Patent Application 18331311 - MODULATION OF GYS1 EXPRESSION - Rejection

Patent Application 18331311 - MODULATION OF GYS1 EXPRESSION

Title: MODULATION OF GYS1 EXPRESSION

Application Information

• Invention Title: MODULATION OF GYS1 EXPRESSION
• Application Number: 18331311
• Submission Date: 2025-04-10T00:00:00.000Z
• Effective Filing Date: 2023-06-08T00:00:00.000Z
• Filing Date: 2023-06-08T00:00:00.000Z
• National Class: 514
• National Sub-Class: 04400A
• Examiner Employee Number: 80520
• Art Unit: 1636
• Tech Center: 1600

Rejection Summary

• 102 Rejections: 0
• 103 Rejections: 1

Cited Patents

No patents were cited in this rejection.

Office Action Text

    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 .
Applicant’s election without traverse of SEQ ID NO: 6 and non-bicyclic in the reply filed on 2/5/05 is acknowledged.

 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 65-84 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of inhibiting GYS1, does not reasonably provide enablement for a method of inhibiting GYS1treating adult polyglucosan body disease via broad delivery of the instant genus of oligonucleotides.  The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to: 
(A) The breadth of the claims; 
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and 
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. 
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The instant claims are directed to a method of treating adult polyglucosan body disease comprising broad systemic delivery of any modified antisense oligonucleotide that is 15-30 nucleotides in length and comprises a sequence at least 95% complementary to an equal length portion of SEQ ID NO: 6, wherein the oligonucleotide comprises a phosphorothioate modification.
The specification demonstrates intracerebroventricular injection into mice of ISIS 648402 and 648327 and resultant in vivo inhibition of GYS1.  Lafora bodies were quantified resulting in decreased levels with ISIS 648402 and 648327 compared to control (Example 5). The specification does not adequately draw a nexus between any decrease in GYS1 and any decrease in Lafora bodies and the predictable treatment of adult polyglucosan body disease.  
The specification discloses: "Adult polyglucosan body disease" is characterized by dysfunction of the central and peripheral nervous systems. Associated symptoms and findings may include sensory loss in the legs, progressive muscle weakness of the arms and legs, gait disturbances, urination difficulties, and/or cognitive impairment or dementia. Any level of decrease of Lafora bodies would not necessarily equate with the treatment of adult polyglucosan body disease.  
Additionally, injection into mice of two specific oligomers is not commensurate in scope and is not representative of the entire claimed genus of oligomers, which encompasses oligonucleotides that are 15 nucleotides in length and are at least 95% complementary to any region of SEQ ID NO: 6, which is approximately 31,000 nucleotides in length.  These two oligos are not representative of any 15-30 mer antisense oligonucleotide with a sequence that is at least 95% complementary to an equal length of any portion of SEQ ID NO: 6, which is 31,000 nucleotides in length.  It is noted that the search was limited to first 15000 nucleotides.
For example, Table 1 of the specification demonstrates oligomers that resulted in 0% inhibition.  The claims are not limited to delivery of any specific oligomer that has been demonstrated to result in treatment of adult polyglucoson body disease upon broad systemic delivery.
The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of treating adult polyglucoson body disease via broad delivery of any antisense oligonucleotide with the instant structural requirements targeted to any possible region of a 31,000 nucleotide sequence encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.

Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of
the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed
invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27
USPQ2d 1510, 1513 (Fed. Cir. 1993).

 	Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of RNA in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful treatment of adult polyglucoson body disease.  To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the oligomer molecule in vivo, delivery of the molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein.  Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).

Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA  35 U.S.C. 102 and 103 (or as subject to pre-AIA  35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA  to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.  
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.

