocytes, or a mixed cell population comprising one or more of those cells from the NPCs generated by the method of claim 1, wherein at least 80% NPCs are FOXG1+ NPCs. These are product-by-process limitations. Product-by-process limitations are considered only in so far as the method of production affects the structure of the final product. In the instant case, there is no evidence that the production method of instant claim 1 imparts any particular structure or significance to the NPCs, other than requiring the NPCs to express FOXG1. Thus, the claims will be interpreted as if NPCs derived from any source or production method fulfills the recited claim limitation, so long as the NPCs express FOXG1. See MPEP § 2113.
Furthermore, instant claim 17 recites an intended use limitation. Intended use limitations are considered only in so far as they physically limit the claimed NPCs. Therefore, so long as the NPCs are physically capable of being configured for use in the instantly recited applications, they will read on the claim as written.
Claim Rejections - 35 USC § 112
Claims 1-5, 7-17, 19, and 21 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1: Instant claim 1 contains the trademark/trade names “KnockOut™ DMEM/F12 medium”, “Neurobasal™ Medium”, “GlutaMAX™-I Supplement”, and “B-27™ Supplement”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names are used to identify/describe cell culture mediums or cell culture supplements and, accordingly, the identification/description of each is indefinite.
Instant claims 2-5, 7-17, 19, and 21 are included within the rejection because the depend from or fully incorporate the limitations of rejected parent claim 1.
Appropriate correction is required.
Regarding claim 2: The instant claim contains the trademark/trade name “CTS™ grade”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a certain product for cell therapy manufacturing that has high quality and meets the cGMP standards and, accordingly, the identification/description is indefinite. See Paragraph [0055] of the instant Specification.
Appropriate correction is required.
Regarding claim 4: The instant claim contains the trademark/trade names “NutriStem® hPSC XF Medium”, “CTS™ Essential 8 Medium”, “StemFit® Basic03”, “StemMACS™ iPSC-Brew”, “Stem-Partner® ACF”, “TeSR™-AOF”, and “TeSR™2”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names are used to identify/describe stem cell culture mediums and, accordingly, the identification/description of each is indefinite.
Appropriate correction is required.
Regarding claim 9: The instant claim contains the trademark/trade names “KnockOut™ DMEM/F12 medium”, “Neurobasal™ Medium”, “GlutaMAX™-I Supplement”, and “B-27™ Supplement”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names are used to identify/describe cell culture mediums or cell culture supplements and, accordingly, the identification/description of each is indefinite.
Appropriate correction is required.
Regarding claim 11: The instant claim contains the trademark/trade names “Neurobasal™ Medium”, “GlutaMAX™-I Supplement”, and “B-27™ Supplement”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names are used to identify/describe cell culture medium or cell culture supplements and, accordingly, the identification/description of each is indefinite.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 16-17 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to a nature-based product without significantly more.
Claim 16 is directed to neural progenitor cells (NPCs) that are produced by the production method according to claim 1, or cells derived therefrom, wherein at least 80% of the NPCs are FOXG1+. Instant claim 16 comprises a product-by-process limitation, as can be observed in the Claim Interpretation section above and is incorporated in its entirety herein.
The test for 101 eligibility of judicial exceptions can be found at MPEP § 2106:
“First, the claimed invention must be to one of the four statutory categories. 35 U.S.C. 101 defines the four categories of invention that Congress deemed to be the appropriate subject matter of a patent: processes, machines, manufactures and compositions of matter.”
“Second, the claimed invention also must qualify as patent-eligible subject matter, i.e., the claim must not be directed to a judicial exception unless the claim as a whole includes additional limitations amounting to significantly more than the exception. The judicial exceptions (also called "judicially recognized exceptions" or simply "exceptions") are subject matter that the courts have found to be outside of, or exceptions to, the four statutory categories of invention, and are limited to abstract ideas, laws of nature and natural phenomena (including products of nature). Alice Corp. Pty. Ltd. v. CLS Bank Int'l, 573 U.S. 208, 216, 110 USPQ2d 1976, 1980 (2014) (citing Ass'n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 589, 106 USPQ2d 1972, 1979 (2013).”
