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 .
DETAILED ACTION
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
2. Applicant’s amendment filed October 22, 2025 is acknowledged. Claims 2-9 and 12-15 are cancelled. Claims 1 and 10-11 are amended. Claim 16 is newly added. Claims 1, 10-11 and new claim 16 are pending in this application. Election was made without traverse in the reply filed on July 17, 2025.
3. Claims 1, 10-11 and 16 are under examination with respect to an antisense oligonucleotide targeting glycogen synthase and Alzheimer’s disease (AD) in this office action.
4. Applicant’s arguments filed on October 22, 2025 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Claim Rejections/Objections Withdrawn
5. The rejection of claims 14-15 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement is moot because the claims are canceled.
Claim Rejections/Objections Maintained
In view of the amendment filed on October 22, 2025, the following rejections are maintained.
Claim Objections
6. Claim 1 stands objected to because of the recitation “GYS” recited in claim 1. The recitation of “GYS” is not a unique or common abbreviation in the art. Applicants are required to spell out “GYS” at the first usage. Appropriate correction is required.
Claim Rejections - 35 USC § 112
7. 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 1, 10-11 and 16 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The rejection is maintained for the reasons of record and the reasons set forth below.
Claims 1, 10-11 and 16 as amended are drawn to a method for reducing glycogen synthesis in a subject having Alzheimer’s disease (AD) or an increased risk thereof, comprising administering to the subject an antisense oligonucleotide targeting glycogen synthase (GYS) (GYS-ASO), wherein the antisense oligonucleotide comprises a nucleotide sequence complementary to an mRNA sequencing coding for brain-specific GYS.
Response to Arguments
On p. 4-5 of the response, Applicant argues that i) the rejection has been overcome in view of amendment to the claims by reciting “a method for reducing glycogen synthesis in a subject having Alzheimer’s disease” in claim 1 and specifying the antisense oligonucleotide (AS) comprising a nucleotide sequence complementary to an mRNA sequence encoded by SEQ ID NO:1 as in claim 16; ii) the experimental data shown in the specification provides support for the claimed method recited in instant claims and cites paragraphs [0051]; [0018], [0072], Figs.3A-3D and paragraphs [0019],[0058], [0020], [0021],[0059], [0063], Figs.5-6), Examples 1-2 and para. [0078] and Fig 10 in support of the arguments.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2164, MPEP §§2164.01-2164.06(b) & 2164.08, the specification provides insufficient guidance to enable a skilled artisan to practice the full scope of the claimed invention without undue experimentation because of the following:
i. The specification provides no support or well-established structural and functional relationship or correlation between administering an antisense oligonucleotide targeting glycogen synthase (GYS) (GYS-ASO) and reducing glycogen synthesis in a subject with AD or an increased risk thereof because glycogen synthesis in a subject involves multiple enzymes and multiple molecular mechanisms, not the level of a single enzyme, glycogen synthase only.
ii. Based on Applicant’s own admission in paragraphs [0066] and [0070] of the instant specification, the regulation of glycogen synthesis involves multiple enzymes, and the protein and mRNA levels do not represent activity of these enzymes, and the dysregulation of these enzymes can result in AD-PGB formation.
[0066].., “the biosynthesis and breakdown of glycogen involves both glycogen synthase (GYS) and glycogen phosphorylase (GP)….Both enzymes are subjected to post-translation modifications, and thus protein and mRNA levels do not always represent enzyme activity”.
[0070]… “Glycogen chain length, branching and phosphate content are regulated by the coherent synergy between branching enzyme (BE), debranching enzyme (GDE) and laforin……and interaction with AMPK…Dysregulation of any of these three enzyme could result in AD-PGBs formation…..”.
iii. Based on Applicant’s own admission on p. 5 of the response, Example 1 only showed that AD-PGBs inhibit AMPK activity and disrupt glucose metabolism in astrocytes, and Example 2 only showed that AD-PGBs directly bind and modulate AMPK.
