DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim(s) 1-20 are pending and under consideration.
Status of the claims: Applicant amended claim 15 in the reply filed 09/16/2025.
Applicant’s arguments filed 09/16/2025 have been thoroughly reviewed and are persuasive for the reasons that follow. Any rejections and objections not reiterated in this action have been withdrawn. This action is NON-FINAL.
Priority
Acknowledgement is made that this application is a 371 of PCT/US2020/037580 filed 06/12/2020 and claims priority based on provisional application filed as 62/860,843 on 06/13/2019.
All claims are given the priority date of 06/13/2019.
Drawings
The drawings (replacement sheets) were received on 09/16/2025. These drawings are accepted.
Nucleotide and/or Amino Acid Sequence Disclosure
Acknowledgement is made of Applicant submitting a Sequence listing, filed 09/16/2025, and a corresponding SEQUENCE LISTING statement with the ASCII text file and its corresponding size in bytes.
Response to Arguments – Nucleotide and/or Amino Acid Sequence Disclosure
The lack of compliance with ST.25 for the Nucleotide and/or Amino Acid Sequence Disclosure, i.e., nucleotide and/or amino acid sequences appearing in the drawings without proper identification via a SEQ ID NO, has been remedied through Applicant supplying replacement drawings filed 09/16/2025.
Response to Arguments – Specification
The previous objection to the specification for containing trademarks and/or tradenames without capitalization and/or a proper symbol indicating use in commerce, has been withdrawn in view of Applicant’s amendments filed 09/16/2025.
The substitute specification filed 9/16/2025 has been entered.
Claim Objections
Claim 1 objected to because of the following informalities: claim 1 recites the acronym “ADAR” in line 3 without introducing it first. It would be remedial to amend the claim to recite “. . . wherein the double stranded nucleic acid complex is capable of recruiting an adenosine deaminase acting on RNA (ADAR) enzyme for deamination . . .”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) – indefiniteness
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.
Claim 5 is 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. This is a new rejection.
Regarding claim 5, the phrase "may be" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It would be remedial to replace the phrase “that may be interrupted” with the phrase “that is optionally interrupted.”
Claim Rejections - 35 USC § 112(a) – Enablement
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(s) 9 and 15 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 treating a genetic disorder caused by a guanosine (G) to adenosine (A) mutation in a gene selected from the group consisting of CFTR, A1AT, GNAQ, and IDUA, does not reasonably provide enablement for treating or preventing a genus of genetic disorders in a subject in need thereof. 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. This is a new rejection.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention and Breadth of the claims:
The claimed invention reads on treating or preventing a genetic disorder in a subject in need there of. The nature of the invention broadly encompasses hundreds of genetic disorders. Dependent claim 15 recites specific genetic disorders. Several of the disorders listed in claim 15 have no known gene related to the disorder that can be edited to treat or prevent the disorder. In addition, a variety of genetic disorders have no known methods steps to identify the subject in need.
The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples:
The specification teaches:
“Cystic fibrosis, Hurler Syndrome, alpha-1-antitrypsin (A1AT) deficiency, Parkinson's disease, Alzheimer's disease, albinism, Amyotrophic lateral sclerosis, Asthma, B3-thalassemia, CADASIL syndrome, Charcot- Marie-Tooth disease, Chronic Obstructive Pulmonary Disease (COPD), Distal Spinal Muscular Atrophy (DSMA), Duchenne/Becker muscular dystrophy, Dystrophic Epidermolysis bullosa, Epidermolysis bullosa, Fabry disease, Factor V Leiden associated disorders, Familial Adenomatous Polyposis, Galactosemia, Gaucher's Disease, Glucose-6-phosphate dehydrogenase deficiency, Haemophilia, Hereditary Hemochromatosis, Hunter Syndrome, Huntington's disease, Inflammatory Bowel Disease (IBD), Inherited polyagglutination syndrome, Leber congenital amaurosis, Lesch-Nyhan syndrome, Lynch syndrome, Marfan syndrome, Mucopolysaccharidosis, Muscular Dystrophy, Myotonic dystrophy types I and II, neurofibromatosis, Niemann-Pick disease type A, B and C, NY-eso1 related cancer, Peutz-Jeghers Syndrome, Phenylketonuria, Pompe's disease, Primary Ciliary Disease, Prothrombin mutation related disorders, such as the Prothrombin G20210A mutation, Pulmonary Hypertension, (autosomal dominant) Retinitis Pigmentosa, Sandhoff Disease, Severe Combined Immune Deficiency Syndrome (SCID), Sickle Cell Anemia, Spinal Muscular Atrophy, Stargardt Disease, Tay-Sachs Disease, Usher syndrome (such as Usher syndrome type I, type II, and type Ill), X-linked immunodeficiency, Sturge-Weber Syndrome, and cancer.”, (p. 10-11).
