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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/06/2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of the species EZH2 in the reply filed on 3/11/2025 is acknowledged.
Claims 5-6 and 8-11 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/11/2025.
Claims 2 and 4 are cancelled.
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.
Claims 1, 3, 7, 12, 13, 15, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Windrem et al. (Human Glial Progenitor Cells Effectively Remyelinate the Demyelinated Adult Brain, Cell Reports, 2020) in view of Heinen et al (Histone Methyltransferase Enhancer of Zeste Homolog 2 Regulates Schwann Cell Differentiation, GLIA, 2012) and Sher et al. (Ezh2 Expression in Astrocytes Induces Their Dedifferentiation Toward Neural Stem Cells, Cellular Reprogramming, 2011), as evidenced by Sher et al. (Differentiation of Nerual Stem Cells into Oligodendrocytes: Involvement of the Polycomb Group Protein EZH2, 2008)
Windrem et al. teaches use of the adult Shiverer mouse model (demyelination mouse model) to study the effect of administering human glial progenitor cells (hGPCs) on remyelination of the brains of the animals (pg 4-5, “Resident hGPCs Can Remyelinate the Cuprizone-Demyelinated Corpus Callosum) and if demyelinated axons could be remyelinated. (pg 3, first full paragraph)
Heinen et al. teaches the impact of histone methyltransferase (EZH2) gene on Schwann cell (a type of glial cell) differentiation. In addition to this, Heinen teaches that suppression of EZH2 interferes with in vitro myelination. (pg 1696, Abstract) Heinen teaches that suppression of EZH2 in Schwann cells resulted in impaired cellular maturation, inhibition of myelin gene expression, and decreased myelination in DRG axons. (pg 1704, Discussion)
Sher et al. (2011) teaches that forced expression of EZH2 in cultured astrocytes results in partial dedifferentiation of the cells. (pg 1, Abstract) This led to increased cell proliferation (Pg 4, Discussion) and the astrocytes to retract their extensions and take on a more round appearance (Pg 3, Results)
Sher et al. (2008) teaches that EZH2 is highly expressed in proliferating neural stem cells (which glial stem cells differentiate from) and that EZH2 expression is downregulated at the time oligodendrocytes enter the myelination state. (Pg 2882, Discussion)
Regarding Claim 1 and 3: Windrem et al. teaches that hGPCs administered to the adult Shiverer mouse resulted in significant remyelination (pg 4, Fig 1C-1F) and led to increased cell densities for hGPCs, oligodendrocytes, and astrocytes (pg 4, Fig 1G-1M) This reads on the claimed method of administering glial progenitor cells to a subject resulting in remyelination in the subject and rejuvenation in the adult glial progenitor cells. Windrem fails to teach that the hGPCs express BCL11A, HDAC2, EZH2, MYC, HMGI-C, NFIB, or TEAD2.
Heinen et al. teaches the effects of EZH2 suppression on Schwann cell differentiation as it compares to EZH2 expressing Schwann cells. (pg 1696, Abstract) Specifically, Heinen teaches that suppression of EZH2 via a shRNA construct significantly decreases myelination in Schwann cultures. (pg 1704-1705, “Knockdown of EZH2 Interferes with Myelination of DRG Cocultures”) In addition to this, Heinen teaches that suppression of EZH2 in Schwann cells results in downregulation of genes associated with myelination. (pg 1705, Discussion) Heinen further references Sher et al. (2008), which states that EZH2 is suppressed during the myelination of oligodendrocytes as well. (Pg 2882, Discussion) In addition to this, Sher (2008) states that neural stem cells highly express EZH2 (Pg 2875, Abstract) and express EZH2 throughout the differentiation process to oligodendrocytes up until myelination. (Pg 2882, Discussion). This is evidence to state that manipulation of EZH2 during the glial cell differentiation process impacts myelination. This reads on the claimed method of EZH2 expression in the glial progenitor cell inducing myelination. Heinen et al. fails to teach that EZH2 expression leads to rejuvenation of the cell population.
