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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 03/04/2026 is acknowledged. Claims 59,62 and 63 were cancelled. Claims 1,34,40 and 64-68 were amended. Claims 69 and 70 are new.
Applicant elected Group III (claims 40 and 59-68) without traverse in the reply filed on 07/21/2025 and the Examiner rejoined Group I (claims 1 and 34-36)
Claim 39 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant elected IRES and PTV-1 based IRES (SEQ ID NO: 1) as Species A and SYNGAP1 as Species B without traverse in the reply filed on 07/21/2025. Species A was expanded to include EMCV IRES, and Species B was expanded to include SCN1A mRNA due to art found for these limitations.
Claims 1,34-36,40,60,61 and 64-70 are under examination.
Priority
This application is a 371 of PCT/US2021/070200, filed 02/26/2021, which claims benefit of PRO 62/993,151, filed 03/23/2020, and claims benefit of PRO 62/983,030, filed 02/28/2020.
Withdrawn Rejections
Applicant’s arguments and amendments, see page 4, filed 03/04/2026, with respect to the 35 U.S.C. 112(b) rejection of claims 34 and 65-68 have been fully considered and are persuasive due to the amendment to claim 34 to recite “the chimeric nucleic acid” and the amendments to claims 65-67 correcting the preamble to recite “The method” and dependency on the correct claims and correcting the antecedent basis issue and correct dependency in claim 68. The 35 U.S.C. 112(b) rejection of claims 34 and 65-68 has been withdrawn.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 60,61 and 68 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 60 and 61, line 1 of each claim recites “wherein the mRNA…”. Claims 60 and 61 depend on claim 40 which has been amended and no longer recites “a mRNA”. There is insufficient antecedent basis for this limitation in the claims.
Regarding claim 68, which was amended to depend on claim 1, it recites “wherein the targeting region comprises a region that is complementary to a mRNA…”. Claim 1 has been amended and no longer recites “a targeting region”. There is insufficient antecedent basis for this limitation in the claims.
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.
Claim Rejections- Written Description
Claims 40,60,61,64-67 and 69 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.
Claims 40,60,61,64-67 and 69 encompass a method for treating a haploinsufficiency disorder in a subject, wherein the haploinsufficiency disorder is further defined as a deficiency in the protein expression of one or both alleles of a of target gene and wherein the haploinsufficiency disorder comprises a SYNGAP1-related intellectual disability or autism spectrum disorder or Dravet Syndrome, and wherein the target gene comprises SYGNAP1 or SCN1A respectively, the method comprising administering to the subject a genus of chimeric nucleic acids comprising a genus of antisense nucleic acids complementary to a genus of target RNA, a linker region and an eIF translation factor binding site.
Regarding the state of the art, California (WO 2019204828), cited on an IDS, teaches a fusion RNA (chimeric nucleic acid) comprising or consisting of (i) a guide nucleotide sequence-programmable RNA which may be a guide RNA (targeting region) and (ii) one or more internal ribosome entry sites (IRES) or a portion thereof (translational activating region comprising a ribosome binding site) (page 58, lines 17-23), and wherein the guide nucleotide sequence-programmable RNA comprises a nucleotide sequence complementary to a target nucleic acid, which is mRNA (page 58, lines 29-31). California teaches the systems are for increasing translation of target mRNA (page 120, lines 25-28) and teaches methods of treating a disease or disorder comprising administering to a subject a composition of the disclosure (page 124, lines 21-23) and the disease or disorder is a genetic disease or disorder (page 125, lines 17-18).
Creson et al. (eLife8:e46752, Published 26 April 2019) teach that SYNGAP1 haploinsufficiency causes a severe NDD defined by autistic traits, cognitive impairment, and epilepsy (Abstract, and page 2). Creson et al. teach that gene restoration in an adult mouse model for SYNGAP1 haploinsufficiency improved behavioral and electrophysiological measures of memory and seizure (Abstract and Discussion page 10), and therefore the impact of these findings is that therapies that improve the expression and/or function of SynGAP protein may be beneficial to Autosomal Dominant Mental Retardation-5 (MRD5) patients of all ages (page 11, first paragraph).
Arnarez et al. (US 20180369275, Published 27 Dec 2018) teach mental retardation is the most prevalent handicap of children affecting 1-3% of the population and Autosomal Dominant Mental Retardation-5 (MRD5) is a prevalent nonsyndromic form of the disorder characterized by the lack of associated morphologic, radiologic and metabolite features (paragraphs 0003,0057). Arnarez et al. teach identification of de novo lesions in the SYNGAP1 gene that resulted in production of truncated proteins in approximately 3% of patients with unexplained nonsyndromic mental retardation, and SYNGAP1 is a GTPase-activating enzyme that is selectively expressed in the brain and required for normal development (paragraphs 0003,0057). Arnarez et al. also teach that mutations in the SCN1A gene are associated with the development of the disease Dravet Syndrome, also known as severe myoclonic epilepsy of infancy or SMEI (paragraphs 0004,0060). Arnarez et al. teach SCN1A gene is located in the cluster of sodium channel genes on human chromosome 2q24 and encodes the alpha-pore forming subunits known as Nav1.1 of the neuronal voltage gated sodium channel (paragraph 00620, and therefore teaches that SCN1A mRNA would be endogenously produced mRNA from a cell (paragraph 0062). Arnarez et al. teach methods of treating Autosomal Dominant Mental Retardation-5 (MRD5) or Dravet Syndrome in a subject by increasing the expression of the target protein or functional RNA by cells of the subject, by contacting the cells of the subject with an antisense oligomer complementary to a targeted portion of retained intron-containing pre-mRNA encoding the target protein or functional RNA (paragraph 0005), and increasing expression of a target protein which is SYNGAP1 or SCN1A by contacting the cells with the ASO complementary to the RIC pre-mRNA encoding SYNGAP1 or SCN1A protein (paragraph 0006). Arnarez et al. teach the treating a subject in which the cells are in a subject having a condition caused by a deficient amount or activity of SYNGAP1 or SCN1A protein, and in some embodiments, the deficient amount of the target protein is caused by haploinsufficiency (paragraphs 0007,0056,0093).
Therefore, the state of the art teaches the association of the haploinsufficiency of the SYNGAP1 gene with severe NDD and MRD5, and the SCN1A gene with Dravet Syndrome, and therapies that improve the expression and/or function of SynGAP protein or SCN1A protein, including using an ASO complementary to the mRNA of the SYNGAP1 can be used to treat MRD5 and for SCN1A protein can be used to treat Dravet Syndrome.