“Preferred examples of genetic diseases that can be prevented and/or treated with oligonucleotides according to the invention are any disease where the modification of one or more adenosines in a target RNA will bring about a (potentially) beneficial change. Especially preferred are Usher syndrome and CF, and more specifically the RNA editing of adenosines in the disease-inducing PTCs in CFTR RNA is preferred. Those skilled in the art of CF mutations recognise that between 1000 and 2000 mutations are known in the CFTR gene, including G542X, W1282X, R553X, R1162X, Y122X, W1089X, W846X, W401X, 621+1G>T or 1717-1G>A. It should be clear, that targeted editing according to the invention can be applied to any adenosine, whether it is a mutated or a wild-type nucleotide in a given sequence.”, (p. 19 line 16-24).
Figures 9-10 teaches editing of IDUA.
Predictability/state of the art:
A search of the prior art indicates that it was not routine in the art to prevent a genetic disorder in a subject using an RNA editing technique. Bertolli et al (ADAR Therapeutics as a New Tool for Personalized Medicine, Genes (Basel), vol 16, issue 1, pages 1-12, published January 11th, 2025) teaches, “Programmable RNA editing leveraging ADAR enzymes represents a groundbreaking approach to treat genetic disorders at the RNA level, bypassing the potential risks associated with permanent DNA modifications (Table 4).”, (p.9 para 3).
Further, the broadest reasonable interpretation of the claimed invention embraces in utero gene editing, which lacks enablement (e.g., performing gene editing on a fetus has certain ethical issues as well as methods of delivery of a AON to a fetus that would prevent a skilled artesian from carrying out the method). Jeanne et al (Opportunities and Challenges of Fetal Gene Therapy, Prenatal Diagnosis, vol 45, pages 764-771, published May 5th, 2025) teaches the following:
“The delivery of gene therapy vectors during prenatal development requires precise targeting to avoid off-target effects and ensure therapeutic efficacy. Delivery methods, such as intra-amniotic, intraperitoneal, intravascular, or intracerebral injections, can be technically challenging and require advanced imaging techniques and highly skilled individuals. . .
Determining the severity of a genetic disorder and deciding whether to intervene prenatally can be challenging, especially for conditions with variable expressivity or incomplete penetrance. Current prenatal diagnostic tools can identify a pathogenic variant, but they often cannot accurately predict disease severity or response to therapy. This uncertainty complicates clinical decision making and raises ethical concerns regarding overtreatment. . .
Fetal gene therapy requires invasive procedures that carry risks for the mother. These include potential complications such as infection of the uterus, bleeding, preterm labor, and risk to the mother's health. In addition, the mother may have to undergo emergency procedures such as cesarean section secondary to fetal complications resulting from the gene therapy procedure – fetal hemorrhage, fetal bradycardia, premature rupture of the membranes, infection, and preterm birth. Furthermore, maternal immunologic responses to the therapeutic vector or the introduced transgenic protein can compromise the efficiency of gene transfer to the fetus and potentially affect maternal health. Another critical consideration is the risk of unintended maternal gene integration or editing. . .
As an invasive procedure, fetal gene therapy can result in fetal injury, hemorrhage, infection due to breaching, preterm birth, or even fetal death. . .
While fetal gene therapy offers the theoretical advantage of early intervention, its long-term efficacy and durability compared to established postnatal treatments remains to be demonstrated. Limited clinical data make it difficult to assess whether the benefits of prenatal correction outweigh the risks, especially when postnatal therapies are already available.”, (page 766 col 2 under Challenges and Limitations to page 768 col 2 para 3).
The specification does not teach how to identify a subject who might have a genetic disease before the subject has the disease.
For example, if a person is having an asthma attack, it is unpredictable that administering the AON would treat or prevent the attack due to the time it takes for the AON to be delivered into the cells and reduce/restore expression of the target gene or genes. A method of identifying a subject who might develop a genetic disease is considered unpredictable due to genetic and/or environmental factors and the possibility of the subject never developing the disease for unknown factors (e.g., epigenetic repression). Furthermore, the specification does not teach when to administer or how much to administer the AON to prevent the genetic disease from developing in a subject.
It is acknowledged that some of the genetic diseases listed in claim 15 have been treated by inhibiting/restoring expression of a gene in the subject using antisense oligonucleotide. However, several genetic diseases listed in the claim have not been treated using an AON to reduce/restore expression of a gene in a subject in need thereof. Some of the diseases do not have a known gene or genes associated with the disease where reducing/restoring expression of a gene would result in treating or preventing the disease. Not every disease listed in claim 15 has an art-accepted model for genetic testing. For any disease without an art-accepted model for genetic testing, it is not apparent what reduced/restored expression level or amount of the antisense oligonucleotide is required to observed a therapeutic effect in a subject having the disease.
For example, El Hadad et al (The Genetics of Inflammatory Bowel Disease, Molecular Diagnosis & Therapy, vol 28, pages 27-35, published October 17th, 2023) teaches, “The progress made in the genetics of IBD over the last 20 years is impressive with over 200 different gene loci identified. However, the contribution of a single polymorphism to the development of IBD or its disease course is small, and most risk alleles are rare. The pathophysiology of IBD appears to be too complex in order to be explained by a few genes or pathways.”, (p. 32, col 1, para 2).
