DETAILED ACTION
Claims 1-27, 29-68, 71-78, 80-97, and 99 are currently pending.
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 .
Election/Restrictions
Applicant’s election without traverse of Invention Group 1 (claims 1-16) in the reply filed on 5/29/2026 is acknowledged.
Claims 17-27 and 29-68, 71-78, 80-97, and 99 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/29/2026.
Priority
Acknowledgement is made of the instant application being a national stage entry under 35 USC 371 of international application PCT/US2022/032146, filed 6/3/2022, which claims the benefit of provisional application No. 63/197,007, filed 6/4/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 3/25/2024 and 5/29/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
The listing of references in the specification (pages 83-90) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The use of the terms Neurobasal™ medium and B-27™, for example, are trade names or a mark used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 9 and 10 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 9 recites the limitation “wherein the amount of time required to obtain an astrocyte is reduced relative to a comparator” and claim 10 recites the limitation “wherein a comparator comprises an otherwise similar method using induced pluripotent stem cells (iPSC) to obtain an astrocyte.”
Upon review of the specification, the specification shows that Applicants have not provided sufficient description of the invention to support they were in possession of a method of obtaining at least one astrocyte wherein the amount of time required to obtain an astrocyte is reduced relative to a comparator, wherein the comparator comprises an otherwise similar method using induced pluripotent stem cells.
In the instant case the only references in the specification to obtaining astrocytes by differentiation of gingiva-derived mesenchymal stem cells are directed to conducting culturing with a first medium for about 65-80 hours, and conducting culturing with a second medium for an additional 65-80 hours, i.e., 5-7 days (Specification at pages 2, 25 and 55). The specification at page 52 discloses the GMSC-to-astrocyte process takes only a fraction of the time compared to iPSCs since the step of dedifferentiation to iPSCs is unnecessary, thus the specification supports the amount of time required for the claimed method to obtain an astrocyte is less than methods that require dedifferentiation of cells to obtain induced pluripotent stem cells.
A review of the specification shows that Applicants have not provided sufficient description of the invention to support they were in possession of conducting a comparative culture with induced pluripotent stem cells to obtain astrocytes.
Accordingly, the claims are considered to lack sufficient written description and are properly rejected under 35 USC 112, first paragraph.
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 9-10 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.
Claim 9 recites the limitation “wherein the amount of time required to obtain an astrocyte is reduced relative to a comparator” and claim 10 recites the limitation “wherein a comparator comprises an otherwise similar method using induced pluripotent stem cells (iPSC) to obtain an astrocyte.”
The limitation “reduced relative to a comparator” in claim 9 is a relative limitation which renders the claim indefinite. The limitation directed to the “comparator” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Although the specification at page 25 discloses a comparator comprises an otherwise similar method using induced pluripotent stem cells (iPSC) to obtain an astrocyte, the specification does not further describe in what way the comparator method is similar. Is it similar in requiring the same first medium, or requiring the same second medium, or in requiring contacting with the first medium for about 72 hours, or requires contacting with the second medium for about 72 hours.
Given the specification does not define what is meant by “an otherwise similar method”, one of ordinary skill in the art would not understand the metes and bounds of the reduction of time relative to a comparator.
In the interest of compact prosecution, given the specification at page 52 discloses the GMSC-to-astrocyte process takes only a fraction of the time compared to iPSCs since the step of dedifferentiation to iPSCs is unnecessary, it is noted that claim 9 is interpreted as the amount of time required for the claimed method to obtain an astrocyte is less than methods that require dedifferentiation of cells to obtain induced pluripotent stem cells.
Claim 10 is rejected based on its dependency to claim 9.
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.
Claim(s) 1-12 and 15-16 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Pitaru et al., (US 2014/0335059, published Nov. 13, 2014; PTO-892) (“Pitaru”).
Pitaru is directed to methods and uses of neural cells differentiated from adult stem cells of the oral mucosa for cell therapy of neurological and psychiatric diseases and disorders. Methods include directed differentiation of oral mucosal stem cells into neuronal or neuron supporting cells (Abstract).
Regarding claims 1-3 and 6-7, Pitaru, at [0199], teaches a two-step differentiation method for induction of neuron support cells from hOMSCs (human oral mesenchymal stem cells). Pitaru teaches the oral MSCs are obtained from the lamina propria of the human gingiva and are thus considered gingiva-derived mesenchymal stem cells (GDMSCs), and read on “providing at least one gingiva-derived mesenchymal stem cell” ([0187] and [0195]).
Pitaru (at [0199] and claims 43-44) teaches the first step of the differentiation method incubates (i.e., contacting) the provided GDMSCs for 72 hours (i.e., lies within claimed range) (claim 2) in the first medium (DMEM low glucose/SPN/Glutamine) comprising serum-free conditions with the addition of N2 supplement, basic Fibroblast Growth Factor 2 (bFGF) and Epidermal Growth Factor (EGF), each at a 20 ng/mL final concentration (claim 1, step (i) and claim 6).