The instant specification discloses a chimeric nucleic acid comprising a targeting region complementary to a genus of mRNAs, including tumor suppressor mRNA and lists many specific tumor suppressor mRNAs (paragraph 0016), and targeting region complementary to mRNA from the SYNGAP1, ATP1A3, SCN1A, SCN2 or SIMI1 gene (paragraph 0017), or the PPIB gene (paragraph 0020). The specification discloses that the nucleic acid is used for treating many different disorders, treating SYNGAP 1-related intellectual disability or autism spectrum disorder, treating ATP1A3-related neurological disorders, neurological disorders, alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, dystonia 12, cerebellar ataxia, areflexia, pes cavus, optic atrophy, or sensorineural hearing loss, treating epileptic encephalopathy, epilepsy, epilepsy with febrile seizures, familial hemiplegic migraine, or Lennox-Gastaut syndrome, treating neutropenia, severe congenital neutropenia, autosomal dominant neutropenia, nonimmune chronic idiopathic neutropenia, myeloid leukemia, AML, myelodysplastic syndrome, or myeloproliferative disease, the nucleic acid is used in a method for treating obesity, obesity due to SIMI deficiency, and SIMI-related Prader-Willi-Like Syndrome (paragraphs 0017). The specification discloses using the nucleic acids to treat many haploinsufficiency disorders (the haploinsufficiency disorder comprises Wolfram syndrome; the haploinsufficiency disorder comprises Alzheimer's Disease; the haploinsufficiency disorders comprises cancer, 1q21.1 deletion syndrome, 5q- syndrome in myelodysplastic syndrome (MDS), 22q11.2 deletion syndrome, CHARGE syndrome, cleidocranial dysostosis, Ehlers-Danlos syndrome, frontotemporal dementia caused by mutations in progranulin, GLUT1 deficiency (DeVivo syndrome), haploinsufficiency of A20, holoprosencephaly caused by haploinsufficiency in the Sonic Hedgehog gene, Holt-Oram syndrome, Marfan syndrome, Phelan-McDermid syndrome, polydactyly, or Dravet Syndrome (paragraph 0020).
The instant specification discloses that the chimeric nucleic acid comprises gRNA as the targeting domain, and an IRES as the translational activating region (paragraph 0041), and discloses specific IRES Sequences (pages 14-21,49 and 50). The specification discloses targeting regions or gRNA to specific mRNAs on page 22, include SEQ ID NOs 6-21), and which are specific to Lux, PPIB, p21, WFS1, and ABCA7 (page 22).
Regarding the examples, Example 1 shows the design and construction of gRNA-IRES with EMCV, HCV, PTV-1 or CrPV IRES, but the guide RNA are reversely complementary to firefly luciferase mRNA (paragraph 0115), and then PPIB was selected as the first endogenous target and the gRNA-PTV-1 was used in HEK293T cells and showed significant higher protein amount when adding 3’ UTR targeting gRNA (paragraph 0117, Fig. 3A).
Paragraph 0119 shows the inventors designed and tested gRNA for WFS1 mRNA (associated with Wolfram syndrome) with PTV-1 IRES and tested efficacy for protein level increase in HEK293T cells and Western Blot analysis showed higher protein amount (Fig. 4A).
Paragraph 0120 shows the inventors designed and tested gRNA for ABCA7 and PTV-1 IRES and results showed higher ABCA7 protein amount in HEK293T cells (Fig. 4B).
Example 2 shows a 40-nt 3-UTR targeting gRNA design and PTV-1 IRES as the translational machinery recruiting domain (paragraph 0123), and additional testing of the chimeric nucleic acid comprising gRNA targeting the 3’UTR of PPIB, p21 and PTEN fused to PTV-IRES in HEK293T cells, which led to increased protein level of PPIB, p21, and PTEN (Paragraph 0124, Figs. 7A-7C).
Paragraph [0128] shows the J-K region of the EMCV IRES is also effective as the taRNA recruiting domain (Fig. 9D).
While the specification discloses various sequences of gRNA for targeting specific mRNAs, some of which are associated with haploinsufficiency disorders, and the specification discloses using EMCV, HCV, PTV-1 or CrPV IRES in the chimeric nucleic acids, the specification does not provide a structure-function correlation for the genus of chimeric nucleic acids having the function of treating a haploinsufficiency disorder comprising a SYNGAP1-related intellectual disability or autism spectrum disorder or Dravet Syndrome. Claims 40,60,61,64-67 and 69 are directed to encompass a large genus of chimeric nucleic acids having an antisense nucleic acid that is complementary to a genus of target RNA having the recited function of treating a haploinsufficiency disorder comprising a SYNGAP1-related intellectual disability or autism spectrum disorder or Dravet Syndrome, which only correspond in some undefined way to specifically instantly disclosed chemicals. None of these chimeric nucleic acids meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, due to lacking chemical structural information for what they are and chemical structures are highly variant and encompass a myriad of possibilities. The specification does not show what the required structure is of chimeric nucleic acid consisting of an antisense nucleic acid that is complementary to a target RNA, linker region(s), and an eIF translation factor binding site that has the function of treating a haploinsufficiency disorder comprising a SYNGAP1-related intellectual disability or autism spectrum disorder or Dravet Syndrome. While the specification shows some in vitro results in cells using chimeric nucleic acids comprising gRNAs for a few target mRNAs (PPIB, p21 and PTEN) and the increase in protein expression, this does not provide written support for the genus of chimeric nucleic acids having the function of treating the recited haploinsufficiency disorders which are a deficiency in the protein expression of one or both alleles of the target gene SYNGAP1 or SCN1A. The specification provides insufficient written description to support the genus encompassed by the claim. Note: MPEP 2163.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, (Fed. Cir. 1991), makes clear that "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.)
Univ. of Rochester v. G.D. Searle, 69 USPQ2d 1886, 1892 (CAFC 2004), further supports this by stating that:
The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. A description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) described even in terms of its functioning of lessening inflammation of tissues fails to distinguish any steroid from others having the same activity or function. A description of what a material does, rather than of what it is, usually does not suffice…. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. (Emphasis added).
The skilled artisan cannot envision the detailed chemical structure of the
encompassed chimeric nucleic acids used in the method of treating a haploinsufficiency disorder comprising a SYNGAP1-related intellectual disability or autism spectrum disorder or Dravet syndrome wherein the target gene comprises SYNGAP1 or SCN1A, respectively. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The chemical structure itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Circ. 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, (Fed. Cir. 1991). In Fiddes v. Baird, 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 (Fed. Cir. 1997) held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Furthermore, to the extent that a functional description can meet the requirement for an adequate written description, it can do so only in accordance with PTO guidelines stating that the requirement can be met by disclosing “sufficiently detailed, relevant identifying characteristics,” including “functional characteristics when coupled with a known or disclosed correlation between function and structure.” Univ. of Rochester v. G.D. Searle, 68 USPQ2d 1424, 1432 (DC WNY 2003).
