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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/05/25 has been entered.
Claim Status
Claims 1, 14, 15, 17, 29-30, 32-33, 38, 48, 50, 53-54, 59-63 are pending.
Claims 1, 14, 15, 17, 29-30, 32-33, 38, 48, 50, 53-54, 62, 63 are examined here.
Claims 59-61 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Although, claims 59-61 recite species found in the references noted in the instant rejection, the claims also note additional species that would require further search and consideration, along with 35 USC 112 statutory consideration, and the claims are not rejoined currently.
Priority
Application’s filing of 371 of PCT/US2019/037754 on 06/18/2019, claiming benefit of U.S. Provisional 62/686,346, filed on 06/18/2018 is acknowledged. All examined claims enjoy the benefit of ‘346 filing date.
Claim Rejections - 35 USC § 102
Rejection of claim 1 is withdrawn. The Remarks of 12/05/25 and the Declaration of Ms. Grunzweig of 1/13/2026 indicate that the Liu’s reference was placed under embargo and the document was “restricted for everyone” and was not available until after filing of the instant application, i.e. it is a post-filing document and is not available as a 102 reference.
Claim Rejections - 35 USC § 103
Rejection of claims 14, 15, 17, 29, 30, 32, 33, 38, 48, 50, 53, 54, 62 and 63 under references, including Liu, is withdrawn, since the Liu reference, as noted above, is a post-filing document. However, upon further search, the examined claims, including claim 1, are rejected as noted below.
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, 14, 17, 29, 32, 62 is rejected under 35 U.S.C. 103 as being unpatentable over Sedaghat et al. (WO2011031998, pub. 03/2011, referred as Sedaghat) in view of Tong et al. (2014, Nature Neuroscience, 17, 694-703, referred as Tong) and Phillips (1997, Hypertension, 29, 177-187).
Sedaghat discloses antisense oligonucleotide (ASO) that targets REST (also termed neuron-restrictive silencer factor (NRSF)) transcript and reduces its expression (abstract, see generally Ex. 6, ASOs of Table 11 demonstrate reduction in REST mRNA expression in vivo in mice, pg. 47, line 7 to pg. 48, line 19). Further, Example 8 of Sedaghat indicates administering ASO targeting REST to R6/2 mice at 8 weeks of age intracerebroventricularly along with resulting decreasing in its expression in the striatum (Ex. 8, pg. 51, line 20 to pg. 53, line 11). R6/2 mice exhibit progressive neurological phenotype that exhibits many features of Huntington’s disease (HD, a neuropsychiatric disorder), including epileptic seizure (pg. 52, line 1-3, relevant to instant cl. 1, 14, 29).
Sedaghat does not disclose the inhibitor is packaged in a delivery vehicle that comprises a glial cell targeting moiety.
Tong discloses using adeno-associated virus of the 2/5 serotype (AAV2/5) to preferentially target astrocytes and express genes of interest in the astrocytes in the HD mouse models (pg. 698, used to deliver GFP-tagged Kir4.1 channels, control vector, relevant to instant cl. 1, 14, 62). A skilled artisan recognizes that an ASO sequence can be inserted into any viral vector, including AAV.
Philips discloses ASO sequence can be inserted into a AAV vector, and that AAV based vectors are safe and efficient for in-vivo “long-term therapy” for chronic conditions (Fig. 2, pg. 182-184, relevant to instant cl. 1, 14, 62).
Tong discloses decreased expression of inward rectifier K+ channel (Kir4.1) in astrocytes of R6/2 HD mouse model that correlates with elevated levels of K+ in HD model mice and that “subtly elevated extracellular K+ levels (by ~2mM) depolarized MSNs [medium spiny neurons] and increased their excitability” (abstract, pg. 694, relevant to instant cl. 14, 32).