“The Supreme Court in Mayo laid out a framework for determining whether an applicant is seeking to patent a judicial exception itself, or a patent-eligible application of the judicial exception. See Alice Corp., 573 U.S. at 217-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. 66, 101 USPQ2d 1961). This framework, which is referred to as the Mayo test or the Alice/Mayo test, is discussed in further detail in subsection III, below. The first part of the Mayo test is to determine whether the claims are directed to an abstract idea, a law of nature or a natural phenomenon (i.e., a judicial exception). Id. If the claims are directed to a judicial exception, the second part of the Mayo test is to determine whether the claim recites additional elements that amount to significantly more than the judicial exception. Id. citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966). The Supreme Court has described the second part of the test as the "search for an 'inventive concept'". Alice Corp., 573 U.S. at 217-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966).”
Examiners should determine whether a claim satisfies the criteria for subject matter eligibility by evaluating the following steps outlined in a flow chart at MPEP 2106(III) and 2106.04(II)(A):
Step 1: is the Claim to a process, machine, manufacture or composition of matter? If Yes, proceed to Step 2A;
Step 2A, prong one: Is the Claim directed to a law of nature, a natural phenomenon (product of nature), or an abstract idea? If Yes, proceed to Step 2A, prong two;
Step 2A, prong two: Does the claim recite additional elements that integrate the judicial exception into a practical application? If No, proceed to Step 2B;
Step 2B: Does the claim recite additional elements that amount to significantly more (an inventive concept) than the judicial exception? If No, the claim is not eligible subject matter under 35 USC 101.
With regard to Step 1: YES, the claim is directed to a composition of matter, or product.
With regard to Step 2A, prong one: YES, the claim is directed to neural progenitor cells (NPCs), which are nature-based products. More specifically, since the instantly claimed NPCs comprise product-by-process limitations – see Claim Interpretation section above – the claimed NPCs are compared to the closest naturally occurring counterpart, which are NPCs, per se. Thus, there is no marked different between the claim and product of nature, as NPCs in nature express FOXG1. See, for example, Page 3 and Figure 1 of Hou et al (Front Cell Neurosci, 2020).
With regard to Step 2A, prong two: No, the claim does not include any additional elements that integrate the judicial exceptions into a practical application. Integration into a practical application requires additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the exception.
The claims do not modify or transform the naturally occurring NPCs, nor apply the cells for a particular treatment or medical condition, nor imposes a meaningful limit on the cells recited therein. In regards to the percentage of NPCs required to express FOXG1, the enrichment or isolation of NPCs that naturally express FOXG1 does not impose a meaningful limit on the judicial exception, as it is not structurally modifying the NPCs or integrating the NPCs into a practical application.
With regard to Step 2B: No, the claim does not provide any additional elements that amount to significantly more (an inventive concept) than the judicial exception.
Taken together, the claim encompasses a natural product. The judicial exception is not integrated into practical applications as iterated above. The claim does not include additional elements
that are sufficient to amount to significantly more than the judicial exception as iterated above.
Claim 17 is included in the rejection because it fully incorporates the limitations of rejected claim 16.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 16-17 and 19 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Ramirez et al (US 2022/0233602 A1). Ramirez et al has an effective filing date of 23 December 2019.
Ramirez et al disclose highly pure neural stem cell populations, a method for obtaining such a highly pure stem cell-derived line of neural stem cells, such as a neural stem cell line derived from human embryonic stem cells (Abstract).
As such, Ramirez et al disclose populations of neural progenitor cells (NPCs), wherein at least 80% of the NPCs are quadruple positive for OTX2/PAX6/SOX2/FOXG1 (Paragraphs [0050]-[0051], [0053], [0073]-[0076], [0105]-[0108], [0163], [0171], [0368], [0370]).