Therefore, in view of the prior art there is sufficient written description for a method of treating Autosomal Dominant Mental Retardation-5 (MRD5) comprising administering a chimeric nucleic acid comprising a gRNA targeting SYNGAP1 and an IRES, and treating Dravet Syndrome comprising administering a chimeric nucleic acid comprising gRNA targeting SCN1A and an IRES, but not the full breadth of the claim(s) meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC § 112 is severable from its enablement provision. (See page 1115.)
Response to Arguments
Applicant's arguments and amendments, filed 03/04/2026 have been fully considered and are partially persuasive, therefore the rejection is partially withdrawn in regards to claims 1,34-36 and 68, due to them being product claims without a recited function. However, the rejection remains for claims 40,60,61,64-67 and 69.
Applicant argues on page 4 of response that the current claims have been amended to what is considered supported according to the office action and no further arguments were made.
While, the amendments to these claims do help with some of the written description issues, including the amendment to claim 40 regarding more specific haploinsufficiency disorders and the target genes SYNGAP1 or SCN1A, the chimeric nucleic acid that is being administered (consisting of an antisense nucleic acid that is complementary to a target RNA, linker region(s), and an eIF translation factor binding site) still encompasses a large genus of chimeric nucleic acids that carry out the recited function of treating the recited haploinsufficiency disorders with deficiency in the protein expression of one or both alleles of a target gene, which comprises SYNGAP1 or SCN1A. Applicant did not amend the chimeric nucleic acid that is being administered to recite that the antisense nucleic acid is complementary to target RNA of SYNGAP1 or SCN1A, and therefore still encompasses administering a chimeric nucleic acid that includes an antisense nucleic acid that is complementary to any target RNA, including those that do not have any relationship to haploinsufficiency disorders or the recited target genes, SYNGAP1 or SCN1A. See the final paragraph of the written description rejection on page 13 of the Office Action, where the Examiner stated, in view of the prior art there is sufficient written description for a method of treating Autosomal Dominant Mental Retardation-5 (MRD5) comprising administering a chimeric nucleic acid comprising gRNA targeting SYNGAP1 and an IRES and treating Dravet Syndrome comprising administering a chimeric nucleic acid comprising gRNA targeting SCN1A and an IRES. Amending the claims to recite that the chimeric acid consisting of an antisense nucleic acid that is complementary to target RNA which is SYNGAP1 or SCN1A, respectively, linker region(s), and an eIF translation factor binding site would be sufficient to overcome the rejection.
Claim Rejections-Scope of Enablement
Claims 40,60,61,64-67 and 69 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 treating a haploinsufficiency disorder in a subject which is a deficiency in the protein expression of one or both alleles of a target gene, wherein the haploinsufficiency disorder comprises a SYNGAP1-related intellectual disability or autism spectrum disorder or Dravet syndrome and wherein the target gene comprises SYNGAP1 or SCN1A, respectively comprising parenterally administering a chimeric nucleic acid consisting of an antisense nucleic acid complementary to mRNA of SYNGAP1 or SCN1A respectively, a linker and IRES by way of the prior art, does not reasonably provide enablement for a method of treating a haploinsufficiency disorder in a subject wherein the haploinsufficiency disorder is further defined as a deficiency in the protein expression of one or both alleles of a target gene, wherein the haploinsufficiency disorder comprises a SYNGAP1-related intellectual disability or autism spectrum disorder or Dravet syndrome, and wherein the target gene comprises SYNGAP1 or SCN1A respectively, the method comprising parenterally administering a genus of chimeric nucleic acids consisting of a genus of antisense nucleic acids that are complementary to any target RNA, linker region(s), and an eIF translation factor binding site to the subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessary needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
The Breadth of the Claims and The Nature of the Invention
Claims 40,60,61,64-67 and 69 encompass a method for treating a haploinsufficiency disorder in a subject, wherein the haploinsufficiency disorder is further defined as a deficiency in the protein expression of one or both alleles of a target gene and wherein the haploinsufficiency disorder comprises a SYNGAP1-related intellectual disability or autism spectrum disorder or Dravet Syndrome, and wherein the target gene comprises SYGNAP1 or SCN1A respectively, the method comprising administering to the subject a genus of chimeric nucleic acids comprising a genus of antisense nucleic acids complementary to a genus of target RNA, a linker region and an eIF translation factor binding site.
The State of the Prior Art
Regarding the state of the art, California (WO 2019204828) teaches a fusion RNA (chimeric nucleic acid) comprising or consisting of (i) a guide nucleotide sequence-programmable RNA which may be a guide RNA (targeting region) and (ii) one or more internal ribosome entry sites (IRES) or a portion thereof (translational activating region comprising a ribosome binding site) (page 58, lines 17-23), and wherein the guide nucleotide sequence-programmable RNA comprises a nucleotide sequence complementary to a target nucleic acid, which is mRNA (page 58, lines 29-31). California teaches the systems are for increase translation of target mRNA (page 120, lines 25-28) and teaches methods of treating a disease or disorder comprising administering to a subject a composition of the disclosure (page 124, lines 21-23) and the disease or disorder is a genetic disease or disorder (page 125, lines 17-18).
Creson et al. (eLife8:e46752, Published 26 April 2019) teach that SYNGAP1 haploinsufficiency causes a severe NDD defined by autistic traits, cognitive impairment, and epilepsy (Abstract, and page 2). Creson et al. teach that gene restoration in an adult mouse model for SYNGAP1 haploinsufficiency improved behavioral and electrophysiological measures of memory and seizure (Abstract and Discussion page 10), and therefore the impact of these findings is that therapies that improve the expression and/or function of SynGAP protein may be beneficial to Autosomal Dominant Mental Retardation-5 (MRD5) patients of all ages (page 11, first paragraph).
Arnarez et al. (US 20180369275, Published 27 Dec 2018) teach mental retardation is the most prevalent handicap of children affecting 1-3% of the population and Autosomal Dominant Mental Retardation-5 (MRD5) is a prevalent nonsyndromic form of the disorder characterized by the lack of associated morphologic, radiologic and metabolite features (paragraphs 0003,0057). Arnarez et al. teach identification of de novo lesions in the SYNGAP1 gene that resulted in production of truncated proteins in approximately 3% of patients with unexplained nonsyndromic mental retardation, and SYNGAP1 is a GTPase-activating enzyme that is selectively expressed in the brain and required for normal development (paragraphs 0003,0057). Arnarez et al. also teach that mutations in the SCN1A gene are associated with the development of the disease Dravet Syndrome, also known as severe myoclonic epilepsy of infancy or SMEI (paragraphs 0004,0060).