Thus, R6/2 mice, which exhibits many features of HD, inherently have astrocytes with decreased expression of Kir4.1 channel, and consequently, the glial cells have reduced K+ intake. Results of treatment with ASOs targeting REST demonstrated decreased mRNA levels of REST in brain tissue, which inherently increases K+ uptake in glial cells, thus fulfilling the required steps of administering a REST ASO to a R6/2 mouse subject, which exhibits many HD features including with astrocytes with decreased K+ uptake, the result will be a byproduct that will inherently flow from the administration step, i.e. restoration of K+ uptake by astrocytes (relevant to instant cl. 1, 14, 17, 29, 32).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have incorporated the antisense oligonucleotide targeting REST mRNA of Sedaghat into an AAV2/5 as taught by Tong to target astrocytes in vivo. Since Sedaghat demonstrates ASOs successfully inhibit REST mRNA in vivo in R6/2 HD mouse model, and Tong and Phillips demonstrate the use of AAV2/5 for delivering a gene of interest to glial cell for a long-term to treat a chronic condition (i.e. HD), and Tong also teaches decreased expression of inward rectifier K+ channel (Kir4.1) in astrocytes of R6/2 HD mouse model that correlates with elevated levels of K+ in HD model mice, a skilled artisan would reasonably expect success by modifying an ASO targeting REST mRNA in vivo in R6/2 mice of Sedaghat and incorporating the ASO of Sedaghat into a delivery vehicle of an AAV2/5 to target glial cells taught by Tong to treat a chronic condition as taught by Phillips. Following administration of ASO targeting REST mRNA incorporated into an AAV2/5 for delivery to astrocytes in vivo to a subject with HD would result in restoration of K+ uptake by astrocytes as a byproduct that will inherently flow from the administration step of ASO targeting REST/NRSF mRNA in a HD subject. Therefore, claims 1, 14, 17, 29, 32, 62 are rejected under 103.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Sedaghat et al. (WO2011031998, pub. 03/2011, referred as Sedaghat) in view of Tong et al. (2014, Nature Neuroscience, 17, 694-703, referred as Tong) and Phillips (1997, Hypertension, 29, 177-187), and further as evidenced by Curtis et al. (2007, Clinical and Experimental Pharmacology and Physiology, pg. 1, of record).
Regarding instant cl. 15, one of the responses to degeneration in the brain during HD is for the increased production of progenitor cells in the subventricular zone (SVZ) “that migrate towards the site of the damage where they can differentiate into mature neurons and glial cells” and “in response to Huntington’s disease, most of the SVZ cell proliferation is glial” (Curtis et al., 2007, Clinical and Experimental Pharmacology and Physiology, pg. 1). Thus, evidenced by Curtis et al., one of the response to HD is increased production of progenitor cells that differentiate into glial cells, which include astrocytes. Thus, as noted above, Sedaghat in Ex. 6 administered intracerebroventricularly ASO targeting REST/NRSF in R6/2 mice, which exhibit progressive neurological phenotype that exhibits many feature of Huntington’s disease (a neuropsychiatric disorder), including epileptic seizure (pg. 52, line 1-3, relevant to instant cl. 29, 38). Thus, it is inherent that the R6/2 mice have progenitor cells in the SVZ that differentiate into mature glial cells.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Sedaghat et al. (WO2011031998, pub. 03/2011, referred as Sedaghat) in view of Tong et al. (2014, Nature Neuroscience, 17, 694-703, referred as Tong) and Phillips (1997, Hypertension, 29, 177-187) as applied to claim 14 above, and further as evidenced by McClelland et al. (2011, Ann. Neurol., 70, 454-464, referred as McClelland).
Regarding instant cl. 33, Sedaghat discloses R6/2 mice exhibit progressive neurological phenotype that exhibits many feature of Huntington’s disease (HD, a neuropsychiatric disorder), including epileptic seizure (pg. 52, line 1-3).
As evidenced by McClelland, which discloses the use of oligodeoxynucleotide (ODN) decoys that bind to RE-1 silencing transcription factor (REST, also termed neuron-restrictive silencer factor (NRSF)) and significantly reduced the mean number of seizures (see Fig. 6C) and general neuronal activity (Fig. 6E) in rats treated with drug that induces epilepsy, a type of seizure (see Fig. 6C, pg. 461). McClelland indicates that NRSF, a transcription factor, binds to its cognate sequence present on “several hundred neuronal genes” and causes “persistent repression of gene expression” (pg. 455).