The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary.  Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 65-84 are rejected under 35 U.S.C. 103 as being unpatentable over Zois et al. (J Mol Med (2016) 94:137–154), in view of Clayton et al. (Molecular Therapy-Nucleic Acids (2014) 3, e206, 1-11), and Bhat (WO2014/179445 A1).
The references are considered as enabled as the instant specification. 
Zois et al. teach: Glycogen synthase In mammals, glycogen synthase exists in two isoforms, the glycogen synthase 1 (GYS1; 84 kDa, 737 aa), which is expressed in skeletal muscle and other tissues, and the GYS2 (81 kDa, 703 aa), which is expressed predominately in the liver. The liver isoform (GYS2, 81 kD) is about 70 % identical to the muscle isoform (GYS1, 84 kD) and has several phosphorylation sites near the N- and C-terminus [11]. GYS1 and GYS2 deficiency cause the muscle and liver glycogen storage disease type 0, respectively. Symptoms involved within those deficiencies are inability to form glycogen, muscle weakness, arrhythmia, sudden death and hypoglycemia. Glycogen synthase exists in a phosphorylated (glycogen synthase b) and a dephosphorylated form (glycogen synthase a). Phosphorylation causes inactivation of the enzyme by decreasing the affinity for UDP-glucose [12, 13], whilst glucose-6- phosphate (G6P) is an allosteric activator of the phosphorylated form [14, 15] (Figs. 2 and 3). The crystal structure of the glycogen synthase in yeast was reported in 2010 in the presence and absence of the allosteric activator G6P [16]. Glycogen synthase exists as a tetrameric form and has direct interaction with glycogenin and glycogen branching enzyme in order to facilitate glycogen synthesis (page 139)
Importantly, the investigators found that GYS1, UTP:glucose-1-phosphate uridylyltransferase (UGP2) and 1,4-alpha glucan branching enzyme (GBE1) were significantly increased after hypoxia conditions. Further, by knocking down either HIF1α or GYS1 attenuated hypoxia-induced glycogen accumulation, whilst GYS1 overexpression was sufficient to mimic this effect, suggesting that GYS1 regulation by HIF1α plays a central role in the hypoxic accumulation of glycogen [116]. Also, hypoxia preconditioning protects cells during anoxia whilst knockdown of GYS1 expression impairs hypoxic preconditioning and protection, suggesting the important role of glycogen metabolism in acute and chronic hypoxia (pages 145-146).
	Zois et al. teach: Glycogen branching enzyme deficiency is associated with an accumulation of insoluble polysaccharide particles, which lead to the autosomal recessive glycogen storage disorder type IV. Glycogen storage disorder type IV (GSDIV) is a severe disorder with variable onset age and clinical severity, including a classical hepatic form in neonates and children that progresses to cirrhosis (Andersen disease), a neuromuscular form classified into four subtypes (perinatal, congenital, juvenile and adult onset) and a late-onset adult polyglucosan body disease, a neurological disorder affecting mainly the Ashkenazi Jewish population (page 140).
	Zois et al. teach: Glycogen accumulation in neurons during aging is an evolutionarily conserved process from flies to mammals, and Laforin disease resulting from rare mutations in malin and laforin increases the rate of this process. Laforin is a phosphatase of glycogen synthase that can directly bind glycogen through a carbohydrate-binding domain as well as other glycogen metabolizing proteins. Malin is an E3-ubiquitin ligase that is recruited to its substrates through the interaction with Laforin. Furthermore, Laforin and malin form a complex, and with the glycogenolytic enzymes, glycogen debranching enzyme 1 (AGL1) and brain isoform glycogen phosphorylase orchestrate the degradation of the polyglucosan bodies [87]. Brain glycogen or glycogen-like inclusions accumulate in several pathologies such as Pombe disease [88], Lafora disease [89], Alzheimer disease [90], amyotrophic lateral sclerosis [91] and adult polyglucosan body disease (page 144).
	Therefore, it would have been obvious to inhibit GYS1 in adult polyglucosan body disease in a neuron.
	Clayton et al. teach antisense Oligonucleotide-mediated Suppression of Muscle Glycogen Synthase 1 with  phosphorodiamidate morpholino oligomers (title, abstract)
	Clayton et al. teach: GS-PPMO systemic administration to Pompe mice led to a dose-dependent decrease in glycogen synthase transcripts in the quadriceps, and the diaphragm but not the liver. An mRNA response in the heart was seen only at the higher dose tested. Associated with these decreases in transcript levels were correspondingly lower tissue levels of muscle specific glycogen synthase and activity. Importantly, these reductions resulted in significant decreases in the aberrant accumulation of lysosomal glycogen in the quadriceps, diaphragm, and heart of Pompe mice. Treatment was without any overt toxicity, supporting the notion that substrate reduction by GS-PPMO-mediated inhibition of muscle specific glycogen synthase represents a viable therapeutic strategy for Pompe disease after further development (abstract).