Biocytogen (Fully Human Antibody Discovery, Animal models & Preclinical CRO Services, pages 1-9; accessed September 11th, 2026) teaches the mouse models used to induce IBD –“To better understand disease mechanisms and evaluate novel therapies, researchers widely employ preclinical IBD models and IBD mouse models to replicate human disease pathology. Among them, the DSS-induced colitis model is one of the most established in vivo IBD models. When dextran sulfate sodium (DSS) is administered in drinking water, it damages the intestinal epithelial barrier, activates innate immune cells, promotes cytokine release, and disrupts mucosal integrity, leading to colitis symptoms—including weight loss, diarrhea, hematochezia, and inflammatory cell infiltration—that closely mimic human ulcerative colitis.”, (page 1 para 2 to page 2 para 1).
When it comes to the use of ADAR in the central nervous system disease, Zheng et al (ADAR-mediated RNA editing in CNS disorders: from pathogenic mechanisms to therapeutic opportunities, vol 31, issue 130, pages 1-37, published July 25th, 2026) teaches, “Clinical studies for ADAR-mediated RNA editing treatment have not yet been conducted for CNS diseases. Most research on LEAPER and CLUSTER is limited to cell culture or mouse models (mostly liver), and both remain in the preclinical stage [104, 105]. Hurler syndrome mice have been used to test RtABE, but models of CNS diseases have not yet been used [107]. Delivery across the BBB and the absence of proven CNS disorder targets where temporary editing is the best therapeutic approach are the main obstacles. Clinically, the most sophisticated RNA editing techniques target retinal problems (e.g., EDIT-101 for CEP290 mutations), which might lead to CNS uses [123, 124].”, (p.26 para 3 to p. 27 para 1).
Table 5 of Zheng et al teaches challenges of CNS-ADAR therapy below.
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Amount of experimentation necessary:
The quantity of experimentation required to carry out the scope of the invention is too large. While it is acknowledged that applicant is not required to provide a working example to enable a claimed invention. This is not the case here. The prior art of record teaches that observations in a cell line do not provide enablement for treating or preventing a genetic disorder with RNA editing. In addition, treating a disease does not provide guidance for preventing a disease because when treating the subject who already has the disease or condition, the target RNA is present and/or being expressed. If the target RNA is already present then preventing the disease is too late because the subject already has the disease or condition.
The prior art does not teach that treating or preventing a genetic disorder in a subject using an AON was routine. The skilled artisan would look to the specification for how to carry out the method. The target RNA would have to be expressed and/or present in the subject for the AON to edit the RNA. The applicant does not teach how to identify a subject that might have a genetic disorder and administering the AON to the subject to target an RNA that might not even be present. In addition, the applicant does not teach an endpoint (how to determine if the genetic disorder was prevented) to the method for the skilled artisan to determine that the method steps have been obtained. Other than contemplating the preventive method, the specification does not teach how to use the claimed invention.
See Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 clearly states:
"Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. See Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention."
Applicant cannot rely on the knowledge of one skilled in the art to supply information on
the novel aspects of the claimed invention.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claim(s) 9 and 15 are not considered to be enabled, but are scoped, by the instant disclosure.
Response to Arguments - Claim Rejections - 35 USC § 102
Applicant’s arguments, see pages 11-14, filed 09/16/2025, with respect to the rejection of claim(s) 1 and 4-20 under 35 U.S.C. 102 (a)(2) as being anticipated by Fraley et al (US 2023/0332143 A1, Published October 19th, 2023, Effective filing date January 22nd, 2019; cited on PTO 892 mailed 06/16/2025) have been fully considered and are persuasive. The rejection of claim(s) 1 and 4-20 under 35 U.S.C. 102 (a)(2) as being anticipated by Fraley et al (supra) has been withdrawn.
Applicant’s arguments, see pages 14-15, filed 09/16/2025, with respect to the rejection of claim(s) 2-3 under 35 U.S.C. 102 (a)(2) as being anticipated by Fraley et al (supra) as evidenced by Hirao (Natural versus artificial creation of base pairs in DNA: origin of nucleobases from the perspectives of unnatural base pair studies, Acc Chem Res, vol 45, issue 12, pages 2055-2065; published December 18th, 2012; cited on PTO 892 mailed 06/16/2025) have been fully considered and are persuasive. The rejection of claim(s) 2-3 under 35 U.S.C. 102 (a)(2) as being anticipated by Fraley et al (supra) as evidenced by Hirao (supra) has been withdrawn.
Applicant asserts that Fraley et al does not disclose an oligonucleotide comprising a base modification that is a cytidine analog that serves as an H-bond donor at the N3 site (i.e., a nitrogen at position 3 in a nitrogen-containing ring), specifically at the orphan nucleotide position in the AON as recited in claim 1.
Examiner agrees with this assertion. Fraley et al does not teach a cytidine analog capable of N3 H-bond donating, especially at the orphan nucleotide position.
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.