Similarly, a skilled artisan would recognize that R6/2 mice, which are prone to increased epileptic seizure activity, treated with Sedaghat’s ASOs targeting REST/NRSF would have decreased REST/NRSF protein levels and decreased numbers of REST/NRSF protein binding to the cognate gene sequence, i.e. NRSE, and result in decreased seizures incidence and decreased neuronal excitability. Thus a skilled artisan would expect that following administration of ASOs targeting REST/NRSF, it would naturally flow that it would also decrease the seizure incidence as well as neuronal excitability.
Claims 14, 29, 30, 38, 48, 50, 53, and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Ayano (2016, Bipolar Disord., 2, pg. 1-5) and Zhao et al. (2017, Mol. Neurobiol., 54, 541-550, “Zhao”, of Record, IDS of 12/18/2020) and da Silveira Paulsen et al. (2014, Schizophrenia Res., 154, 30-35, “Paulsen”), Sedaghat et al. (WO2011031998, pub. 03/2011, referred as Sedaghat) in view of Tong et al. (2014, Nature Neuroscience, 17, 694-703, referred as Tong) and Phillips (1997, Hypertension, 29, 177-187).
Ayano discloses that valproate is a medication used to treat epilepsy, bipolar disorder (neuropsychiatric disorder), and prevention of seizures, and has a superior efficacy than lithium in treating schizoaffective disorders and augmentation therapy for schizophrenic patients not adequately responding to antipsychotic medication (pg. 1, relevant to instant cl. 14, 29, 30, 38).
Zhao discloses that valproic acid (aka valproate) that targets REST/NRSF have been shown to be clinically effective at rescuing seizures (pg. abstract, pg. 544). Zhao discloses that VPA treatment represses REST/NRSF and the histone deacetylase (HDAC) complex and restores impaired astrocytes (pg. 544, relevant to select astrocytes of cl. 14, 38).
Paulsen discloses that valproate reverses zinc and potassium imbalance in schizophrenia-derived reprogrammed cells (title). Paulsen discloses that there is a presence of elevated levels of potassium and zinc in neural progenitor cells of schizophrenic patients (abstract). Treatment of neural cells with valproate brought potassium and zinc content back to control levels (abstract, relevant to instant cl. 14 and 38). So although Paulsen discloses that it is the neural cells and is silent to glial cells, based on the disclosure of Zhao that repression of REST/NRSF restores impaired astrocytes, which as noted by Tong, plays a role in potassium homeostasis, a skilled artisan would reasonably expect success by treating glial cells.
Ayano, Zhao and Paulsen do not disclose the inhibitor as an ASO targeting REST/NRSF and the inhibitor is packaged in a delivery vehicle that comprises a glial cell targeting moiety.
Sedaghat discloses antisense oligonucleotide (ASO) that targets REST (also termed neuron-restrictive silencer factor (NRSF)) transcript and reduces its expression (abstract, see generally Ex. 6, ASOs of Table 11 demonstrate reduction in REST mRNA expression in vivo in mice, pg. 47, line 7 to pg. 48, line 19). Further, Example 8 of Sedaghat indicates administering ASO targeting REST to R6/2 mice at 8 weeks of age intracerebroventricularly along with resulting decreasing in its expression in the striatum (Ex. 8, pg. 51, line 20 to pg. 53, line 11). R6/2 mice exhibit progressive neurological phenotype that exhibits many features of Huntington’s disease (HD, a neuropsychiatric disorder), including epileptic seizure (pg. 52, line 1-3, relevant to instant cl. 14).
Ayano, Zhao, Paulsen, and Sedaghat do not disclose the inhibitor is packaged in a delivery vehicle that comprises a glial cell targeting moiety.