The specification provides no data or demonstration to support that administering an antisense oligonucleotide targeting glycogen synthase (GYS) (GYS-ASO) to a subject with AD or an increased risk thereof to reduce the protein or mRNA expression of GYS can really reduce glycogen synthesis in the subject with AD or an increased risk thereof, or specifically target to and reduce glycogen synthesis in astrocytes in the brain of the subject with AD or an increased risk thereof .
iv. The specification only describes: i) a correlation between the increased glycogen content from AD patient brain samples and the worse prognosis based on Braak staging and a correlation between increased total glycogen and decreased free glucose in AD brain samples (Example 1, Figure 8A-B); ii) detecting glycogen accumulation based on GCMS quantitation of glycogen in 5xFAD and rTg4510 AD mouse models and human APOE4 “knock-in” mice (Example 1, Figures 9A-B, figures 11A-B); iii) cerebroventricular (CV) administration of an antibody-enzyme fusion VAL-0417 to an animal model of Lafora disease, Epm2a-/- mice, reduced total glycogen levels and AD-PGBs in the Epm2a-/- mice, wherein the AD-PGBs are up to 50um in diameter, and are found in astrocyte cytoplasm, axons, and dendrites of the cerebral cortex in AD patient and architecturally similar to glycogen storage disease (GSD)-PGBs (see Example 3, Figures 18A-D).
Based on the specification, Applicant is enabled for reducing levels of AD-PGBs in Epm2a-/- (Lafora disease) mice by CV administration of an antibody-enzyme fusion VAL-0417 to the Epm2a-/- (Lafora disease) mice.
The specification provides no well-established correlation between the treatment of the Epm2a-/- (Lafora disease) mice using an antibody-enzyme fusion VAL-0417 via a CV administration route and reducing glycogen synthesis in a subject with AD or an increased risk thereof using a GYS-ASO. There is no nexus between Epm2a-/- (Lafora disease) mice treated with an antibody-enzyme fusion VAL-0417 and AD or an increased risk thereof treated with a structurally and functionally undefined GYS-ASO.
The specification provides no well-established structural and functional relationship or correlation between an antibody-enzyme fusion VAL-0417 and a GYS-ASO. VAL-0417 is an antibody-enzyme fusion by combining a delivery antibody (3E10) with an enzyme (amylase) to cross cell membranes and break down pathogenic and accumulating glycogen deposits (Lafora bodies) in the brain, which has a function totally different from that of the claimed GYS-ASO because the claimed GYS-ASO is an antisense oligonucleotide targeting to glycogen synthase (GYS) to inhibit or reduce expression of GYS. While the GYS-ASO may reduce production of GYS, the reduction of GYS does not necessarily reduce production of glycogen or glycogen deposit or break down glycogen or glycogen deposits because glycogen synthesis is regulated by multiple enzymes, and the protein and mRNA levels do not represent activity of these enzymes, and the dysregulation of these enzymes can result in AD-PGB formation.
There is no well-established correlation between the Lafora disease and AD or unknown conditions with an increased risk thereof because Lafora disease is a severe, autosomal recessive genetic disorder resulting in progressive myoclonus epilepsy, which is characterized by a disruption in glycogen metabolism and caused by loss of function mutations in EPM2A and EPM2B (NHLRC1) genes. While the PGB-like granules can be found in 5xFAD, rTg4510 AD and human APOE4 “knock-in” mice or in astrocyte cytoplasm, axons, and dendrites of the cerebral cortex in AD patients, the specification provides no support to demonstrate that reducing the protein and mRNA levels of GYS can reduce glycogen synthesis in either Epm2a-/- (Lafora disease) mice or in AD animal models of 5xFAD, rTg4510 AD and human APOE4 “knock-in” mice or even AD patients or other conditions with an increased risk of developing AD.
In addition, lacking neuronal glycogen impairs memory formation. A mouse model of lacking glycogen synthase specifically in the Camk2a-expressing postnatal forebrain pyramidal neurons (GYS1Camk2a-KO) showed a significant deficiency in the acquisition of an instrumental learning task-a type of associative learning involving prefrontal and hippocampal circuits (see p.1, abstract; Duran et al. Front. Cell. Neurosci. 2019; doi:10.3389/fncel.2019.00374). The specification fails to provide sufficient guidance as to how to reduce glycogen synthesis in AD patients or at an increased risk thereof without impairing memory formation.