Claim(s) 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1, 26, 29, and 33 of copending Application No. 19/607,401 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
Claim 1 of 401 recites, “An RNA editing antisense oligonucleotide (ASO) forming a double-stranded complex with a human IDUA RNA molecule, wherein the RNA molecule comprises a target adenosine at position 1205 in SEQ ID NO: 135, optionally wherein the ASO is 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 nucleotides in length, wherein the ASO comprises the nucleotide sequence:5'-...rm5CeoZd*Ad^GmeAf*Ge...-3',wherein:i) m5Ce is a 5-methyl-cytidine comprising a 2'-O-methoxyethyl (2'-MOE) ribose substitution;ii) Zd is a deoxyribonucleoside that is directly opposite the target adenosine and comprises a Benner's base;iii) Ad is a deoxyadenosine;iv) Gm is a guanosine nucleoside comprising a 2'-O-methyl (2'-OMe) ribose substitution;v) Af is an adenosine nucleoside comprising a 2'-fluoro (2'-F) ribose substitution;vi) Ge is a guanosine comprising a 2'-MOE ribose substitution;vii) e denotes a phosphodiester (PO) internucleoside linkage;viii) * denotes a phosphorothioate (PS) internucleoside linkage; andix) ^ denotes a methylphosphonate (MP) internucleoside linkage,wherein the nucleoside position numbering is such that Z is nucleoside position 0, and the internucleoside linkage numbering is such that the linkage 5' from Z is linkage number 0, wherein the nucleoside positions and the linkage positions in the ASO are positively (+) incremented toward the 5' end and negatively (-) incremented towards the 3' end.”
Claim 1 of 401 anticipates instant claim(s) 1-7 and 13-14.
Claim 26 of 401 recites, “A pharmaceutical composition comprising an ASO according to any of claims 1-25, and a pharmaceutically acceptable carrier.”
Claim 26 of 401 anticipates instant claim 8.
Claim 29 of 401 recites, “A method for the treatment of MPS 1, preferably Hurler syndrome caused by a c.1205G>A mutation in the human IDUA gene, comprising administering to a patient in need thereof a therapeutically effective amount of an ASO according to any one of claims 1-25, or a pharmaceutical composition according to claim 26.”
Claim 29 of 401 anticipates instant claims 9 and 15.
Claim 33 of 401 recites, ““A method for the deamination of a target adenosine present in a target RNA molecule in a cell, wherein the target RNA molecule is a human IDUA pre-mRNA or mRNA, or a part thereof, wherein the target adenosine is the c. 1205G>A mutation in SEQ ID NO: 135, the methodcomprising the steps of:i) contacting the cell with an ASO according to any one of claims I to 25, or a pharmaceutical composition according to claim 26 under conditions suitable for:- uptake of the ASO by the cell;- annealing of the ASO to the target RNA molecule; and- deamination of the target adenosine in the target RNA molecule to an inosine by a naturally present mammalian ADAR enzyme present in the cell; and ii) optionally processing the cellular pre-mRNA or mRNA to determine the presence of an inosine at the position of the target adenosine in the target RNA molecule”, wherein step (ii) comprises:- determining the sequence of the target RNA molecule;- assessing the presence of a functional, elongated, full length and/or wild type Iduronidase protein; or - using a functional read-out, wherein the target RNA after the deamination encodes a functional, full length, elongated and/or wild type Iduronidase protein.”
Claim 33 of 401 anticipates instant claims 10-12 and 16-20.
Accordingly, claim(s) 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 19/607,401.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim(s) 1-2, 6, and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 7 of copending Application No. 18/838,201 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
Claim 7 of 201 recites, “A guide oligonucleotide capable of inducing editing of a nucleic acid encoding a human Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9 proprotein, wherein the nucleic acid decreases or prevents the ability of the PCSK9 proprotein from being processed by auto-cleavage of a proteolytic cleavage site,” “wherein the nucleic acid is RNA or DNA,” “wherein the nucleic acid is RNA and wherein the guide oligonucleotide can form a double stranded complex with a human PCSK9 pre-mRNA, mRNA, or a part thereof, wherein the guide oligonucleotide when complexed with the PCSK9 pre-mRNA, mRNA, or part thereof, is able to engage an endogenous human Adenosine Deaminases acting on RNA (ADAR) enzyme, thereby allowing the deamination of a target adenosine in the human PCSK9 pre-mRNA, mRNA, or part thereof,” wherein the guide oligonucleotide comprises an orphan nucleotide that is a cytidine, a cytidine analog, a uridine, or a uridine analog,” wherein the orphan nucleotide is a cytidine analog comprising a 6-amino-5-nitro-3-(1'-p-D-2'-deoxyribofuranosvl)-2(1H)-pyridone base.”
Claim 7 of 201 anticipates instant claims 1-2, 6, and 13.
Accordingly, claim(s) 1-2, 6, and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 18/838,201.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim(s) 3-5, 7-12, 14, and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 7 of copending Application No. 18/838,201 as applied to claim(s) 1-2, 6, and 13 above, in view of Turunen et al (WO 2018/041973 A1; published March 8th, 2018; listed as B29 on IDS filed 08/22/2022).