Arnarez et al. teach SCN1A gene is located in the cluster of sodium channel genes on human chromosome 2q24 and encodes the alpha-pore forming subunits known as Nav1.1 of the neuronal voltage gated sodium channel (paragraph 00620, and therefore teaches that SCN1A mRNA would be endogenously produced mRNA from a cell (paragraph 0062). Arnarez et al. teach methods of treating Autosomal Dominant Mental Retardation-5 (MRD5) or Dravet Syndrome in a subject by increasing the expression of the target protein or functional RNA by cells of the subject, by contacting the cells of the subject with an antisense oligomer complementary to a targeted portion of retained intron-containing pre-mRNA encoding the target protein or functional RNA (paragraph 0005), and increasing expression of a target protein which is SYNGAP1 or SCN1A by contacting the cells with the ASO complementary to the RIC pre-mRNA encoding SYNGAP1 or SCN1A protein (paragraph 0006). Arnarez et al. teach the treating a subject in which the cells are in a subject having a condition caused by a deficient amount or activity of SYNGAP1 or SCN1A protein, and in some embodiments, the deficient amount of the target protein is caused by haploinsufficiency (paragraphs 0007,0056,0093).
Regarding the route of administration, Arnarez et al. teach routes for administration vary depending on the cell type to which delivery of the ASO is desired and multiple tissues and organs are affected by AD mental retardation 5 and Dravet syndrome with the brain being the most significantly affected tissue and administration may be to patients parenterally, for example by intrathecal injection, intracerebroventricular injection, intraperitoneal injection, intramuscular injection, subcutaneous injection or intravenous injection (paragraph 0176).
Therefore, the state of the art teaches the association of the haploinsufficiency of the SYNGAP1 gene with severe NDD and MRD5, and the SCN1A gene with Dravet Syndrome, and therapies that improve the expression and/or function of SynGAP protein or SCN1A protein, including using an ASO complementary to the mRNA of the SYNGAP1 can be used to treat MRD5 and for SCN1A protein can be used to treat Dravet Syndrome, and the state of the art teaches particular routes of administration for MRD5 and Dravet Syndrome as the brain is the most affected tissue.
The Level of Predictability in the Art
The instant claimed invention is highly unpredictable due to the claims encompassing a method of treating a haploinsufficiency disorder in a subject wherein the haploinsufficiency disorder is further defined as a deficiency in the protein expression of one or both alleles of a target gene, wherein the haploinsufficiency disorder comprises a SYNGAP1-related intellectual disability or autism spectrum disorder or Dravet syndrome, and wherein the target gene comprises SYNGAP1 or SCN1A respectively, the method comprising parenterally administering to the subject a genus of chimeric nucleic acids consisting of a genus of antisense nucleic acids that are complementary to any target RNA, linker region(s), and an eIF translation factor binding site. It is unpredictable that the method as recited is capable of treating the recited haploinsufficiency disorders which are SYNGAP-1 related or SCN1A-related by administering any chimeric nucleic acid consisting of a genus of antisense nucleic acids that are complementary to any target RNA, linker region(s), and an eIF translation factor binding site as encompassed by the instant claims because the administered chimeric nucleic acid encompasses an antisense nucleic acid complementary to any target RNA, including those that have no relationship with SYNGAP-1 or SNC1A. The instant specification shows that the target mRNA could be tumor suppressor genes. Administering a chimeric nucleic acid that includes an antisense nucleic acid complementary to a target RNA that does not have anything to do with haploinsufficiency disorders pertaining to SYNGAP-1 or SNC1A would be unlikely to result in treating the recited haploinsufficiency disorders.
The Amount of Direction Provided by the Inventor and
The Presence or Absence of Working Examples
Regarding claims 40,60,61,64-67 and 69, the specification does not enable any person skilled in the art to which it pertains to make and/or use the invention commensurate in scope with the claims.
The instant specification discloses a chimeric nucleic acid comprising a targeting region complementary to a genus of mRNAs, including tumor suppressor mRNA and lists many specific tumor suppressor mRNAs (paragraph 0016), and targeting region complementary to mRNA from the SYNGAP1, ATP1A3, SCN1A, SCN2 or SIMI1 gene (paragraph 0017), or the PPIB gene (paragraph 0020). The specification discloses that the nucleic acid is used for treating many different disorders treating SYNGAP 1-related intellectual disability or autism spectrum disorder, treating ATP1A3-related neurological disorders, neurological disorders, alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, dystonia 12, cerebellar ataxia, areflexia, pes cavus, optic atrophy, or sensorineural hearing loss, treating epileptic encephalopathy, epilepsy, epilepsy with febrile seizures, familial hemiplegic migraine, or Lennox-Gastaut syndrome, treating neutropenia, severe congenital neutropenia, autosomal dominant neutropenia, nonimmune chronic idiopathic neutropenia, myeloid leukemia, AML, myelodysplastic syndrome, or myeloproliferative disease, the nucleic acid is used in a method for treating obesity, obesity due to SIMI deficiency, and SIMI-related Prader-Willi-Like Syndrome (paragraphs 0017). The specification discloses using the nucleic acids to treat many haploinsufficiency disorders (the haploinsufficiency disorder comprises Wolfram syndrome; the haploinsufficiency disorder comprises Alzheimer's Disease; the haploinsufficiency disorders comprises cancer, 1q21.1 deletion syndrome, 5q- syndrome in myelodysplastic syndrome (MDS), 22q11.2 deletion syndrome, CHARGE syndrome, cleidocranial dysostosis, Ehlers-Danlos syndrome, frontotemporal dementia caused by mutations in progranulin, GLUT1 deficiency (DeVivo syndrome), haploinsufficiency of A20, holoprosencephaly caused by haploinsufficiency in the Sonic Hedgehog gene, Holt-Oram syndrome, Marfan syndrome, Phelan-McDermid syndrome, polydactyly, or Dravet Syndrome (paragraph 0020).
The instant specification discloses that the chimeric nucleic acid comprising gRNA as the targeting domain, and an IRES as the translational activating region (paragraph 0041), and discloses specific IRES Sequences (pages 14-21,49 and 50). The specification discloses targeting regions or gRNA to specific mRNAs on page 22, include SEQ ID NOs 6-21), and which are specific to Lux, PPIB, p21, WFS1, and ABCA7 (page 22).
Regarding the examples, Example 1 shows the design and construction of gRNA-IRES with EMCV, HCV, PTV-1 or CrPV IRES, but the guide RNA are reversely complementary to firefly luciferase mRNA (paragraph 0115), and then PPIB was selected as the first endogenous target and the gRNA-PTV-1 was used in HEK293T cells and showed significant higher protein amount when adding 3’ UTR targeting gRNA (paragraph 0117, Fig. 3A).