Ramirez et al further disclose that the NPCs are generated in Nutristem® hPSC XF Medium (Paragraphs [0017], [0085]-[0091], [0349], [0351]). It is of note that Nutristem® hPSC XF Medium is inherently of clinical grade, as evidenced by Paragraph [0010] of the instant disclosure.
Ramirez et al further disclose that the NPCs are differentiated into cells of the neuroectodermal lineage, including neurons, astrocytes, and oligodendrocytes (Paragraphs [0035], [0075], [0175], [0294]-[0297]).
Accordingly, Ramirez et al anticipate the claims as follows:
Regarding claim 16: The instant claim comprises product-by-process language. The effect of the
product-by-process language is discussed above – see Claim Interpretation – and is incorporated herein in its entirety.
Accordingly, Ramirez et al disclose populations of NPCs, wherein at least 80% of the NPCs are quadruple positive for OTX2/PAX6/SOX2/FOXG1. This therefore reads on the NPCs of the instant claim.
Regarding claim 17: As aforementioned in the discussion of claim 16, Ramirez et al disclose NPCs. As the NPCs are physically capable, or suitable, for use in drug development, pre-clinical use, or clinical use, this therefore anticipates the NPCs of the instant claim for the same reasons as discussed in the rejection of instant claim 16. See Claim Interpretation section for the discussion of the intended use limitation.
Regarding claim 19: The instant claim comprises product-by-process language. The effect of the
product-by-process language is discussed above – see Claim Interpretation – and is incorporated herein in its entirety.
Accordingly, as aforementioned, Ramirez et al disclose populations of neural progenitor cells (NPCs), wherein at least 80% of the NPCs are quadruple positive for OTX2/PAX6/SOX2/FOXG1.
Ramirez et al further disclose that the NPCs are generated in Nutristem® hPSC XF Medium. It is of note that Nutristem® hPSC XF Medium is inherently of clinical grade, as evidenced by Paragraph [0010] of the instant disclosure.
Ramirez et al further disclose a method of differentiating the NPCs into cells of the neuroectodermal lineage, including neurons, astrocytes, and oligodendrocytes.
This therefore reads on the method of the instant claim.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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 1-3, 5, 7-8, 10, 14-15, and 21 remain rejected under 35 U.S.C. 103 as being unpatentable over Muotri et al (US 2020/0348287 A1, of record) in view of Tan et al (Bio-protocol Exchange, 2018, of record) and Matsumoto et al (US 2019/0024047 A1, of record on IDS filed 20 June 2023).
Muotri et al is considered prior art under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2). Tan et al is considered prior art under 35 U.S.C. 102(a)(1). Matsumoto et al is considered prior art under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2).
Regarding claims 1, 7, and 21: Muotri et al disclose methods of making functional cortical organoids from stem cells, and methods of using the functional organoids (Abstract).
As such, Muotri et al first disclose a method of generating neural progenitor cells, wherein iPSCs are originally cultured in mTESR™1 media, switched to Neurobasal media supplemented with at least GlutaMAX, N2, dorsomorphin, and SB431542 to allow the formation and culture of embryoid bodies, plated on Matrigel-coated dishes and cultured in supplemented DMEM/F12 media to allow the formation of rosettes, maintained in the supplemented DMEM/F12 media until neurospheres are developed, and dissociated into single cells, wherein the single cells are neural progenitor cells that are plated on poly-L-lysine/Laminin-coated culture plates and allowed to form a monolayer while maintained in supplemented Neurobasal media (Paragraphs [0008], [0067]-[0069], [0092], [0140]-[0141]; Figure 1B). Muotri et al then disclose that the neural progenitor cells are subsequently cultured in serum-free Neurobasal media comprising BDNF, GDNF, neutropin-3, a fibroblast growth factor, L-ascorbic acid, and dibutyryl-cAMP to allow the formation of functional cortical organoids (Paragraphs [0008]-[0009], [0055], [0059], [0066]-[0068], [0070]-[0071], [0092]; Figure 1B).