Thus, it is unpredictable whether administration of the claimed GYS-ASO can reduce glycogen synthesis in a subject having AD or an increased risk thereof, indicating undue experimentation is required by a skilled artisan to perform while practicing the claimed invention. Note that the scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without such guidance, it is unpredictable whether administering the claimed GYS-ASO can reduce glycogen synthesis in AD or an increased risk thereof; and thus the experimentation left to those skilled in the art is extensive and undue. See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Int. 1986). Thus, the skilled artisan cannot readily know how to use the claimed invention as currently claimed without further undue experimentation. In re Marzocchi, 439 F.2d 220, 223-24, 169 USPQ 367, 369-70 (CCPA 1971). See MPEP § 2164.03.
A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. In the decision of Genentec, Inc, v. Novo Nordisk, 42 USPQ 2d 100,(CAFC 1997), the court held that: “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable” and that “[t]ossing out the mere germ of an idea does not constitute enabling disclosure”. The court further stated that “when there is no disclosure of any specific starting material or of any of the conditions under which a process is to be carried out, undue experimentation is required; there is a failure to meet the enablement requirements that cannot be rectified by asserting that all the disclosure related to the process is within the skill of the art”, “[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement”.
The instant specification is not enabling because one cannot follow the guidance presented therein and practice the claimed method without first making a substantial inventive contribution. Therefore, in view of the breadth of the claims, the lack of guidance in the specification, no working examples, the unpredictability of inventions, and the current status of the art, undue experimentation would be required by a skilled artisan to perform in order to practice the claimed invention as it pertains to a method for reducing glycogen synthesis in a subject having AD or an increased risk thereof by administering to the subject the claimed GYS-ASO.
Accordingly, the rejection of claims 1, 10-11 and 16 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, lack of scope of enablement is maintained.
Claim Rejections - 35 USC § 112
8. Claims 1, 10-11 and 16 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. The rejection is maintained for the reasons of record and the reasons set forth below.
Response to Arguments
On p. 6-7 of the response, Applicant argues that i) the rejection has been overcome in view of amendment to the claims by reciting “a method for reducing glycogen synthesis in a subject having Alzheimer’s disease” in claim 1 and specifying the antisense oligonucleotide (AS) comprising a nucleotide sequence complementary to an mRNA sequence encoded by SEQ ID NO:1 as in claim 16; ii) Examples 1-2 shown in the specification provide support for the claimed method recited in instant claims and cites paragraphs [0051]; [0018], [0072], Figs.3A-3D and paragraphs [0019],[0058], [0020], [0021],[0059], [0063], Figs.5-6), Examples 1-2 and para. [0078] and Fig 10 in support of the arguments.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2163, MPEP §§2163.01-2163.03, the specification fails to provide sufficient description or information or evidence to demonstrate that Applicant is in possession of the claimed method of using the claimed GYS-ASO for reducing glycogen synthesis in a subject having Alzheimer’s disease (AD) or an increased risk thereof because:
i. The specification provides no support or well-established structural and functional relationship or correlation between administering an antisense oligonucleotide targeting glycogen synthase (GYS) (GYS-ASO) and reducing glycogen synthesis in a subject with AD or an increased risk thereof because glycogen synthesis in a subject involves multiple enzymes and multiple molecular mechanisms, not the level of a single enzyme, glycogen synthase only.
ii. As stated in M.P.E.P. § 2163(II)(A)(3), a specification may describe an actual reduction to practice by showing that the inventor constructed an embodiment or performed a process that met all the limitations of the claim and determined that the invention would work for its intended purpose. Cooper v. Goldfarb, 154 F.3d 1321,1327, 47 USPQ2d 1896, 1901 (Fed. Cir. 1998). See also UMC Elecs. Co. v. United States, 816 F.2d 647, 652, 2 USPQ2d 1465, 1468 (Fed. Cir. 1987) (“[T]here cannot be a reduction to practice of the invention ... without a physical embodiment which includes all limitations of the claim.”); Estee Lauder Inc. v. L’Oreal, S.A., 129 F.3d 588, 593, 44 USPQ2d 1610, 1614 (Fed. Cir. 1997) (“[A] reduction to practice does not occur until the inventor has determined that the invention will work for its intended purpose.”); Mahurkar v. C.R. Bard, Inc., 79 F.3d 1572, 1578, 38 USPQ2d 1288, 1291 (Fed. Cir. 1996) (determining that the invention will work for its intended purpose may require testing depending on the character of the invention and the problem it solves).