Paragraph 0119 shows the inventors designed and tested gRNA for WFS1 mRNA (associated with Wolfram syndrome) with PTV-1 IRES and tested efficacy for protein level increase in HEK293T cells and Western Blot analysis showed higher protein amount (Fig. 4A).
Paragraph 0120 shows the inventors designed and tested gRNA for ABCA7 and PTV-1 IRES and results showed higher ABCA7 protein amount in HEK293T cells (Fig. 4B).
Example 2 shows a 40-nt 3-UTR targeting gRNA design and PTV-1 IRES as the translational machinery recruiting domain (paragraph 0123), and additional testing of the chimeric nucleic acid comprising gRNA targeting the 3’UTR of PPIB, p21 and PTEN fused to PTV-IRES in HEK293T cells, which led to increased protein level of PPIB, p21, and PTEN (Paragraph 0124, Figs. 7A-7C).
Paragraph [0128] shows the J-K region of the EMCV IRES is also effective as the taRNA recruiting domain (Fig. 9D).
In summary, the specification provides no in vivo examples for treating any haploinsufficiency disorders, and only provides in vitro cell-based experiments for a few target genes using a few exemplified chimeric nucleic acids that result in increased protein level of the target gene.
The Quantity of Experimentation Necessary
Regarding claims 40,60,61,64-67 and 69, in light of the unpredictability surrounding the breadth of the claimed method (i.e. treating a haploinsufficiency disorder in a subject, wherein the haploinsufficiency disorder is further defined as a deficiency in the protein expression of one or both alleles of a target gene and wherein the haploinsufficiency disorder comprises a SYNGAP1-related intellectual disability or autism spectrum disorder or Dravet Syndrome, and wherein the target gene comprises SYGNAP1 or SCN1A respectively, the method comprising administering to the subject a genus of chimeric nucleic acids comprising a genus of antisense nucleic acids complementary to a genus of target RNA, a linker region and an eIF translation factor binding site), one wishing to practice the presently claimed invention would be unable to do so without engaging in undue experimentation. While the art (California (WO 2019204828) teach a fusion RNA comprising a guide nucleotide sequence-programmable RNA which may be a guide RNA complementary to a target mRNA, linker and (ii) IRES or a portion thereof (page 58, lines 17-23), and treating genetic diseases with the fusion RNA and Arnarez et al. teach treatment of Autosomal Dominant Mental Retardation-5 (MRD5) in a subject by administering a chimeric nucleic acid comprising a targeting region complementary to mRNA of SYNGAP1 and wherein the translational activation region comprises an IRES, and a method of treating Dravet Syndrome in a subject by administering a chimeric nucleic acid comprising a targeting region complementary to mRNA of SCN1A and wherein the translational activation region comprises an IRES and wherein administration is parenterally (intrathecal injection, intracerebroventricular injection, intraperitoneal injection, intramuscular injection, subcutaneous injection or intravenous injection), the instant specification does not enable the full scope of the claim. Additional experimentation regarding the chimeric nucleic acid consisting of an antisense nucleic acid that is complementary to any target RNA of any gene, linker region and an eIF translation factor binding site would be needed, and would be considered undue.
Therefore, given the lack of guidance present in the specification for the recited method, further experimentation would be required and would be considered undue.
Conclusion of 35 U.S.C. 112(a) (Enablement) Analysis
After applying the Wands factors and analysis to claims 40,60,61,64-67 and 69, in view of the applicant’s entire disclosure, it is concluded that the specification is not enabled for the full scope as discussed above. Therefore, claims 40,60,61,64-67 and 69 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to use the invention commensurate in scope with these claims.
Response to Arguments
Applicant's arguments and amendments, filed 03/04/2026 have been fully considered but are not persuasive.
Applicant argues on page 4 of response that the current claims have been amended to what is considered enabled according to the office action and no further arguments were made.
While, the amendments to these claims do help with some of the enablement issues, including the amendment to claim 40 regarding more specific haploinsufficiency disorders and the target genes SYNGAP1 or SCN1A, and reciting “parenterally administering”, the chimeric nucleic acid that is being administered (consisting of an antisense nucleic acid that is complementary to a target RNA, linker region(s), and an eIF translation factor binding site) still encompasses a large genus of chimeric nucleic acids that result in treating the recited haploinsufficiency disorders with deficiency in the protein expression of one or both alleles of a target gene, which comprises SYNGAP1 or SCN1A. Applicant did not amend the chimeric nucleic acid that is being administered to recite that the antisense nucleic acid is complementary to target RNA of SYNGAP1 or SCN1A, and therefore still encompasses administering a chimeric nucleic acid that includes an antisense nucleic acid that is complementary to any target RNA, including those that do not have any relationship to haploinsufficiency disorders or the recited target genes, SYNGAP1 or SCN1A. Amending the claims to recite that the chimeric acid consisting of an antisense nucleic acid that is complementary to target RNA which is SYNGAP1 or SCN1A, respectively, linker region(s), and an eIF translation factor binding site would be sufficient to overcome the rejection.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by California (WO 2019204828, Published 24 Oct 2019), cited on an IDS.
Claim Interpretation: Regarding the amendment to claim 1, requiring the chimeric nucleic acid to include an eIF translation factor binding site, the examiner is interpreting that this still encompasses an IRES based on dependent claims 64 and 66.
Regarding claim 1, California teaches a fusion RNA (chimeric nucleic acid) consisting of (i) a guide nucleotide sequence-programmable RNA which may be a single guide RNA (targeting region) and (ii) one or more internal ribosome entry sites (IRES) or a portion thereof (translational activating region comprising a ribosome binding site) (page 58, lines 17-23), and wherein the guide nucleotide sequence-programmable RNA comprises a nucleotide sequence complementary to a target nucleic acid, which is mRNA (page 58, lines 29-31). California teaches the fusion RNA comprising the sgRNA fused to a type I or type II IRES (page 206, lines 5-7), and which is EMCV-IRES (page 206, lines 14-15,25).
California teaches the fusion RNA further comprises a linker sequence located between the guide nucleotide sequence-programmable RNA and the IRES (Page 59, lines 27-28). California teaches the IRES is an RNA element that allows for translation initiation in a cap-independent manner (page 50, lines 25-26).
Response to Arguments
Applicant's arguments and amendments, filed 03/04/2026 have been fully considered but they are not persuasive.