	Clayton et al. teach: Skeletal muscle glycogen synthase activity is the result of transcription of the Gys1 gene (OMIM 606800). In contrast, liver glycogen synthase activity is generated mostly by expression of the Gys2 gene (OMIM 138571) and its encoded enzyme produces glycogen as a ready store of glucose for body-wide metabolism (page 2).
	Although Clayton et al. teach treating a different condition, Clayton et al. teach utilizing GYS1 ASO, wherein it was obvious to inhibit GYS1 to treat adult polyglucosan body disease in a neuron, as evidenced by Zois et al.. Clayton et al. is evidence that it was known to utilize ASO to inhibit GYS1 successfully.  Therefore, it would have been obvious to utilize the oligomers of Clayton et al. in the method of Zois et al. with a reasonable expectation of success.
	Additionally, it would have been obvious to incorporate other known modifications that were known to benefit ASOs. The entire target sequence was known, as evidenced by Clayton et al.
Bhat teaches: Described herein are conjugated modified oligonucleotides that are complementary to a target RNA. The conjugate facilitates cellular uptake of the modified oligonucleotide, resulting improved potency (abstract).
Bhat teaches: Provided herein are compounds comprising modified oligonucleotides covalently attached to a conjugate moiety. In certain embodiments, a compound has the structure Ln-linker-X-MO, wherein each L is, independently, a ligand and n is from 1 to 10; X is a phosphodiester linkage or a phosphorothioate linkage; and MO is a modified oligonucleotide.
Bhat teaches: In certain embodiments, where p is 1, 2, 3, or 4, at least one N' comprises a pyrimidine nucleobase. In certain embodiments, N" comprises a pyrimidine nucleobase. In certain embodiments, each pyrimidine nucleobase is independently selected from cytosine, 5-methylcytosine, thymine, uracil, and 5,6-dihydrouracil.
Bhat teaches that the oligomer can be a gapmer and teaches that: "Gapmer” means a modified oligonucleotide having an internal region of linked β-D- deoxyribonucleosides positioned between two external regions of linked nucleosides, where each nucleoside of each external region comprises a modified sugar moiety. The β-D-deoxyribonucleosides may or may not have a modified nucleobase.
Bhat teaches: "Gap" is an internal region of a gapmer that is positioned between the external regions. "Wing" is an external region of a gapmer that is adjacent to a 5'or 3' end of the internal region of the gapmer. "Symmetric gapmer” means each nucleoside of each external region comprises the same sugar modification. "Asymmetric gapmer” means each nucleoside of one external region comprises a first sugar modification, and each nucleoside of the other external region comprises a second sugar modification.
"2'-0-methyl sugar" or "2'-OMe sugar" means a sugar having a O-m ethyl modification at the 2' position.
"2'-0-methoxyethyl sugar" or "2'-MOE sugar" means a sugar having a O-m ethoxy ethyl modification at the 2' position.
"Bicyclic sugar moiety" means a modified sugar moiety comprising a 4 to 7 membered ring (including by not limited to a furanosyl) comprising a bridge connecting two atoms of the 4 to 7 membered ring to form a second ring, resulting in a bicyclic structure. In certain embodiments, the 4 to 7 membered ring is a sugar ring. In certain embodiments the 4 to 7 membered ring is a furanosyl. In certain such embodiments, the bridge connects the 2'-carbon and the 4'-carbon of the furanosyl. Nonlimiting exemplary bicyclic sugar moieties include LNA, ENA, cEt, S-cEt, and R-cEt. "Locked nucleic acid (LNA) sugar moiety" means a substituted sugar moiety comprising a (CH2)-0 bridge between the 4' and 2' furanose ring atoms.
"S-cEt sugar moiety" means a substituted sugar moiety comprising an S-constrained CH(CH3)-0 bridge between the 4' and the 2' furanose ring atoms.
"R-cEt sugar moiety" means a substituted sugar moiety comprising an R-constrained CH(CH3)-0 bridge between the 4' and the 2' furanose ring atoms.
In certain embodiments, a modified oligonucleotide consists of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 linked nucleosides. In certain embodiments, a modified oligonucleotide consists of 7 to 10 linked nucleosides. In certain embodiments, a modified oligonucleotide consists of 8 to 10 linked nucleosides. In certain embodiments, a modified oligonucleotide consists of 8 to 12 linked nucleosides. In certain embodiments, a modified oligonucleotide consists of 8 to 25 linked nucleosides. In certain embodiments, a modified oligonucleotide consists of 12 to 25 linked nucleosides. In certain embodiments, a modified oligonucleotide consists of 15 to 25 linked nucleosides. In certain embodiments, a modified oligonucleotide consists of 15 to 22 linked nucleosides. 