Sher et al. (2011) teaches that forced expression of EZH2 in adult astrocytes leads to partial de-differentiation of the cells. (Pg 3, Results) Specifically, expression of EZH2 led to a complete retraction of the astrocyte extensions and a switch to a round cell phenotype, in addition to onset of cellular division. (Pg 3, Results) qPCR of the expression profiles of the astrocytes overexpressing EZH2 compared to normal astrocytes showed genes associated with astrocytes (GFAP and S100b) were downregulated and markers associated with stemness (nestin, vimentin, SOX2, CD133) were expressed. (Pg 3, Results, Pg 5, Fig 3) Importantly, Sher teaches that EZH2 expression is only sufficient for partial differentiation of the cells, without losing their identity. (Pg 3, Results) This reads on the claimed method of inducing rejuvenation in the glial progenitor cells, as applicant states that rejuvenation can be defined as “revision of the aging process in a cell and a return to youthful cell state, in particular with regard to proliferative and/or differentiation capacity, without loss of cell identity.”
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the cells in the protocol as taught by Windrem to express EZH2 as evidenced by the teachings of Heinen and Sher regarding the role of EZH2 in myelination to treat myelin deficiency in the Shiverer mouse. One would have been motivated to do so based on the teachings of Heinen and Sher, which state that EZH2 plays a critical role in remyelination of glial progenitor cells (Heinen) and overexpression of EZH2 results in a return of astrocytes to a stem-like state through partial dedifferentiation, thereby rejuvenating the cells. (Sher)
Regarding Claim 7: Heinen et al. teaches that EZH2 suppression in Schwann cells leads to downregulation of myelin genes and therefore a decrease in myelination of the cells. (pg 1705, “Knockdown of EZH2 Interferes with Myelination of DRG Cocultures”) One of ordinary skill in the art would understand that the Schwann cells taught by Heinen inherently express EZH2. This reads on the claimed method of the expressing step expresses EZH2.
Regarding Claim 12: Heinen teaches use of pSUPER-based vectors (a commercially available RNAi vector) to encode “complementary sequences specific for the sequence of EZH2”. (pg 1697, “Cloning Procedure, Transfection, and Selection of Transfected Cells”) This reads on the claimed method of administering a nucleic acid sequence encoding one or more transcription factors. Heinen also teaches use of p57kip2 control vectors (pg 1697, “Cloning Procedure, Transfection, and Selection of Transfected Cells”) and that this regulatory element (pg 1701, first paragraph) is intrinsic to Schwann cell maturation (pg 1696, Abstract). This reads on the claimed method of having a regulatory element operable linked to the nucleic acid sequence.
Regarding Claim 13: Heinen teaches use of p57kip2 control vectors regarding Schwann cells in their experimental protocol (pg 1697, “Cloning Procedure, Transfection, and Selection of Transfected Cells”) and that p57kip2 is a promotor that is a downstream effector of EZH2. (pg 1696, Abstract) This reads on the claimed method of the regulatory element comprising a glial cell specific promotor.
Regarding Claim 15: Heinen teaches use of pSUPER-based vectors, which are RNAi based vectors. (pg 1697, “Cloning Procedure, Transfection, and Selection of Transfected Cells”) This reads on the claimed method of using a non-viral vector.
Regarding Claim 19: Windrem teaches use of the Shiverer mouse model, which is an established genetic model of congenital demyelination. (pg 1, “In Brief” and “Highlights”)
Claims 14 and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Windrem et al. (Human Glial Progenitor Cells Effectively Remyelinate the Demyelinated Adult Brain, Cell Reports, 2020) in view of Heinen et al (Histone Methyltransferase Enhancer of Zeste Homolog 2 Regulates Schwann Cell Differentiation, GLIA, 2012), Liu et al (A molecular insight of Hes5-dependent inhibition of myelin gene expression: old partners and new players, EMBO journal, 2006), Merten et al. (Viral Vectors for Gene Therapy, Chapters 7, 8, and 9, 2011), and Sher et al. (Ezh2 Expression in Astrocytes Induces Their Dedifferentiation Toward Neural Stem Cells, Cellular Reprogramming, 2011)
The teachings of Heinen, Windrem, Liu, and Sher are described above.