Applicant argues on page 5 that a chimeric nucleic acid as recited in amended claim 1 is not recited in the ‘828 application. Applicant cites page 25 of the Office Action regarding what ‘828 is cited for, and states that according to the ‘828 application, “The term “guide nucleotide sequence-programmable RNA” refers to a CRISPR-associated RNA comprising a sequence that is complementary and/or homologous to a target nucleic acid (page 9, line 9). Applicant argues that the ‘828 application therefore does not disclose or contemplate a nucleic acid that excludes sequences associated with recruiting CRISPR associated machinery, which is exemplified in FIG. 5 of the ‘828 application and also cites page 11, line 3 and page 9, lines 17-18.
This is not found persuasive. While claim 1 was amended to recite “A chimeric nucleic acid consisting of…”, page 58 of California that was cited in the rejection recites the fusion RNAs comprising, consisting of, or consisting essentially of (i) a guide nucleotide sequence-programmable RNA and (ii) one or more IRES or portion thereof, and page 59 of California discloses the fusion RNA further comprises a linker and teaches a linker sequence located between the guide nucleotide sequence-programmable RNA and the IRES. Based on the broadest reasonable interpretation of amended claim 1, the antisense nucleic acid that is complementary to a target RNA reads on a guide RNA. It is noted that page 22 of the instant specification shows exemplary oligonucleotides which are referred to as guide RNAs to specific mRNAs including Lux gRNA, PPIB gRNA, p21 gRNA, WFS1 gRNA. Even instant Example 1 on pages 46-47 disclose that the inventors designed an antisense translation activating RNA that comprises an anti-sense guide RNA (targeting region) that recognizes and binds target mRNA and an IRES RNA (paragraph 0112) and that the inventors chose to fuse the guide RNA to the more exposed 5’ end of IRES (paragraph 0113). See also paragraph 0124 of the instant specification “The inventors engineered at least two guide RNAs targeting 3' UTR of endogenous transcripts, including PPIB, p21CIPl/WAFl and PTEN, and fused them with PTV-IRES to make individual taRNA”. Therefore, Applicants own disclosure refers to the antisense nucleic acid that is complementary to a target RNA as a guide RNA, and there does not appear to be any structural difference between the instant claimed chimeric nucleic acid and that of the fusion RNA of California which is disclosed as a guide nucleotide sequence-programmable RNA which may be a single guide RNA and wherein the guide nucleotide sequence-programmable RNA comprises a nucleotide sequence complementary to a target nucleic acid, which is mRNA.
Therefore the rejection is maintained.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 34-36 are rejected under 35 U.S.C. 103 as being unpatentable over California as applied to claim 1 above, and further in view of Klickstein et al. (Current Protocols in Molecular Biology, Vol. 29, Issue 1, Jan 1995).
The teachings of California as applicable to claim 1 are described above. Additionally, California teach vectors comprising a sequence encoding a fusion protein of the disclosure (page 14, lines 15-16, and page 113, lines 16-25) and cells comprising the fusion RNA (page 116, lines 26-28).
California does not teach a cDNA of the nucleic acid comprising the (i) a guide nucleotide sequence-programmable RNA which may be a guide RNA (targeting region) and (ii) one or more internal ribosome entry sites (IRES) or a portion thereof, or a vector comprising the cDNA or a host cell comprising the cDNA.
However, before the effective filing date, Klickstein et al. teach that enzymatic conversion of mRNA into double-stranded insert DNA can be accomplished by different procedures, all of which involve the action of reverse transcriptase and oligonucleotide primed synthesis of cDNA (Unit 5.5). Klickstein et al. teach the major goals of the procedures are to construct insert DNA that is as long as possible with a high yield of conversion of mRNA into DNA that can ligate to vector DNA (Unit 5.5). Klickstein et al. teach conversion of mRNA into double-stranded cDNA for insertion into a vector (Unit 5.5.2). Klickstein et al. teach cDNA synthesis and subsequent library preparation are necessary for the study of most mRNAs (Unit 5.5.11).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have provided the fusion RNA of California as cDNA, as well as a vector comprising the cDNA and a host cell comprising the cDNA, based on the teachings of Klickstein et al. with a reasonable expectation of success. There would be a reasonable expectation of success, because California teach vectors and cells comprising the fusion RNA, and Klickstein et al. teach forming cDNA from mRNA for insertion into a vector. One of ordinary skill in the art would have been motivated to provide the fusion RNA of California as cDNA, and to provide a vector and a host cell comprising the cDNA of the fusion RNA, because Klickstein et al. teach conversion of mRNA into double-stranded cDNA for insertion into a vector, and the need for cDNA synthesis in order to study most mRNAs, and would make obvious the limitations of claims 34-36.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 40,60,61,64,66,68 and 69 are rejected under 35 U.S.C. 103 as being obvious over California (WO 2019204828, Published 24 Oct 2019) in view of Arnarez et al. (US 20180369275, Published 27 Dec 2018).
Regarding claim 40, California teaches a fusion RNA (chimeric nucleic acid) consisting of (i) a guide nucleotide sequence-programmable RNA which may be a single guide RNA (targeting region) and (ii) one or more internal ribosome entry sites (IRES) or a portion thereof (translational activating region comprising a ribosome binding site) (page 58, lines 17-23), and wherein the guide nucleotide sequence-programmable RNA comprises a nucleotide sequence complementary to a target nucleic acid, which is mRNA (page 58, lines 29-31). California teaches the fusion RNA comprising the sgRNA fused to a type I or type II IRES (page 206, lines 5-7), and which is EMCV-IRES (page 206, lines 14-15,25).
California teaches the fusion RNA further comprises a linker sequence located between the guide nucleotide sequence-programmable RNA and the IRES (Page 59, lines 27-28). California teaches the systems are for increased translation of target mRNA (page 120, lines 25-28) and teaches methods of treating a disease or disorder comprising administering to a subject a composition of the disclosure (page 124, lines 21-23) and the disease or disorder is a genetic disease or disorder (page 125, lines 17-18).
Regarding claim 60, California teaches the target mRNA is in a prokaryotic cell, or in a mammalian cell (page 124, lines 13-15).
Regarding claims 64 and 66, California teaches the fusion RNA comprising the sgRNA fused to a type I or type II IRES (page 206, lines 5-7), and which is EMCV-IRES (page 206, lines 14-15,25).
Regarding claim 69, California teaches the sequence that is complementary to a target nucleic acid is about 8 to about 100, about 10 to about 50, about 15 to about 40, about 15 to about 30 or about 20 to about 30 nucleotides in length and in some embodiments is about 20 nucleotides in length (page 59, lines 3-6) and the linker sequence is about 1 to about 3, about 1 to about 5, about 1 to about 10, about 5 to about 20, about 10 to about 50 nucleobases in length (page 60, lines 1-2). While the exact length of the fusion RNA consisting of the guide RNA, linker and IRES is not disclosed by California, it is generally noted that differences in length do not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such length is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Given that applicant did not point out the criticality of the length of the chimeric nucleic acid of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to determine where in a disclosed set of ranges is the optimum length. NOTE: MPEP 2144.05.