Tong discloses using adeno-associated virus of the 2/5 serotype (AAV2/5) to preferentially target astrocytes and express genes of interest in the astrocytes in the HD mouse models (pg. 698, used to deliver GFP-tagged Kir4.1 channels, control vector, relevant to instant cl. 14, 38, 48, 50, 63). A skilled artisan recognizes that an ASO sequence can be inserted into any viral vector, including AAV. Tong discloses decreased expression of inward rectifier K+ channel (Kir4.1) in astrocytes of R6/2 HD mouse model that correlates with elevated levels of K+ in HD model mice and that “subtly elevated extracellular K+ levels (by ~2mM) depolarized MSNs [medium spiny neurons] and increased their excitability” (abstract, pg. 694, relevant to instant cl. 14, 38, 53).
Philips discloses ASO sequence can be inserted into a AAV vector, and that AAV based vectors are safe and efficient for in-vivo “long-term therapy” for chronic conditions (Fig. 2, pg. 182-184, relevant to instant cl. 14, 63).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have substituted valproate of Ayano, Zhao, and Paulsen for ASOs targeting REST of Sedaghat, to restore K+ uptake in glial cells having decreased K+ uptake, and the ASO can be delivered using AAV 2/5 of Tong for conditions that require long term therapy as taught by Philips.
Thus, with the understanding that a) valproate is a medication used to treat bipolar disorder, schizophrenia, and seizures as taught by Ayano, b) valproate represses REST/NRSF activity and restores impaired astrocytes as taught by Zhao, c) valproate restores imbalance of potassium levels in schizophrenic neural cells as taught by Paulsen, and d) like valproate, ASOs targeting REST/NRSF specifically repress REST/NRSF expression in vivo as taught by Sedaghat, a skilled artisan would reasonably expect success in restoration of K+ imbalance and increased K+ uptake in glial cells following treatment with valproate or ASOs targeting REST/NRSF in either neurons or glial cells as taught by Paulsen and Zhao, respectively. Thus, cl. 14, 29, 30, 38, 48, 50, 53, 63 are obvious.
Claim 54 is rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (2017, Mol. Neurobiol., 54, 541-550, “Zhao,” of Record, IDS of 12/18/2020) and da Silveira Paulsen et al. (2014, Schizophrenia Res., 154, 30-35, “Paulsen”) and Sedaghat et al. (WO2011031998, pub. 03/2011, referred as Sedaghat) in view of Tong et al. (2014, Nature Neuroscience, 17, 694-703, referred as Tong) and Phillips (1997, Hypertension, 29, 177-187) as applied to claims 14, 29, 30, 38, 48, 50, 53, 63 above, and further in view of as evidenced by McClelland et al. (2011, Ann. Neurol., 70, 454-464, referred as McClelland).
Rejection of instant cl. 38, 48, 50, 53 and 63 is noted above.
Liu, Sedaghat, Tong, Phillips do not disclose the decrease in seizure incidence in subject.
McClelland discloses the treatment with oligodeoxynucleotide (ODN) decoys binding to REST protein, also termed neuron-restrictive silencer factor (NRSF), significantly reduced the mean number of seizures (see Fig. 6C) and general neuronal activity (i.e. excitability, Fig. 6E) in rats treated with drug that induces epilepsy, a type of seizure (see Fig. 6C, pg. 461, relevant to instant cl. 53, 54). McClelland indicates that NRSF, a transcription factor, binds to its cognate sequence present on “several hundred neuronal genes” and causes “persistent repression of gene expression” (pg. 455). Thus reducing NRSF/REST expression levels in a subject by treatment of ASO targeting REST transcript, as taught by Sedaghat, would also reduce its activity. As evidenced by McClelland, decreasing REST/NRSF activity also reduced seizure incidence (relevant to instant cl. 54), similarly treatment with ASO targeting REST/NRSF would also reduce seizure incidence. Thus cl. 54 is obvious.
Response to Arguments
Applicant's arguments filed 12/05/2025 (“the Remarks”) have been fully considered but they are not persuasive. The response will address the references that are still noted in this action.