	Bhat teaches: In certain embodiments, at least one internucleoside linkage of a modified oligonucleotide is a modified internucleoside linkage. In certain embodiments, each internucleoside linkage of a modified oligonucleotide is a modified internucleoside linkage. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage. In certain embodiments, at least one nucleoside of a modified oligonucleotide comprises a modified nucleobase. In certain embodiments, at least one pyrimidine of the modified oligonucleotide comprises a 5-methyl group. In certain embodiments, at least one nucleoside of a modified oligonucleotide comprises a 5-methylcytosine In certain embodiments, each cytosine of a modified oligonucleotide is a 5-methylcytosine.
In certain embodiments, each nucleoside of the modified oligonucleotide comprises a bicyclic sugar moiety. In certain embodiments, the bicyclic sugar moiety is a cEt sugar moiety. In certain embodiments, the cEt sugar moiety is an S-cEt sugar moiety. In certain embodiments, the bicyclic sugar moiety is an LNA sugar moiety. In certain embodiments, a modified oligonucleotide is a gapmer.
	Bhat teaches: In certain embodiments, a modified oligonucleotide has a gapmer motif. In certain embodiments, each nucleoside of each external comprises the same modified sugar moiety. In certain embodiments, at least two nucleosides of one external region comprise modified sugar moieties that are different from one another. In certain embodiments, at least two nucleosides of each external region comprise modified sugar moieties that are different from one another. In certain embodiments, each nucleoside of each external region comprises a 2'-0-methoxyethyl sugar. In certain embodiments, each nucleoside of each external region comprises a bicyclic sugar moiety. In certain embodiments, the bicyclic sugar moiety is a cEt sugar moiety. In certain embodiments, the cEt sugar moiety is an S-cEt sugar moiety. In certain embodiments, the bicyclic sugar moiety is an LNA sugar moiety.
	In certain embodiments, each external region of a gapmer consists of the same number of linked nucleosides. In certain embodiments, one external region of a gapmer consists a number of linked nucleosides different than that of the other external region.
In certain embodiments, each external region comprises, independently, from 1 to 6 nucleosides. In certain embodiments, an external region comprises 1 nucleoside. In certain embodiments, an external region comprises 2 nucleosides. In certain embodiments, an external region comprises 3 nucleosides. In certain embodiments, an external region comprises 4 nucleosides. In certain embodiments, an external region comprises 5 nucleosides. In certain embodiments, an external region comprises 6 nucleosides. In certain embodiments, the internal region consists of 17 to 28 linked nucleosides. In certain embodiments, an internal region consists of 17 to 21 linked nucleosides. In certain embodiments, an internal region consists of 17 linked nucleosides. In certain embodiments, an internal region consists of 18 linked nucleosides. In certain embodiments, an internal region consists of 19 linked nucleosides. In certain embodiments, an internal region consists of 20 linked nucleosides. In certain embodiments, an internal region consists of 21 linked nucleosides. In certain embodiments, an internal region consists of 22 linked nucleosides. In certain embodiments, an internal region consists of 23 linked nucleosides. In certain embodiments, an internal region consists of 24 linked nucleosides. In certain embodiments, an internal region consists of 25 linked nucleosides. In certain embodiments, an internal region consists of 26 linked nucleosides. In certain embodiments, an internal region consists of 27 linked nucleosides. In certain embodiments, an internal region consists of 28 linked nucleosides.
	Bhat teaches: In certain embodiments, each external region comprises 5 linked nucleosides, and the internal region comprises 10 linked nucleosides. In certain embodiments, each external region comprises 4 linked nucleosides, and the internal region comprises 10 linked nucleosides. In certain embodiments, each external region comprises 3 linked nucleosides, and the internal region comprises 10 linked nucleosides. In certain embodiments, each external region comprises 2 linked nucleosides, and the internal region comprises 10 linked nucleosides.
	Bhat teaches that the modifications facilitates cellular uptake, increase potency and enhance the stability in the presence of nucleases.  Therefore, it would have been obvious to incorporate any of the modifications of Bhat into an antisense oligomer targeted to GYS1 for utilization in a method of treating adult polyglucosan body disease in a neuron with the oligomers of Clayton et al. with a reasonable expectation of having the benefits taught by Bhat.
	Applicant has not demonstrated any unexpected property for antisense oligonucleotides targeting instant SEQ ID NO: 6, which is a 30,999 nucleotide fragment of NC_000019.10, which is 58,617,616 nucleotides in length.  It was known to design antisense oligomers targeting GYS1 and there was motivation to inhibit GYS1 to treat adult polyglucosan body disease.