Merten et al. teaches an overview of the different types of viral vectors and their specific applications. (pg v and vi, Preface) Specifically, Merten teaches the common uses and benefits of lentiviral vectors (pg 183, Abstract) and adeno-associated viruses (AAVs) (pg 211, Abstract)
Regarding Claim 14 and 16: Neither Windrem nor Heinen nor Liu disclose use of an inducible promotor or viral vector. Merten et al. teaches use of inducible promotor systems as a method for producing vectors for large-scale production (pg 66, Chapter 7) Merten also teaches use of viral vectors. (pg v and vi, Preface) This reads on the claimed method of using an inducible promotor along with viral vectors. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Merten with the cell population and treatment method taught by Windrem, Heinen, and Liu to use an inducible promotor with a viral vector. One would have been motivated to do so based on the teaching of Merten, which states that inducible promoters used with viral vectors are useful for large-scale production.
Regarding Claims 17 and 18: Neither Windrem nor Heinen nor Liu disclose use of an inducible promotor or viral vector. Merten et al. teaches the relevance of lentiviral vectors and how they are powerful, reliable, and safe for stable gene transfer into mammalian cells and allow for stable gene delivery into nondividing primary cells. (pg 183, Abstract) This reads on the method of Claim 17. Merten also teaches the relevance of AAV vectors and how they are beneficial due to staying episomal after gene transfer, which makes it a safer option due to the absence of insertional mutagenesis. They are also non-pathogenic. (pg 211, Abstract) This reads on the method of Claim 18. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Merten with the cell population and treatment method taught by Windrem, Heinen, and Liu to incorporate the sequence into either a lentiviral vector (Claim 17) or an AAV vector (Claim 18). One would have been motivated to do so based on the teachings of Merten who speaks to the specific advantages of both lentiviral and AAV vectors.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Heinen et al (Histone Methyltransferase Enhancer of Zeste Homolog 2 Regulates Schwann Cell Differentiation, GLIA, 2012) in view of Merten et al. (Viral Vectors for Gene Therapy, Chapters 7, 8, and 9, 2011) as evidenced by Sher et al. (Differentiation of Nerual Stem Cells into Oligodendrocytes: Involvement of the Polycomb Group Protein EZH2, 2008)
Regarding Claim 20: Heinen et al. teaches a method of using a pSUPER vector to deliver control and shRNA plasmids to Schwann cells with the sequence being one specific for EZH2. (pg 1697, “Cloning Procedure, Transfection, and Selection of Transfected Cells) Heinen also teaches use of p57kip2 control vectors (pg 1697, “Cloning Procedure, Transfection, and Selection of Transfected Cells”) and that this regulatory element (pg 1701, first paragraph) is intrinsic to Schwann cell maturation (pg 1696, Abstract). Heinen also discloses that p57kip2 is a promotor that is a downstream effector of EZH2. (pg 1696, Abstract) This reads on the claimed method of having an expression vector comprising of BCL11A, HDAC2, EZH2, MYC, HMGI-C, NFIB, or TEAD2, a regulatory element operably linked to the nucleic acid sequence, and the regulatory element comprising a glial progenitor cell-specific promotor. Heinen fails to teach use of a lentiviral vector or AAV vector.
Merten et al. teaches the benefits and specific uses of both lentiviral and AAV vectors; lentiviral vectors being powerful, reliable, and safe for stable gene transfer into mammalian cells and allow for stable gene delivery into nondividing primary cells (pg 183, Abstract) and AAV vectors being beneficial due to staying episomal after gene transfer, which makes it a safer option due to the absence of insertional mutagenesis. They are also non-pathogenic. (pg 211, Abstract) This reads on the claimed method of using a lentiviral vector or AAV vector. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teaching of Heinen of an expression vector comprising of EZH2, a regulatory element, and a glial progenitor cell-specific promotor with the teaching of Merten by incorporating the sequence into a lentiviral or AAV vector. One would have been motivated to do so based on the teachings of Merten regarding the benefits and uses of lentiviral and AAV vectors.