As to claim 1(b), step (ii), Pitaru ([0199] and claims 43-44) teaches contacting the GDMSCs with a second serum-free medium (DMEM low glucose/SPN/Glutamine) following the first 72-hour incubation and the serum-free medium comprises 1 mM dbcAMP (dibutyryl cyclic adenosine monophosphate), 0.5 mM IBMX (3-isobutyl-1-methylxanthine), Neuregulin (50 ng/mL) and PDGF (1 ng/mL) (claim 7). The second incubation step is conducted for 72 hours (i.e., lies within the claimed range) (claim 3).
Pitaru teaches the astrocyte differentiation method produces cells having an astrocyte-like morphology and phenotype as demonstrated by increased expression of specific astrocyte markers, i.e., GFAP, S100β and Glt1 (FIGS 6A and 6B, [0115], [0126] and [0219]), i.e., conditions sufficient to induce differentiation of the GDMSC into an astrocyte.
Thus, Pitaru’s disclosed method anticipates instant claims 1-3 and 6-7.
Regarding claims 4-5, Pitaru ([0199]) teaches the first and second mediums further comprise glutamine, i.e., an amino acid supplement, thus anticipating claims 4-5.
Regarding claim 8, Pitaru ([0183]) teaches the disclosed GDMSCs differentiated into osteoblastic and adipocytic lineages as reflected by the formation of alizarin red and oil red positive cultures, thus anticipating claim 8.
Regarding claims 9-11, it is noted that Pitaru teaches the first stage of culturing is conducted for about 72 hours (3 days) and the second stage of culturing is conducted for 72 hours (3 days), i.e., amount of time to obtain an astrocyte is less than 1 week (claim 11).
As to claims 9 and 10 and the limitations “wherein the amount of time required to obtain an astrocyte is reduced relative to a comparator” (claim 9), and “wherein a comparator comprises an otherwise similar method using induced pluripotent stem cells (iPSC) to obtain an astrocyte” (claim 10), it is noted as discussed above at the rejection of claims 9-10 under 35 USC 112, claim 9 is interpreted as the amount of time required for the claimed method to obtain an astrocyte is less than methods that require dedifferentiation of cells to obtain induced pluripotent stem cells.
It is noted that Pitaru does not comment on reducing the amount of time to obtain an astrocyte. However, although Pitaru does not comment on reduction of the amount of time to obtain an astrocyte, as compared to a similar method using induced pluripotent stem cells, the fact that Pitaru employs the same two-step differentiation method as the instant application (pages 23-25) means that any and all results of the method of Pitaru, whether recognized at the time of publication or not, were inherently achieved by the reference method. MPEP 2112.01
Regarding claim 12, Pitaru teaches the obtained astrocytes express GFAP, S-100 beta and GLT-1 ([0219]), thus anticipating claim 12.
Regarding claim 15-16, Pitaru teaches the method employs human oral mucosa stem cells (hOMSC) derived from gingival lamina propria (GDMSCs) and immunophenotyping of hOMSC revealed a primitive neural crest stem cell (NCSC) phenotype, which is not affected by adult donor age, wherein the results obtained from 3 donors indicated that more than 95% (claimed range overlaps prior art range) of the cells were positive for at least two mesenchymal stem cell markers, demonstrating that essentially the entire population of gingival lamina propria consist of multipotent stem cells and thus are cranial neural crest derived MSCs ([0017], [0123]-[0125], [0183] and [0187]), therefore anticipating claim 15.
As to claim 16 and the recited limitations, it is noted that Pitaru does not further comment on whether or not the GDMSCs have (i) an increased ability to differentiate into neuronal cells as compared to mesoderm derived mesenchymal stem cells; and/or (ii) have an increased immunomodulatory capacity compared to mesoderm derived mesenchymal stem cells, optionally wherein, the immunomodulatory capacity comprises one or more of: (a) an increase in number and/or activity of T regulatory cells; (b) a decrease in number and/or activity of inflammatory T cells such as Th17 cells; or (c) an increase in number and/or activity of cytotoxic T cells.
However, although Pitaru does not comment on an increased ability to differentiate into neuronal cells or increased immunomodulatory capacity compared to mesoderm derived mesenchymal stem cells, the fact that Pitaru employs the same neural crest-derived mesenchymal stem cells (hOMSCs) means that any and all results of the method of Pitaru, whether recognized at the time of publication or not, were inherently achieved by the reference method. MPEP 2112.01
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.
Claim(s) 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Pitaru, as applied to claims 1-12 and 15-16 above, and further in view of O’Donnell et al., (Neural Regeneration Research 13(8): 1327-1331; IDS 3/25/2024) (“O’Donnell”).
The teaching if Pitaru is set forth above and anticipates claims 1-12 and 15-16.
Regarding claims 13-14, it is noted that Pitaru acknowledges the method for obtaining the astrocyte-like cells provides new stem cells for autologous cell therapies for treating Parkinson’s disease and other neurodegenerative and psychiatric diseases ([0127]).