Markush Rejection
Claims 65-84 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives.  See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).  The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.  The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons:  The claims are directed to a method of delivering modified oligonucleotides 15-30 nucleotides in length that target a 31,000 nucleotide target (SEQ ID NO: 6), as well as SEQ ID NOs: 2-5, encompassing an enormous possible genus of oligonucleotides with no common searchable core or activity.  The patent office does not have the resources to search the 31,000 nt sequence in a single application with additional target sequences SEQ ID NOs: 2-5.  
Additionally, a search for one of the sequences would not necessarily return art against any of the others.  Oligonucleotides with completely different sequences different regions have varying activity wherein the activity of each is dependent upon the specific sequence of nucleotides.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature.  This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. 134 and 37 CFR 41.31(a)(1).     
When the Markush grouping is for alternatives of chemical compounds, they shall be regarded as being of a similar nature where the following criteria are fulfilled: 
(A) All alternatives have a common property or activity; and 
(B) (1) A common structure is present, i.e., a significant structural element is shared by all of the alternatives; or 
(B) (2) In cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains. 
In paragraph (B)(1), above, the words “significant structural element is shared by all of the alternatives” refer to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity. The structural element may be a single component or a combination of individual components linked together. 
In paragraph (B)(2), above, the words “recognized class of chemical compounds” mean that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved. 
In order for the members of the Markush group to belong to “recognized class of chemical compounds” there must be an expectation that the members of the class will behave in the same way in the context of the claimed invention.  In other words, each member of the class could be substituted one for the other with the expectation that the same intended result would be achieved.  In the instant case, activity of any specific oligonucleotide is dependent upon the specific sequence of nucleotides.  There is no expectation that any one of the nucleotide sequences as claimed can be substituted for any of the other with a completely different sequence with the expectation of the same activity.
In addition to SEQ ID NO: 6, the claims recite SEQ ID NOs: 2-5.  Each of the sequences have a different order of nucleotides, wherein oligomers targeted to each have different activities.  The oligomers targeting each target have different sequences and do not have identical activity.

Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA  as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). 
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 65-84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,713,462 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of US ‘462 B2 are directed to a method of treating Lafora disease via the same method steps as instantly recited.  The claim sets recite the same types of modifications and patterns.  The instant specification discloses that inhibiting GYS1 resulted in a decrease in Lafora bodies.  The claims are obvious variations of each other.

Claims 65-84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,236,339 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of US ‘339 B2 are directed to a method of treating Lafora disease via the same method steps as instantly recited, wherein US ‘339 B2 is directed to delivery of oligonucleotides of the same length that are at least 95% complementary to an equal length portion of SEQ ID NO: 2, 3, 4, or 5, whereas the instant claims are directed to delivery of oligonucleotides of the same length that are at least 95% complementary to an equal length portion of SEQ ID NO: 6.  However, the sequences contain some common sequence and therefore identical possible oligomers.  For example, SEQ ID NO: 6 comprises the sequence of SEQ ID NO: 2 starting at nucleotide 2648.    The claim sets recite the same types of modifications and patterns.  The instant specification discloses that inhibiting GYS1 resulted in a decrease in Lafora bodies.  The claims are obvious variations of each other.

Conclusion
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636