Claim 7 of ‘201 does not require the limitations as claimed in instant claim(s) 3-5, 7-12, 14, and 16-20.
Turunen et al teaches, “invention relates to antisense oligonucleotides that are capable of bringing about specific editing of a target nucleotide (adenosine) in a target RNA sequence in a eukaryotic cell, wherein said oligonucleotide does not, in itself, form an intramolecular hairpin or stem-loop structure, and wherein said oligonucleotide comprises a non-complementary nucleotide in a position opposite to the nucleotide to be edited in the target RNA sequence”, (abstract).
Regarding instant claim 3, Turunen et al teaches “It is an important aspect of the invention that the nucleotide within the AON of the present invention that is opposite to the nucleotide that needs to be edited does not contain a 2'-0-methyl modification (herein and elsewhere often referred to as a 2'-OMe group, as 2'-0-methylation, or as a 2'-0-methyl group). It is preferred that the nucleotides that are directly 3' and 5' of this nucleotide (the 'neighbouring nucleotides' in the Central Triplet) also lack such a chemical modification, although it is believed that it is tolerated that one or both of the neighbouring nucleotides may contain a 2'-0-alkyl group (such as a 2'-0-methyl group).”, (p.8, lines 37 to p.9 lines 1-4).
Regarding instant claim 4, Turunen et al teaches, “Various chemistries and modification are known in the field of oligonucleotides that can be readily used in accordance with the invention. The regular internucleosidic linkages between the nucleotides may be altered by mono- or di-thioation of the phosphodiester bonds to yield phosphorothioate esters or phosphorodithioate esters, respectively.”, (p.14, lines 17-20).
Regarding instant claim 5, Turunen et al teaches, “The ribose sugar may be modified by substitution of the 2'-0 moiety with a lower alkyl (C1 -4, such as 2'-0-methyl), alkenyl (C2-4), alkynyl (C2-4), methoxyethyl (2'-0-MOE), -H (as in DNA) or other substituent. Preferred substituents of the 2'-OH group are a methyl, methoxyethyl or 3,3'- dimethylallyl group. The latter is known for its property to inhibit nuclease sensitivity due to its bulkiness, while improving efficiency of hybridization (Angus & Sproat. 1993. FEBS Vol. 325, no. 1 , 2, 123-7). Alternatively, locked nucleic acid sequences (LNAs), comprising a 2'-4' intramolecular bridge (usually a methylene bridge between the 2' oxygen and 4' carbon) linkage inside the ribose ring, may be applied. Purine nucleobases and/or pyrimidine nucleobases may be modified to alter their properties, for example by amination or deamination of the heterocyclic rings.”, (p.14, lines 28 to 37).
Regarding instant claim(s) 7 and 14, Turunen et al teaches, “The AON according to the invention should normally be longer than 10 nucleotides, preferably more than 11 , 12, 13, 14, 15, 16, still more preferably more than 17 nucleotides. In one embodiment the AON according to the invention is longer than 20 nucleotides. The oligonucleotide according to the invention is preferably shorter than 100 nucleotides, still more preferably shorter than 60 nucleotides. In one embodiment the AON according to the invention is shorter than 50 nucleotides. In a preferred aspect, the oligonucleotide according to the invention comprises 18 to 70 nucleotides, more preferably comprises 18 to 60 nucleotides, and even more preferably comprises 18 to 50 nucleotides. Hence, in a most preferred aspect, the oligonucleotide of the present invention comprises 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49 or 50 nucleotides.”, (p.15, lines 5-14).
Regarding claim 8, Turunen et al teaches, “Oligonucleotides of the invention are particularly suitable for therapeutic use, and so the invention provides a pharmaceutical composition comprising an oligonucleotide of the invention and a pharmaceutically acceptable carrier. In some embodiments of the invention the pharmaceutically acceptable carrier can simply be a saline solution. This can usefully be isotonic or hypotonic, particularly for pulmonary delivery.”, (p.23, lines 32-34).
Regarding instant claim 9, Turunen et al teaches treating a genetic disease caused by G-A mutations with the invented oligonucleotide at p. 21 lines 8-10.