Response to Arguments
Applicant argues that the teachings of Windrem fails to teach that the hGPCs express EZH2 and that, at the time of the Windrem publication, functions of the above genes were unknown in the state of the art until the inventors of the present application discovered the genes’ functions and developed the claimed methods of the present application and therefore claim 1 should be rendered allowable. This is unpersuasive. Windrem et al. was published in 2020, and while it alone does not teach expression of EZH2, Heinen et al., published in 2012, links the suppression of EZH2 interferes with in vitro myelination, identifying specifically that Hes5, induced upon EZH2 suppression, is expressed and inhibits myelin gene expression. Thus, Heinen definitively linked EZH2 expression as a regulatory mechanism of myelinating glial cell differentiation. (Pg 1696-1697, Introduction) Therefore, there is evidence in the that the function of EZH2 as it relates to myelination was known as far back as 2012, rendering the argument that the inventors discovered the function of the gene unpersuasive.
Applicant further argues that, as stated in the submitted Goldman Declaration, Schwann cells are not considered in the field to be glial progenitor cells as they reside in the PNS, not the CNS, and goes on to state that oligodendrocytes and fibrous astrocytes are responsible for myelination in the CNS. This is unpersuasive due to Heinen stating that the mechanism discussed in the findings by Heinen are crucial for glial cell differentiation to proceed (Pg 1696, Abstract), thus confirming their status in the art as glial precursor cells. In addition to this, Heinen goes on to reference Sher et al., which details that EZH2 has previously been shown to control oligodendral determination and differentiation through the same mechanism via Hes5 binding and repressing myelin genes. (Pg 1703, Results) Therefore, it is interpreted that regardless of if discussing Schwann cells or oligodendrocytes, the mechanism of action impacting myelination is the same. In fact, Heinen states that it has already been established that EZH2 plays a role in neural stem cell differentiation regarding astrocyte and oligodendrocyte precursor cells, which as the Declaration states, are responsible for the myelination of the CNS. (Pg 1696, Introduction)
Examiner has clarified that obviousness in this instance is not based on the cells taught by Heinen, but instead of the importance of EZH2 expression and its effect on myelination on a variety of glial progenitor cells in both the CNS and PNS, as evidenced by the teachings of Heinen and Sher.
Examiner recognizes that Applicant has elected to cancel claims 2 and 4, therefore making the rejections moot.
Applicant further argues that claims 14 and 16-19 should be made allowable on the same bases as independent claim 1, as the aforementioned claims depend from claim 1. However, based on the above discussion regarding claim 1, the arguments regarding claims 14 and 16-19 are considered unpersuasive on the same basis. Therefore, the rejections for claims 14 and 16-19 are upheld.
Applicant further argues that as Heinen discusses use of p57kip2, a promoter that is a downstream effector of EZH2, regarding Schwann cells, that Heinen fails to disclose use of the glial progenitor cell specific promoter on glial progenitor cells. However, as discussed above, Heinen states that the mechanism discussed in the findings by Heinen are crucial for glial cell differentiation to proceed (Pg 1696, Abstract), thus confirming their status in the art as glial precursor cells. Furthermore, Heinen references Sher et al. (2008) which directly correlates EZH2 downregulation to myelination and states that EZH2 is upregulated in neural stem cells throughout the differentiation process (including glial precursor cells, as glial cells differentiate from neural stem cells into oligodendrocytes, as is known throughout the art). Therefore, p57kip2 functions as a glial progenitor cell specific promoter.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNA M THUESON whose telephone number is (571) 272-3680. The examiner can normally be reached M-F 7:30-5 EST. 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.
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/HANNA MARIE THUESON/ Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638