It is of note that Muotri et al disclose that the basal mediums and supplements are from suppliers including STEMCELL Technologies and ThermoFisher Scientific (Gibco) (Paragraphs [0047], [0052], [0066], [0069], [0140]-[0141]). The instant Specification discloses that the same basal mediums and supplements are inherently at least cGMP grade. See Paragraph [0079] and Table 1 of the instant Specification. In addition, Muotri et al disclose that the generated cerebral organoids are used in pre-clinical testing (Paragraph [0007]), which further supports that the basal mediums and supplements are inherently clinical grade given the definition provided by Applicant in the Claim Interpretation section above.
Muotri et al further disclose that the resulting cerebral organoids comprise neurons of the upper cortex, and can be used for testing drugs that affect dopamine levels (Paragraphs [0076], [0157]; Figures 1N, 2C).
Muotri et al do not disclose that the embryoid body Neurobasal medium is in combination with DMEM/F12, as required by instant claim 1.
Tan et al, however, disclose the differentiation of iPSCs into dopaminergic neurons, wherein iPSCs are formed into embryoid bodies and cultured in a combination of DMEM/F12 media and Neurobasal media supplemented with N2 and B27 (Page 1).
Therefore, it would have been prima facie obvious to have modified the method of Muotri et al such that the EBs are cultured in a basal medium comprising a combination of DMEM/F12 and Neurobasal medias, as detailed in Tan et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to utilize an embryoid body culture medium that supports the formation of dopaminergic neurons, as Muotri et al disclose the testing of drugs that affect dopamine levels, and would have had a reasonable expectation of success since the disclosures of both Muotri et al and Tan et al are concerned with the intermediate generation of NPCs via the formation of embryoid bodies derived from iPSCs. Furthermore, the ordinary artisan would have recognized that the combination of DMEM/F12 and Neurobasal medias as disclosed in Tan et al are serum-free medias (Muotri et al: Paragraphs [0008], [0049]), and can be supplemented with GlutaMAX, N2, and B27 as serum replacements using principles and techniques well-known in the art (Matsumoto et al: Paragraphs [0140]). This further supports the conclusion that the ordinary artisan would have a reasonable expectation of success in culturing the EBs in a combination of DMEM/F12 and Neurobasal medias that have been supplemented with at least GlutaMAX and N2. See MPEP § 2143(I)(G).
Consequently, Muotri et al as modified by Tan et al and Matsumoto et al render obvious a method of generating neural progenitor cells (NPCs), wherein iPSCs are originally cultured in mTESR™1 media (hPSC medium), switched to a combination of Neurobasal media and DMEM/F12 media that has been supplemented with GlutaMAX, N2, dorsomorphin, and SB431542 (EB medium) (claim 7) to allow the formation and culture of embryoid bodies (EBs), plated on Matrigel-coated dishes and cultured in supplemented DMEM/F12 media (NIM) to allow the formation of rosettes, maintained in the supplemented DMEM/F12 media until neurospheres are developed, and dissociated into single cells, wherein the single cells are neural progenitor cells that are plated on poly-L-lysine/Laminin-coated culture plates and allowed to form a monolayer while maintained in supplemented Neurobasal media (NPC medium). As the basal mediums and supplements are all inherently cGMP grade (claims 2-3, 21), this therefore reads on the method of instant claim 1.
Regarding claim 5 and 8: Following the discussion of claim 1, Muotri et al further disclose that the mTESR™1 media (hPSC medium) is supplemented with ROCK inhibitors, including at least Y-27632 from Sigma-Aldrich (Paragraph [0068]). As the ROCK inhibitors are inherently clinical grade (claim 8) due to the fact the resulting NPCs and differentiated cortical organoids are used for clinical means – see Claim Interpretation section above – this therefore reads on the method of instant claim 5.