While California does teach methods of using the fusion RNA for treating genetic diseases and disorders, California et al. does not teach that the methods are specifically treating haploinsufficiency disorders or wherein the targeting region comprises a region complementary to a mRNA from the SYNGAP1 or SCN1A gene.
However, before the effective filing date, Arnarez et al. teach mental retardation is the most prevalent handicap of children affecting 1-3% of the population and Autosomal Dominant Mental Retardation-5 (MRD5) is a prevalent nonsyndromic form of the disorder characterized by the lack of associated morphologic, radiologic and metabolite features (paragraphs 0003,0057). Arnarez et al. teach identification of de novo lesions in the SYNGAP1 gene that resulted in production of truncated proteins in approximately 3% of patients with unexplained nonsyndromic mental retardation, and SYNGAP1 is a GTPase-activating enzyme that is selectively expressed in the brain and required for normal development (paragraphs 0003,0057).
Arnarez et al. also teach that mutations in the SCN1A gene are associated with the development of the disease Dravet Syndrome, also known as severe myoclonic epilepsy of infancy or SMEI (paragraphs 0004,0060). Arnarez et al. teach SCN1A gene is located in the cluster of sodium channel genes on human chromosome 2q24 and encodes the alpha-pore forming subunits known as Nav1.1 of the neuronal voltage gated sodium channel (paragraph 00620, and therefore teaches that SCN1A mRNA would be endogenously produced mRNA from a cell (paragraph 0062).
Arnarez et al. teach methods of treating Autosomal Dominant Mental Retardation-5 (MRD5) or Dravet Syndrome in a subject by increasing the expression of the target protein or functional RNA by cells of the subject, by contacting the cells of the subject with an antisense oligomer complementary to a targeted portion of retained intron-containing pre-mRNA encoding the target protein or functional RNA (paragraph 0005), and increasing expression of a target protein which is SYNGAP1 or SCN1A by contacting the cells with the ASO complementary to the RIC pre-mRNA encoding SYNGAP1 or SCN1A protein (paragraph 0006). Arnarez et al. teach the treating a subject in which the cells are in a subject having a condition caused by a deficient amount or activity of SYNGAP1 or SCN1A protein, and in some embodiments, the deficient amount of the target protein is caused by haploinsufficiency (paragraphs 0007,0056,0093).
Arnarez et al. teach routes for administration vary depending on the cell type to which delivery of the ASO is desired and multiple tissues and organs are affected by AD mental retardation 5 and Dravet syndrome with the brain being the most significantly affected tissue and administration may be to patients parenterally, for example by intrathecal injection, intracerebroventricular injection, intraperitoneal injection, intramuscular injection, subcutaneous injection or intravenous injection (paragraph 0176).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to design a fusion RNA consisting of a gRNA, linker and IRES as taught by California, that targets SYNGAP1 or SCN1A mRNA in order to treat AD mental retardation 5 associated with haploinsufficiency of SYNGAP1 or treating Dravet syndrome associated with haploinsufficiency of SCN1A protein as taught by Arnarez et al., with a reasonable expectation of success. There would be a reasonable expectation of success as one skilled in the art would recognize that a gRNA that targets SYNGAP1 mRNA and a gRNA that targets SCN1A mRNA can be made and Arnarez et al. provides motivation to target SYNGAP1 and SCN1A mRNA to treat AD mental retardation 5 associated with haploinsufficiency of SYNGAP1 or treat Dravet syndrome associated with haploinsufficiency of SCN1A protein. One of ordinary skill in the art would have been motivated to design a fusion RNA consisting of a gRNA that targets SYNGAP1 or SCN1A mRNA, linker and an IRES, and to use the fusion RNA in a method of treating AD mental retardation 5 or Dravet syndrome, respectively, because Arnarez et al. teach the prevalence of mental retardation affecting children, that mutations in the SYNGAP1 gene are associated with Autosomal Dominant Mental Retardation-5 (MRD5), that mutations in the SCN1A gene are associated with the development of the disease Dravet Syndrome and teach methods of treating Autosomal Dominant Mental Retardation-5 (MRD5) or Dravet Syndrome in a subject by increasing expression of a target protein which is SYNGAP1 or SCN1A by contacting the cells with the ASO complementary to the RIC pre-mRNA encoding SYNGAP1 or SCN1A protein (paragraph 0006).
Accordingly the limitations of claims 40,60,61,64,66,68 and 69 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 65 is rejected under 35 U.S.C. 103 as being obvious over California in view of Arnarez et al. (US 20180369275, Published 27 Dec 2018) as applicable to claims 40,60,61,64,66 and 68 above, as evidenced by Imai et al. (Nature Structural and Molecular Biology, Vol. 23, No. 9 Sept 2016).
The teachings of California and Arnarez et al. as applied to claims 40,60,61,64,66,68 and 69 are described above.
While California teaches an EMCV-IRES (page 206, lines 14-15,25), California and Arnarez et al. do not explicitly teach that the IRES comprises the IIIabc domain and/or a J-K region.
However, as evidenced by Imai et al., the EMCV-IRES has a J-K region which is composed of two stem-loops (J and K domains) and is responsible for mediating the interaction with the HEAT-1 domain of eIF4G (page 859, right column).
Therefore, it would have been obvious that the methods of California and Arnarez et al. would have used a fusion RNA comprising an IRES comprising a J-K region, with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to use such an IRES comprising a J-K region in the fusion RNA, because California teaches using an EMCV-IRES in the fusion RNA that is used for treating genetic disorders, and as evidenced by Imai et al. the EMCV-IRES has a J-K region and is responsible for interaction with the HEAT-1 domain of eIF4G (page 859, right column).
Accordingly the limitations of claim 65 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 67 is rejected under 35 U.S.C. 103 as being unpatentable over California in view of Arnarez et al. as applied to claims 40,60,61,64,66 and 68 above, and further in view of Pan et al. (Journal of Virology, Published 16 Nov 2011, p. 1129-1144) as evidenced by Genbank Access. No. AB038528.
The teachings of California and Arnarez et al. as applied to claims 40,60,61,64,66,68 and 69 are described above.
California and Arnarez et al. do not teach wherein the eIF translation factor binding site comprises the nucleic acid sequence of SEQ ID NO: 1 or a fragment thereof or a nucleic acid sequence with at least 80% identity to SEQ ID NO: 1 or a fragment thereof.