Regarding instant claims 10-12 and 16-20, Turunen et al teaches, “The invention also relates to a method for the deamination of at least one specific target adenosine present in a target RNA sequence in a cell, said method comprising the steps of: providing said cell with an AON according to the invention; allowing uptake by the cell of said AON; allowing annealing of said AON to the target RNA sequence; allowing a mammalian ADAR enzyme comprising a natural dsRNA binding domain as found in the wild type enzyme to deaminate said target adenosine in said target RNA sequence to an inosine; and optionally identifying the presence of said inosine in the RNA sequence. Introduction of the AON according to the present invention into the cell is performed by general methods known to the person skilled in the art. After deamination the read-out of the effect (alteration of the target RNA sequence) can be monitored through different ways. Hence, the identification step of whether the desired deamination of the target adenosine has indeed taken place depends generally on the position of the target adenosine in the target RNA sequence, and the effect that is incurred by the presence of the adenosine (point mutation, early stop codon, aberrant splice site, alternative splice site, misfolding of the resulting protein, etc.). Hence, in a preferred aspect, depending on the ultimate deamination effect of A-to-l conversion, the identification step comprises: sequencing the target RNA; assessing the presence of a functional, elongated, full length and/or wild type protein when said target adenosine is located in a UGA or UAG stop codon, which is edited to a UGG codon through said deamination; assessing the presence of a functional, elongated, full length and/or wild-type protein when two target adenosines are located in a UAA stop codon, which is edited to a UGG codon through the deamination of both target adenosines; assessing whether splicing of the pre-mRNA was altered by said deamination; or using a functional read-out, wherein the target RNA after said deamination encodes a functional, full length, elongated and/or wild type protein.”, (p. 24, lines 6-27).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the requirements of claim 7 of ‘201 with the teachings of Turunen et al, i.e., the nucleotide that is opposite to the nucleotide that needs to be edited does not contain a 2'-0-methyl modification, to yield the predictable results of the cytidine analog does not carry a 2’OME modification. One would be motivated to combine such teachings because claim 7 of 201 requires the cytidine analog to be the orphan nucleotide (i.e., the one directly across from the nucleotide to be targeted), and Turunen et al teaches that keeping 2’OME modifications from the nucleotide opposite, and the two that are 5’ and 3’ are important aspects to keeping the central triplet well-tolerated. One of skill could have looked to the requirements of claim 7 of 201 and the disclosure of Turunen et al and arrived at instant claim 3 with a high-likelihood of success.
Further it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to substitute the internucleosidic linkages between the nucleotides required of claim 7 of 201, with phosphorothioate linkages as taught by Turunen et al, to yield the predictable results of an antisense oligonucleotide comprising at least one phosphorothiate linkage. Both phosphodiester and phosphorothioate linkages were known in the art before the effecitive filing date of the claimed invention. One could have looked to the teachings of Turunen et al, i.e., “the regular internucleosidic linkages between the nucleotides may be altered by mono- or di-thioation of the phosphodiester bonds to yield phosphorothioate. . .” and the requirements of claim 7 of 201 and arrived at the claimed invention of instant claim 4 with a high likelihood of success.
It would have been obvious to one of skill in the art before the effective filing date of the claimed invention to modify claim 7 of 201 with the teachings of Turunen et al, i.e., the ribose sugar may be modified by substitution of the 2'-0 moiety with a lower alkyl (C1 -4, such as 2'-0-methyl), alkenyl (C2-4), alkynyl (C2-4), methoxyethyl (2'-0-MOE), -H (as in DNA) or other substituent, preferred substituents of the 2'-OH group are a methyl, methoxyethyl or 3,3'- dimethylallyl group, to yield the predictable results of a AON with one or more nucleotides modified at the 2’ position of the ribose. One of skill would be motivated to do so because Turunen et al teaches that such modifications, e.g., methyl, methoxyethyl or 3,3'- dimethylallyl group are known for their property to inhibit nuclease sensitivity due to its bulkiness, while improving efficiency of hybridization. One of skill could have looked to the teachings of claim 7 of 201 and the disclosure of Turunen et al and arrived at instant claim 5 with a high likelihood of success.
It would have been obvious to one of skill in the art before the effective filing date of the claimed invention to combine the teachings of claim 7 of 201 and Turunen et al, i.e., a pharmaceutical composition comprising an oligonucleotide of the invention and a pharmaceutically acceptable carrier, to yield the predictable results of a pharmaceutical composition comprising an AON and a pharmaceutically acceptable carried. One of skill would be motivated to combine such teachings because Turunen et al teaches that such pharmaceutical compositions can be useful as isotonic or hypotonic, particularly for pulmonary delivery. One of skill could have looked to the teachings of claim 7 of 201 and the disclosure of Turunen et al and arrived at instant claim 8 with a high likelihood of success.
Accordingly, claim(s) 3-5, 7-12, 14, and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 18/838,201 in view of Turunen et al.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim(s) 1-18 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 4, 6-9, 11-12, 14, 16, and 19 of copending Application No. 18/994,574 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
Claim 4 of 574 anticipates instant claims 1-5.
Claim 6 of 574 anticipates instant claims 1-2, 7, and 14.
Claim 7 of 574 anticipates instant claims 1 and 6.
Claim 8 of 574 anticipates instant claim 8.
Claim 9 of 574 anticipates instant claim 9.
Claim 11 of 574 anticipates instant claim 10, 11 and 16.
Claim 12 of 574 anticipates instant claim 12.
Claim 14 of 574 anticipates instant claims 9 and 15.
Claim 16 of 574 anticipates instant claims 17-18, and 20 Claim 19 of 574 anticipates instant claim 13.