Regarding claim 10: As aforementioned in the discussion of claim 1, Muotri et al disclose that the neural rosettes are maintained in the supplemented DMEM/F12 media (NIM) until neurospheres are developed. This therefore reads on the method of the instant claim.
Regarding claim 14: Following the discussion of claim 1, Muotri et al further disclose that the iPSCs are initially dissociated using Accutase prior to the formation of embryoid bodies (Paragraphs [0068], [0141]). This therefore reads on the method of the instant claim.
Regarding claim 15: Following the discussion of claim 1, Muotri et al further disclose that the EBs are formed using two different culture mediums (Paragraphs [0008], [0092], [0140]). This therefore reads on the method of the instant claim.
Claims 1-5, 7-8, 10, 14-15, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Muotri et al (US 2020/0348287 A1, of record) in view of Tan et al (Bio-protocol Exchange, 2018, of record) and Matsumoto et al (US 2019/0024047 A1, of record on IDS filed 20 June 2023), and further in view of Lim et al (Int J Stem Cells, 2019, of record).
The discussion of Muotri et al as modified by Tan et al and Matsumoto et al regarding claim 1
can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Muotri et al as modified by Tan et al and Matsumoto et al render obvious claims 1-3, 5, 7-8, 10, 14-15, and 21. Lim et al is considered prior art under 35 U.S.C. 102(a)(1).
Regarding claim 4: As aforementioned in the discussion of claim 1 above, Muotri et al disclose culturing the iPSCs in mTESR™1 media.
The combination of Muotri et al, Tan et al, and Matsumoto et al fail to teach the culturing of the iPSCs in NutriStem® hPSC XF Medium, CTS™ Essential 8 Medium, StemFit® Basic03, StemMACS™ iPSC-Brew, Stem-Partner® ACF, TeSR™-AOF, or TeSR™2, as required by instant claim 4.
Lim et al, however, disclose that TeSR™2 is the next version of mTESR™1 media for the culture and maintenance of iPSCs (Page 486, Column 1; Table 2).
Therefore, it would have been prima facie obvious to have substituted the mTESR™1 media of Muotri et al for the TeSR™2 media as detailed in Lim et al, as doing so would have been a simple substitution of one known iPSC culture medium for another. See MPEP § 2143(I)(B). One of ordinary skill in the art before the effective filing date of the invention would have recognized that the two iPSC culture mediums are functionally comparable, as both allow for the culture of iPSCs on extracellular matrix supports (Lim et al: Table 2), and would have thereby been able to substitute the iPSC culture mediums with predictable results.
Consequently, Muotri et al as modified by Tan et al, Matsumoto et al, and Lim et al render obvious a method of generating NPCs, wherein iPSCs are initially cultured in TeSR™2 media. This therefore renders obvious the method of the instant claim.
Claims 1-3, 5, 7-10, 14-15, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Muotri et al (US 2020/0348287 A1, of record) in view of Tan et al (Bio-protocol Exchange, 2018, of record) and Matsumoto et al (US 2019/0024047 A1, of record on IDS filed 20 June 2023), and further in view of Lee et al (US 2017/0266235 A1, of record on IDS filed 05 August 2025).
The discussion of Muotri et al as modified by Tan et al and Matsumoto et al regarding claim 1
can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Muotri et al as modified by Tan et al and Matsumoto et al render obvious claims 1-3, 5, 7-8, 10, 14-15, and 21. Lee et al is considered prior art under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2).
Regarding claim 9: As aforementioned in the discussion of claim 1 above, Muotri et al disclose that the EBs are cultured in supplemented DMEM/F12 media. Muotri et al further disclose that the supplements include GlutaMAX and N2 (Paragraph [0141]).