The Remarks argue the following:
For rejection of cl. 14, 17, 29, 32 and 62, Sedaghat is “silent with respect to inhibiting REST gene expression to restore glial cell K+ uptake and does not reference glial cells and K+ uptake at all” (pg. 7) and due to this silence, a skilled artisan would not arrive at the method of instant claim 14 and the references of Tong, Phillips do not cure the deficiencies (pg. 7-8).
The rejection of claims 15 and 33, adding the Curtis and McClelland references, respectively, does not cure the deficiencies of Sedaghat, Tong, and Phillips, since Curtis and McClelland are “silent with respect to inhibiting REST gene expression to restore glial cell K+ uptake,” thus lacking motivation or a reasonable expectation of success (pg. 9, 10).
The examiner is required to consider unexpected results, and points to the Goldman Declaration that “the link between glial REST knockdown and potassium uptake itself was unexpected. Prior to the ‘008 Application, the role that astrocyte dysfunction plays in the development of neuropsychiatric disorders, such as schizophrenia, was unknown” (pg. 11, see also Goldman’s Declaration, pg. 3, par. 10).
The arguments are not persuasive.
First, for arguments 1, 2, in response to applicant's arguments against the references individually, 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).
Thus, regarding Sedaghat (argument 1), which is silent to glial cells and K+ uptake, Sedaghat demonstrates that ASO targeting REST mRNA is administered to the brain, which inherently have glial cells, including astrocytes. The in vivo administration of ASOs targeting REST mRNA and its mRNA decrease was analyzed in brain tissue, including striatum, which includes glial cells or astrocytes (see Ex. 7, 8, Tables 15, 16, pg. 50-53). Further, the effect of ASO administration, which resulted in decrease in REST expression, see Table 16, pg. 53, would necessarily result in the restoration of K+ uptake in the HD mouse model, the R6/2 mice, which, as noted above and in prior action, have reduced K+ intake.
Tong also discloses that glial cells in HD mouse model are also dysfunctional and as noted in prior action, and above, Tong observes “subtly elevated extracellular K+ levels (by ~2mM) depolarized MSNs [medium spiny neurons] and increased their excitability” (pg. 5 of 09/05/2025 action). Thus, this provides a HD mouse model as a subject in need with dysfunctional astrocytes and notes dysfunction of extracellular K+ levels, and thus following the administration of ASOs targeting REST/NRSF mRNA, the animals showed decreased REST/NRSF expression, and thus the administration will expectedly result in restoration of K+ uptake in glial cells having decreased K+ uptake.
Tong is used to teach the AAV2/5, as a glial cell targeting moiety, and that sequence of interest, i.e. inhibitory nucleic acid sequence, can be cloned into the AAV2/5. Tong/Phillips provide a rationale that AAV vector provides a long-term therapeutic inhibition as opposed to transient inhibition and multiple administration of an ASO.
Claims 1 and 14 are not directed to any specific disease and thus one can administer inhibitory nucleic acid molecule, such as a REST/NRSF ASO for a subject with HD.
Regarding the unexpected results, argument 3, MPEP 716.01(c) provides that although factual evidence is preferable to opinion testimony, such testimony is entitled to consideration and some weight so long as the opinion is not on the ultimate legal conclusion at issue (underline added for emphasis). Here, the statements provided in Goldman Declaration are directed to the ultimate legal conclusion at issue, i.e. the language of the claimed invention. And as noted in this action, the rejection of cl. 14 and 30, and cl. 38 and its dependents are in view of references not considered in prior actions. Ayano discloses that valproate is used to treat schizophrenia and other neuropsychiatric disorders, including seizures, and Zhao discloses that through repression of REST/NRSF it is able to improve the function of astrocytes and neurons, and Paulsen discloses that treatment of neural cells with valproate brought potassium and zinc content back to control levels.
Thus, the examined claims are obvious.
Conclusion
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/KEYUR A VYAS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600