However, before the effective filing date, Pan et al. teach comparative sequence analysis of duck hepatitis A virus (DHAV) IRES and that the 3’ part of the DHAV 5’UTR is similar to porcine teschovirus 1 (PTV-1) IRES in sequence and predicted secondary structure (Abstract). Pan et al. teach the sequence PTV-1 Talfan IRES is contained within nt 125-405 of the 5’ UTR (AB038528) (page 1130, right column).
A Blast search of instant SEQ ID NO: 1 shows that all 287 nucleotides of SEQ ID NO: 1 align with nucleotides 125-411 of Porcine teschovirus 1 gene for polyprotein, complete cds having the GenBank Sequence AB038528.1. See the alignment below:
PNG
media_image1.png
470
676
media_image1.png
Greyscale
All nucleotides of instant SEQ ID NO: 1 align with the sequence above which is identified as Genbank Sequence ID AB038528.1 and which was publicly available as taught by Pan et al. before the effective filing date.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date that the methods of California in view of Arnarez et al. would have used a fusion RNA wherein the IRES (translational activating region) comprises the nucleic acid of SEQ ID NO: 1 (from PTV-1) in place of an EMCV-IRES of California to arrive at instant claim 67 with a reasonable expectation of success. There would be a reasonable expectation of success because a Blast search of instant SEQ ID NO: 1 shows that all of the nucleotides of SEQ ID NO: 1 align with nucleotides 125-411 of Porcine teschovirus 1 gene for polyprotein, complete cds having the GenBank Sequence AB038528.1, which was publicly available before the effective filing date as taught by Pan et al. One of ordinary skill in the art would have been motivated to provide an IRES of SEQ ID NO: 1 for use in the methods of treating of California in view of Arnarez et al. because while California et al. teach using an EMCV-IRES, California teaches that this technology is not limited to a particular type of IRES and may comprise any ribonucleic acid sequence that comprises the functional abilities and/or structural properties of an IRES (page 206, lines 14-17). Therefore, using a PTV-1 IRES, and which comprises SEQ ID NO: 1 in the methods of California and Arnarez et al. would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 70 is rejected under 35 U.S.C. 103 as being unpatentable over California as applied to claim 1 above.
The teachings of California as applicable to claim 1 have been described above.
California does not explicitly teach the that fusion RNA is less than 100 nucleotides in length.
However, California teaches the sequence that is complementary to a target nucleic acid is about 8 to about 100, about 10 to about 50, about 15 to about 40, about 15 to about 30 or about 20 to about 30 nucleotides in length and in some embodiments is about 20 nucleotides in length (page 59, lines 3-6) and the linker sequence is about 1 to about 3, about 1 to about 5, about 1 to about 10, about 5 to about 20, about 10 to about 50 nucleobases in length (page 60, lines 1-2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to arrive at the instant claims with a reasonable expectation of success based on the taught length ranges of the guide RNA and linker sequences of the fusion RNA of California. While the exact length of the fusion RNA consisting of the guide RNA, linker and IRES is not disclosed by California, it is generally noted that differences in length do not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such length is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Given that applicant did not point out the criticality of the length of the chimeric nucleic acid of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to determine where in a disclosed set of ranges is the optimum length. NOTE: MPEP 2144.05. In addition, an ordinary artisan would be able to arrive at such a length of less than 100 nucleotides which is a parameter that a person of ordinary skill in the art would routinely optimize. It would have been obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal oligonucleotide length that produce expected results. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955). NOTE: MPEP 2144.05.
Accordingly, the limitations of claim 70 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments for the 103 Rejections
Applicant's arguments and amendments, filed 03/04/2026 have been fully considered but they are not persuasive.
Applicant argues on pages 5-6 regarding the 35 U.S.C. 103 rejection of claims 40,59-64,66 and 68 as obvious over ‘828 in view of Arnarez et al. that ‘828 fails to describe any chimeric nucleic acids of the current claims, and that the methods of ‘828 require administration and/or expression of Cas proteins that associate with the nucleic acids, and the current chimeric nucleic acids and methods of the cited art are distinct from the ‘828 application and an improvement over the cited art since they do not require the expression of any accessory proteins and the simplicity of design allows for the administration of nucleic acids that are smaller than those in the cited art. Arnarez fails to teach administration of any nucleic acids according to the current claims.
Applicant also argues on page 6 that dependent claims 34-36,65 and 67 are non-obvious for the reasons stated above.
This is not found persuasive. The Examiner’s response regarding the ‘828 application (California) was provided above in response to the 102 rejection. The examiner did not cite the teachings of California requiring administration and/or expression of Cas proteins and cited the limitations pertaining to the instant claim limitations, and as noted in the response above, the Applicant’s own specification calls the antisense nucleic acid a guide RNA. Therefore, Applicant’s arguments are not found persuasive, and the above 35 U.S.C. 103 rejections are maintained.
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 1,40,60,61,64-68 and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,2,8,12,14,16, 19,20,24,27,30,32,52,53,64,67,69,70 and 86 of copending Application No. 18/841,152 (‘152) (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 recites a chimeric nucleic acid consisting of an antisense nucleic acid that is complementary to a target RNA, linker region(s), and an eIF translation factor binding site, and claims 1,2,8,12,14,16,19,20,24,27,30,32, 52,53,64 and 67 of ‘152 also recite a chimeric nucleic acid comprising a targeting region, a translational activating region, and a hairpin region; wherein the translational activating region comprises at least one ribosome and/or translation factor binding site and wherein the targeting region comprises a region that is complementary to a target mRNA, with the only difference being that ‘152 recites the chimeric nucleic acid comprises a hairpin region and further details of the hairpin region in dependent claims.
Instant claims 40,60,61,64-68 and 69 recite a method for treating a haploinsufficiency disorder in a subject, wherein the haploinsufficiency disorder is further defined as a deficiency in the protein expression of one or both alleles of a target gene, the method comprising parenterally administering a chimeric nucleic acid consisting of an antisense nucleic acid that is complementary to a target RNA, linker region(s), and an eIF translation factor binding site, ‘152 claims 69,70 and 86 recite a method for increasing translation of a target mRNA in a cell, a method for treating a haploinsufficiency disorder in a subject, and a method for treating a disease in a subject comprising administering the nucleic acid of claim 1 to the subject, and all fall within the scope of instant claims 40 and 59-68. Additionally, claim 52 of ‘152 recites some of the same mRNAs that the targeting region is complementary to as instant claim 68 (SYNGAP1, SIM1, ATP1A3, SCN1A and SCN2).
Therefore, the claims do not appear to be patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant requested that the double patenting rejection be held in abeyance until allowable subject matter has been indicated. Therefore, the rejection has been maintained.
Conclusion
Claims 1,34-36,40,60,61 and 64-70 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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