The combination of Muotri et al, Tan et al, and Matsumoto et al fail to teach that the DMEM/F12 media is KnockOut DMEM/F12, as required by instant claim 9.
Lee et al, however, disclose methods for obtaining neural progenitor cells from stem cells, wherein the culture medium for inducing the neural differentiation of embryoid bodies into neural rosettes comprises DMEM/F12 or KO-DMEM/F12 (Abstract; Paragraph [0028]).
Therefore, it would have been prima facie obvious to have substituted the DMEM/F12 basal medium of Muotri et al for the KO-DMEM/F12 basal medium as detailed in Lee et al, as doing so would have been a simple substitution of one known neural induction basal mediums for another. See MPEP § 2143(I)(B). One of ordinary skill in the art before the effective filing date of the invention would have recognized that the two neural induction basal mediums are functionally comparable, as they are listed as equal alternatives within the disclosure of Lee et al, and would have thereby been able to substitute the neural induction basal mediums with predictable results.
Consequently, Muotri et al as modified by Tan et al, Matsumoto et al, and Lee et al render obvious a method of generating NPCs, wherein EBs are cultured in KO-DMEM/F12 media that has been supplemented with N2 and GlutaMAX. This therefore renders obvious the method of the instant claim.
Claims 1-3, 5, 7-8, 10-15, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Muotri et al (US 2020/0348287 A1, of record) in view of Tan et al (Bio-protocol Exchange, 2018, of record) and Matsumoto et al (US 2019/0024047 A1, of record on IDS filed 20 June 2023), and further in view of Gibco (B-27™ Supplement without Vitamin A Technical Document, 2015, of record).
The discussion of Muotri et al as modified by Tan et al and Matsumoto et al regarding claim 1
can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Muotri et al as modified by Tan et al and Matsumoto et al render obvious claims 1-3, 5, 7-8, 10, 14-15, and 21. Gibco is considered prior art under 35 U.S.C. 102(a)(1).
Regarding claim 11: As aforementioned in the discussion of claim 1, Muotri et al disclose that the NPCs are cultured in supplemented Neurobasal media. Muotri et al further disclose that the supplements include GlutaMAX (Paragraphs [0092], [0141]).
The combination of Muotri et al, Tan et al, and Matsumoto et al fail to teach that the Neurobasal medium is further supplemented with B-27 without vitamin A, as required by instant claim 11.
Gibco, however, discloses that B-27™ Supplement without Vitamin A is ideal for the cultivation of neural progenitor and stem cells, either as neurospheres in suspension or in adherent monolayer culture. With that, Gibco further discloses that the supplement is intended to be used with Neurobasal media (Page 1, Description).
Therefore, it would have been prima facie obvious to have modified the method of Muotri et al, Tan et al, and Matsumoto et al such that the NPC culture medium further comprises B-27 without vitamin A, as suggested by Gibco. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to utilize a culture medium comprising supplements that are known in the art for supporting neural progenitor cell culture, and would have had a reasonable expectation of success since the B-27 without vitamin A supplement is intended to be used with Neurobasal media – which is the basal medium for the NPC culture medium of Muotri et al. See MPEP § 2143(I)(G).
Consequently, Muotri et al as modified by Tan et al, Matsumoto et al, and Gibco render obvious a method of generating NPCs, wherein the NPCs are cultured in Neurobasal medium supplemented with GlutaMAX and B-27 without vitamin A. This therefore renders obvious the method of the instant claim.
Regarding claims 12-13: Following the discussion of claim 11, Muotri et al further disclose that the NPCs are cultured in Neurobasal media supplemented with at least BDNF and GDNF (claim 12), wherein the BDNF and GDNF are sourced from PeproTech (Paragraphs [0059], [0070], [0092]). As the instant Specification defines the BDNF and GDNF from PeproTech as being Animal-Free Recombinant BDNF and GDNF – see Paragraph [00101] of the instant Specification – this therefore reads on the method of instant claim 13. See MPEP § 2112.
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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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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