Accordingly, claim(s) 1-18 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 18/994,574.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim(s) 1-2, 6, and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 10 of copending Application No. 19/137,225 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
Claim 10 of 225 recites, “The EON according to “An RNA editing oligonucleotide (EON) capable of forming a double-stranded complex with a region of a target RNA nucleic acid molecule in a human cell, (a) wherein the double-stranded complex is capable of recruiting recruit an endogenous Adenosine Deaminase Acting on RNA (ADAR) enzyme naturally present in the cell, (b) wherein the region comprises a target adenosine, (c)wherein the nucleotide in the EON that is directly opposite the target adenosine is referred to as the orphan nucleotide, {d) wherein the ADAR enzyme deaminates the target adenosine into an inosine, and (e)wherein the target RNA nucleic acid molecule is a transcript molecule of the human p-1,4- galactosyl-transferase 1 (B4GALT1) gene.”, wherein the orphan nucleotide is a deoxynucleotide comprising a 6-amino-5nitro-3-yl-2(1H)-pyridone nucleobase or an iso-uracil nucleobase.”
Claim 10 of 225 anticipates instant claim(s) 1-2, 6, and 13.
Accordingly, claim(s) 1-2, 6, and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 19/137,225.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim(s) 3-5, 7-12, 14, and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 10 of copending Application No. 19/137,225 as applied to claim(s) 1-2, 6, and 13 above, in view of Turunen et al (supra).
Claim 10 of ‘225 does not require the limitations as claimed in instant claim(s) 3-5, 7-12, 14, and 16-20.
Turunen et al teaches, “invention relates to antisense oligonucleotides that are capable of bringing about specific editing of a target nucleotide (adenosine) in a target RNA sequence in a eukaryotic cell, wherein said oligonucleotide does not, in itself, form an intramolecular hairpin or stem-loop structure, and wherein said oligonucleotide comprises a non-complementary nucleotide in a position opposite to the nucleotide to be edited in the target RNA sequence”, (abstract).
Regarding instant claim 3, Turunen et al teaches “It is an important aspect of the invention that the nucleotide within the AON of the present invention that is opposite to the nucleotide that needs to be edited does not contain a 2'-0-methyl modification (herein and elsewhere often referred to as a 2'-OMe group, as 2'-0-methylation, or as a 2'-0-methyl group). It is preferred that the nucleotides that are directly 3' and 5' of this nucleotide (the 'neighbouring nucleotides' in the Central Triplet) also lack such a chemical modification, although it is believed that it is tolerated that one or both of the neighbouring nucleotides may contain a 2'-0-alkyl group (such as a 2'-0-methyl group).”, (p.8, lines 37 to p.9 lines 1-4).
Regarding instant claim 4, Turunen et al teaches, “Various chemistries and modification are known in the field of oligonucleotides that can be readily used in accordance with the invention. The regular internucleosidic linkages between the nucleotides may be altered by mono- or di-thioation of the phosphodiester bonds to yield phosphorothioate esters or phosphorodithioate esters, respectively.”, (p.14, lines 17-20).
Regarding instant claim 5, Turunen et al teaches, “The ribose sugar may be modified by substitution of the 2'-0 moiety with a lower alkyl (C1 -4, such as 2'-0-methyl), alkenyl (C2-4), alkynyl (C2-4), methoxyethyl (2'-0-MOE), -H (as in DNA) or other substituent. Preferred substituents of the 2'-OH group are a methyl, methoxyethyl or 3,3'- dimethylallyl group. The latter is known for its property to inhibit nuclease sensitivity due to its bulkiness, while improving efficiency of hybridization (Angus & Sproat. 1993. FEBS Vol. 325, no. 1 , 2, 123-7). Alternatively, locked nucleic acid sequences (LNAs), comprising a 2'-4' intramolecular bridge (usually a methylene bridge between the 2' oxygen and 4' carbon) linkage inside the ribose ring, may be applied. Purine nucleobases and/or pyrimidine nucleobases may be modified to alter their properties, for example by amination or deamination of the heterocyclic rings.”, (p.14, lines 28 to 37).
Regarding instant claim(s) 7 and 14, Turunen et al teaches, “The AON according to the invention should normally be longer than 10 nucleotides, preferably more than 11 , 12, 13, 14, 15, 16, still more preferably more than 17 nucleotides. In one embodiment the AON according to the invention is longer than 20 nucleotides. The oligonucleotide according to the invention is preferably shorter than 100 nucleotides, still more preferably shorter than 60 nucleotides. In one embodiment the AON according to the invention is shorter than 50 nucleotides. In a preferred aspect, the oligonucleotide according to the invention comprises 18 to 70 nucleotides, more preferably comprises 18 to 60 nucleotides, and even more preferably comprises 18 to 50 nucleotides. Hence, in a most preferred aspect, the oligonucleotide of the present invention comprises 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49 or 50 nucleotides.”, (p.15, lines 5-14).
Regarding claim 8, Turunen et al teaches, “Oligonucleotides of the invention are particularly suitable for therapeutic use, and so the invention provides a pharmaceutical composition comprising an oligonucleotide of the invention and a pharmaceutically acceptable carrier. In some embodiments of the invention the pharmaceutically acceptable carrier can simply be a saline solution. This can usefully be isotonic or hypotonic, particularly for pulmonary delivery.”, (p.23, lines 32-34).
Regarding instant claim 9, Turunen et al teaches treating a genetic disease caused by G-A mutations with the invented oligonucleotide at p. 21 lines 8-10.