To demonstrate the reduction to practice of a GYS-ASO and a method for reducing glycogen synthesis in a subject having Alzheimer’s disease (AD) or an increased risk thereof requires either a working embodiment, a demonstration of operability in the treatment of an art accepted animal model of the condition to be treated wherein that animal model has been shown to be reliably predictive of efficacy in the treatment of the condition, or a demonstration that the therapeutic agent or GYS-ASO employed therein possesses an activity in which the majority of compounds possessing that activity have been shown to be effective in the treatment of that condition.
In the instant case, Applicant has provided none of these. Consequently, Applicant has failed to demonstrate possession of the claimed method or even a single species of the genus of GYS-ASO for reducing glycogen synthesis in a subject having Alzheimer’s disease (AD) or an increased risk thereof required thereby as of the earliest effective filing date of the instant application.
With respect to the demonstration of a reduction to practice of a generic invention, M.P.E.P. § 2163(II)(A)(3)(ii) states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus, above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
In the instant case, Applicant has failed to demonstrate a reduction to practice of a representative number species of the genus “GYS-ASO”, or even a single species within that genus, much less a method for reducing glycogen synthesis in a subject having Alzheimer’s disease (AD) or an increased risk thereof by the administration of GYS-ASO thereto. The experimental results described in the specification consist primarily of the characterization of i) the increased glycogen content in AD patient brain samples correlated with the worse prognosis based on Braak staging, and increased total glycogen correlated with decreased free glucose in AD brain samples (Example 1, Figure 8A-B); ii) glycogen accumulation based on GCMS quantitation of glycogen in 5xFAD and rTg4510 AD mouse models and human APOE4 “knock-in” mice (Example 1, Figures 9A-B, figures 11A-B); and iii) the effects of an antibody-enzyme fusion VAL-0417 on reducing total glycogen levels and AD-PGBs in an animal model of Lafora disease, Epm2a-/- mice (see Example 3, Figures 18A-D).
These data do not support a conclusion that Applicant was in possession of a method for reducing glycogen synthesis in a subject having AD or an increased risk thereof by administering to the subject a GYS-ASO because there is no well-established structural and functional relationship or correlation between an antibody-enzyme fusion VAL-0417 and a GYS-ASO. VAL-0417 is an antibody-enzyme fusion by combining a delivery antibody (3E10) with an enzyme (amylase) to cross cell membranes and break down pathogenic and accumulating glycogen deposits (Lafora bodies) in the brain, which has a function totally different from that of the claimed GYS-ASO because the claimed GYS-ASO is an antisense oligonucleotide targeting to glycogen synthase (GYS) to inhibit or reduce expression of GYS. While the GYS-ASO may reduce production of GYS, the reduction of GYS does not necessarily reduce production of glycogen or glycogen deposit or break down glycogen or glycogen deposits because glycogen synthesis is regulated by multiple enzymes, and the protein and mRNA levels do not represent activity of these enzymes, and the dysregulation of these enzymes can result in AD-PGB formation. There is also no well-established correlation between the Lafora disease and AD or unknown conditions with an increased risk thereof because Lafora disease is a severe, autosomal recessive genetic disorder resulting in progressive myoclonus epilepsy, which is characterized by a disruption in glycogen metabolism and caused by loss of function mutations in EPM2A and EPM2B (NHLRC1) genes.
Based on MPEP § 2161.01 and §2163, “to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
Therefore, the claimed method has not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
Accordingly, the rejection of claims 1, 10-11 and 16 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.
Conclusion
9. NO CLAIM IS ALLOWED.
10. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Clayton et al. (Mol. Thera. 2014; 3:e206. Doi: 10.1038/mtna.2014.57) teach that systemic administration of GS-PPMO (muscle specific glycogen synthase GS1 phosphorodiamidate morpholino oligonucleotide (PMO)-conjugated to a cell penetrating peptide) to Pompe mice resulted in a dose-dependent decrease in glycogen synthase transcripts in the quadriceps and the diaphragm and heart at the higher dose but not the liver (see abstract).
11. THIS ACTION IS MADE FINAL. 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.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chang-Yu Wang whose telephone number is (571)272-4521. The examiner can normally be reached on Monday-Thursday, 7:00am-5:30pm EST.
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Chang-Yu Wang
February 10, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675