However, Pitaru does not further teach the astrocytes are capable of forming a bundle of astrocytes, wherein the bundle of astrocytes comprises a structure similar or substantially similar to a structure of an astrocyte in an endogenous rostral migratory stream (claim 13), or wherein the bundle of astrocytes comprises a function similar to or substantially similar to a function of an astrocyte in an endogenous rostral migratory stream (claim 14).
O’Donnell is directed to a tissue-engineered rostral migratory stream (RMS) for directed neuronal replacement since the engineered tissue emulates the dense cord-like bundles of astrocytic somata and processes that are the hallmark anatomical feature of the glial tube, and can therefore serve as an in vitro test bed for unlocking the secrets of neuroblast migration and maturation, and may potentially serve as a living transplantable construct derived from a patient’s own cells that can redirect their own neuroblasts into lesion sites for sustained neuronal replacement following brain injury or neurodegenerative disease (Abstract). O’Donnell teaches the tissue-engineered construct, referred to as microtissue astrocytic constructs (MACs)—may be useful for re-directing migration of endogenous neuroblasts in vivo and could also serve as an anatomically-relevant test bed to study the RMS or accelerate neuroblast maturation in vitro. (Introduction, page 1327). O’Donnell teaches glial tube astrocytes possess a bipolar morphology, extending processes in opposite directions along the RMS in parallel with each other to form a cord-like bundle which has been recapitulated in MACs. The MACs are fabricated by seeding the inner lumen of custom-built, hollow hydrogel micro-columns with dissociated astrocytes, then, over a remarkably short timeframe of just several hours, the astrocytes spontaneously self-assemble into dense cables of longitudinally-aligned astrocytes with bipolar morphology (i.e., a structure similar or substantially similar to a structure of an astrocyte in an endogenous RMS), (Anatomical Inspiration and Characterization to Date, page 1327; Figure 1).
O’Donnell further teaches that RMS made from human induced neural progenitor cells would allow investigators to ask specific questions that are currently untestable (page 1329, right col, first paragraph), the MACs have the potential for promoting neuro-regeneration after injury by amplifying and augmenting the brain’s existing mechanisms for replacing lost neurons in order to achieve levels of neuro-regeneration that are sufficient to improve recovery (page 1330 at Neuroregenration after Injury).
O’Donnell teaches that MACs are the first implantable microtissue constructs designed to redirect the migration of endogenous neuroblasts from the RMS to sites throughout the brain, and O’Donnell teaches their method provides a final cytoarchitecture that mimics the RMS and is fully bio-fabricated in vitro and thereafter precisely delivered to redirect migration of endogenous neuroblasts to sites of neurodegeneration (page 1330 at Implantation of MACs to Enhance Endogenous Neuroregenerative Processes).
O’Donnell’s method demonstrates that MACs facilitate migration of neuroblasts in vitro, and functionally mimic the RMS and are structurally similar with the native glial tube (i.e., a function similar to or substantially similar to a function of an astrocyte in an endogenous RMS). The MACs provide a new strategy for replacing lost neurons since the glial tubes of the RMS are the most efficient means of facilitating neuroblast migration and maturation in the mammalian brain through adulthood, thus MACs can enhance and sustain the brain’s natural regenerative response (Conclusions and Future Directions, pages 1330-1331).
Thus, O’Donnell has established that tissue-engineered MACs, comprising rostral migratory stream (RMS) astrocyte bundles (i.e., a structure similar or substantially similar to a structure of an astrocyte in an endogenous RMS), can be prepared by seeding of astrocytes to micro-column scaffolds and thereafter culturing in serum-free medium (Figure 1). The engineered MACs promote re-direction of the migration of endogenous neuroblasts from the RMS to sites throughout the brain (i.e., a function similar to or substantially similar to a function of an astrocyte in an endogenous RMS), thus redirecting migration of endogenous neuroblasts to sites of neurodegeneration, thus MACs can enhance and sustain the brain’s natural regenerative response.
Therefore, taking into hand the teaching of O’Donnell, and given that Pitaru acknowledges the method for obtaining the astrocyte-like cells provides new stem cells for autologous cell therapies for treating neurodegenerative diseases, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further utilize Pitaru’s astrocytes to form engineered bundles of astrocytes, i.e., MACs, as taught by O’Donnell.
The person of ordinary skill in the art would have been motivated to modify the method of Pitaru to include forming bundles of astrocytes having similar structure and function of native, endogenous RMS, for the predictable result of successfully providing engineered neural structures that promote the redirection and migration of endogenous neuroblasts to sites of neurodegeneration, thus promoting neurological regeneration in subjects in need thereof, thus meeting the limitations of claims 13 and 14.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Pitaru and O’Donnell because each of these teachings are directed at therapeutic uses of astrocytes for treating neurological diseases and disorders.
Conclusion
No clam is allowed. No claim is free of prior art.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, CHRISTOPHER BABIC can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
Prosecution Insights