Regarding instant claims 10-12 and 16-20, Turunen et al teaches, “The invention also relates to a method for the deamination of at least one specific target adenosine present in a target RNA sequence in a cell, said method comprising the steps of: providing said cell with an AON according to the invention; allowing uptake by the cell of said AON; allowing annealing of said AON to the target RNA sequence; allowing a mammalian ADAR enzyme comprising a natural dsRNA binding domain as found in the wild type enzyme to deaminate said target adenosine in said target RNA sequence to an inosine; and optionally identifying the presence of said inosine in the RNA sequence. Introduction of the AON according to the present invention into the cell is performed by general methods known to the person skilled in the art. After deamination the read-out of the effect (alteration of the target RNA sequence) can be monitored through different ways. Hence, the identification step of whether the desired deamination of the target adenosine has indeed taken place depends generally on the position of the target adenosine in the target RNA sequence, and the effect that is incurred by the presence of the adenosine (point mutation, early stop codon, aberrant splice site, alternative splice site, misfolding of the resulting protein, etc.). Hence, in a preferred aspect, depending on the ultimate deamination effect of A-to-l conversion, the identification step comprises: sequencing the target RNA; assessing the presence of a functional, elongated, full length and/or wild type protein when said target adenosine is located in a UGA or UAG stop codon, which is edited to a UGG codon through said deamination; assessing the presence of a functional, elongated, full length and/or wild-type protein when two target adenosines are located in a UAA stop codon, which is edited to a UGG codon through the deamination of both target adenosines; assessing whether splicing of the pre-mRNA was altered by said deamination; or using a functional read-out, wherein the target RNA after said deamination encodes a functional, full length, elongated and/or wild type protein.”, (p. 24, lines 6-27).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the requirements of claim 10 of ‘225 with the teachings of Turunen et al, i.e., the nucleotide that is opposite to the nucleotide that needs to be edited does not contain a 2'-0-methyl modification, to yield the predictable results of the cytidine analog does not carry a 2’OME modification. One would be motivated to combine such teachings because claim 10 of ‘225 requires the cytidine analog to be the orphan nucleotide (i.e., the one directly across from the nucleotide to be targeted), and Turunen et al teaches that keeping 2’OME modifications from the nucleotide opposite, and the two that are 5’ and 3’ are important aspects to keeping the central triplet well-tolerated. One of skill could have looked to the requirements of claim 10 of ‘225 and the disclosure of Turunen et al and arrived at instant claim 3 with a high likelihood of success.
Further it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to substitute the internucleosidic linkages between the nucleotides required of claim 10 of ‘225, with phosphorothioate linkages as taught by Turunen et al, to yield the predictable results of an antisense oligonucleotide comprising at least one phosphorothiate linkage. Both phosphodiester and phosphorothioate linkages were known in the art before the effecitive filing date of the claimed invention. One could have looked to the teachings of Turunen et al, i.e., “the regular internucleosidic linkages between the nucleotides may be altered by mono- or di-thioation of the phosphodiester bonds to yield phosphorothioate. . .” and the requirements of claim 10 of ‘225 and arrived at the claimed invention of instant claim 4 with a high likelihood of success.
It would have been obvious to one of skill in the art before the effective filing date of the claimed invention to modify claim 10 of ‘225 with the teachings of Turunen et al, i.e., the ribose sugar may be modified by substitution of the 2'-0 moiety with a lower alkyl (C1 -4, such as 2'-0-methyl), alkenyl (C2-4), alkynyl (C2-4), methoxyethyl (2'-0-MOE), -H (as in DNA) or other substituent, preferred substituents of the 2'-OH group are a methyl, methoxyethyl or 3,3'- dimethylallyl group, to yield the predictable results of a AON with one or more nucleotides modified at the 2’ position of the ribose. One of skill would be motivated to do so because Turunen et al teaches that such modifications, e.g., methyl, methoxyethyl or 3,3'- dimethylallyl group are known for their property to inhibit nuclease sensitivity due to its bulkiness, while improving efficiency of hybridization. One of skill could have looked to the teachings of claim 10 of ‘225 and the disclosure of Turunen et al and arrived at instant claim 5 with a high likelihood of success.
It would have been obvious to one of skill in the art before the effective filing date of the claimed invention to combine the teachings of claim 10 of ‘225 and Turunen et al, i.e., a pharmaceutical composition comprising an oligonucleotide of the invention and a pharmaceutically acceptable carrier, to yield the predictable results of a pharmaceutical composition comprising an AON and a pharmaceutically acceptable carried. One of skill would be motivated to combine such teachings because Turunen et al teaches that such pharmaceutical compositions can be useful as isotonic or hypotonic, particularly for pulmonary delivery. One of skill could have looked to the teachings of claim 10 of ‘225 and the disclosure of Turunen et al and arrived at instant claim 8 with a high likelihood of success.
Accordingly, claim(s) 3-5, 7-12, 14, and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 19/137,225 in view of Turunen et al.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims allowed.
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/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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