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 .
Application Status
The action is written in response to applicant’s correspondence received on 7/17/2026. Claims 1-2, 13-22, 24-26, 28-29, 31-32, and 34-35 are currently pending.
Priority
The instant application claims priority to US provisional application 63/117,862, with an effective filing date of 11/24/2020.
Election/Restriction
Applicant’s election without traverse of the invention of Group I, claims 1-2, 13-22, 24-25, 28-29, 31-32, and 34, drawn to a composition comprising an oligonucleotide that targets SOS2, in the reply filed on 7/17/2026 is acknowledged.
Applicant further elects the following species:
A cholesterol ligand resulting in a cholesterol/lipid-conjugated SOS2-targeting oligonucleotide, as recited in claim 34.
Claim 35 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/17/2026.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Claims 1-2, 13-22, 24-25, 28-29, 31-32, and 34 are currently under examination on the merits.
Specification
The use of the term Opti-MEM, TransIT-X2 (paragraph 0147, 0152), and TaqMan (paragraph 0148, 0153, 0159, 0163, 0168, 0173) which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 13-16, 20-22, 25, and 28 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The factors to be considered when analyzing claims for compliance with the written description requirement include: (A) actual reduction to practice; (B) disclosure of drawings or structural chemical formulas; (C) sufficient relevant identifying characteristics (e.g., complete structure, partial structure, physical and/or chemical properties, structure/function correlation); (D) level of skill and knowledge in the art; and (E) predictability in the art.
Each of the factors (A)-(E) listed above is analyzed below:
Reduction to Practice
The instant specification discloses functional variants of SOS2 and their effects or consequence on a variety of diseases (see page 59). Examples of the instant specification discloses siRNA-mediated knockdown and ASO-mediated knockdown of SOS2 in PODO/TERT256 cell line as well as inhibition of SOS2 in mice disease models using siRNA and ASOs (see pages 63-69). However, the specification only provides experimental steps and only merely states expected results. There are no drawings or tables present to evidence the claims of the function of the structure.
Disclosure of Drawings or Structural Chemical Formulas
The instant specification discloses the sequence listings which lists 9 SEQ ID NOs (SEQ ID NO: 2-11) that correspond to modified RNAi sequences. In all the examples provided, the sequences have a length of 20-22 nucleotides. Applicant does not provide any drawings with the specification but these sequences can also be found on pg. 70-72 of the instant specification. Furthermore, applicant does not disclose or show an oligonucleotide sequence that is a siRNA and that is shorter than 20 nucleotides, specifically one that is 12-19 nucleotides, would impart the desired function of targeting SOS2.
Sufficient Relevant Identifying Characteristics (e.g., structure/function correlation)
For the function of modifying SOS2 expression, the composition of oligonucleotides disclosed in the specification show up in pg. 70-72 as well as the sequence listings. Of the 9 SEQ ID NOs, directed to modified oligonucleotides of SEQ ID NO: 2-11, all sequences have a length of 20-22 nucleotides.
Level of Skill and Knowledge in the Art
The level of skill is high. One would need to design and test multiple oligonucleotides to target SOS2. The knowledge in the art is also high as the state of the art in designing siRNAs is well characterized. For example, in Lee et al. (Small-Interfering RNA (siRNA)-Based Functional Micro- and Nanostructures for Efficient and Selective Gene Silencing, Accounts of Chemical Research, Volume 45, Issue 7, pgs. 1014-1025, published 3/13/2012) teaches where siRNA synthetic double-stranded RNA consists of approximately 21 base pairs (see abstract). Lee teaches where segmented siRNA composed of two segmented sense strands with 10-12 nucleotides and a complementary intact antisense strand with 21 nucleotides exhibited gene expression only with the intact antisense strand, whereas the segmented sense strand showed negligible inhibition. Lee hypothesized that this was due to the minimum length of nucleotides required for successful incorporation into the RISC, an important mechanism of RNAi (see section 2).
Level of Predictability in the Art
The level of predictability in the art is high for siRNA with at least 19-nt sequences. It is well established, as evidenced by Lee et al. and other works, that siRNA of sufficient length resulted in silencing of a target gene. However, the art is very unpredictable regarding siRNA sequences with a length under 19-nts, specifically below 16. Lee exhibited this where split sense strand siRNAs with 10-12 nucleotide sequences showed negligible silencing effects (see section 2 of Lee). While Chu et al. (Potent RNAi by short RNA triggers, RNA, Volume 14, Issue 9, pgs. 1714-1719, published 2008) does test 16-nt siRNAs to trigger RNAi and saw silencing of GFP, Chu does not shed any guidance on whether a shorter sequence, such as a sequence with a sense and antisense strand of 12-15 nucleotides would yield any silencing effects.
In view of the totality of factors analyzed above, it is clear that the instant specification fails to reasonable convey that the instant inventors had possession of the instantly claimed subject matter as of the effective filing date. To be specific, the inventors do not disclose a siRNA with a structure of 12 nucleotides, as recited in claims 1 and 13-16, that could carry on the function of being able to inhibit a gene of interest, or SOS2, in view of the present art. Claims 2, 20-22, 25, and 28 are incorporated into the rejection as being dependent on claim 1, but within the breadth of being an siRNA, and not specifically an ASO.
In view of the foregoing, claims 1-2, 13-16, 20-22, 25, and 28 are rejected under U.S.C. 112(a) as failing to comply with the written description requirement.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 13-19, and 24-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Grupe et al. (WO 2012151305 A2, published 11/8/2012).
Regarding claim 1 and 2, Grupe teaches a composition comprising an oligonucleotide (see abstract) that targets SOS2. Grupe teaches where antisense molecules can be used to inactive mRNA in order to inhibit gene expression and production of defective proteins…the SNPs of the present invention are also useful for designing RNA interference reagents that specifically target nucleic acid molecules having particular SNP variants (see pg. 92, line 3-14). Grupe further teaches RNA interference (RNAi), also referred to as gene silencing, is based on using double-stranded RNA molecules to turn genes off. When introduced into a cell, dsRNAs are processed by the cell into short fragments (generally about 21-23 nucleotide in length) known as small interfering RNAs (siRNAs) which the cell uses in a sequence-specific manner to recognize and destroy complementary RNA (see pg. 92, line 15). Grupe further teaches eight genes with polymorphisms associated with short stature and the corresponding highest odds ratio includes SOS2 (see pg. 122, line 2). As described above, the SNPs of the present invention can be used to design siRNAs, against a gene of interest, such as SOS2. This Is further evidenced in Grupe where Grupe teaches “a therapeutic compound will be administered in a therapeutically effective amount by any one of the accepted modes of administration for agents that serve similar utilities” (see pg. 88, line 30-32) wherein “the variant proteins, or fragments thereof, disclosed herein can themselves be directly used to treat a disorder characterized by the absence of, inappropriate, or unwanted expression or activity of the variant protein” (see pg. 108, line 3-5).
Regarding claim 13-15, Grupe teaches wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand and wherein the fragments are generally about 21, 22, or 23 nucleotides in length (see pg. 92, line 12-19).
Regarding claim 16-19, Grupe teaches a composition comprising an oligonucleotide that inhibits the expression of SOS2, as described in the rejection of claims 1 and 2. Though Grupe does not directly recite SEQ ID NO: 1, Grupe does disclose SOS2 as a target gene of interest (see pg. 122, line 2) wherein SEQ ID NO: 1 of the instant application has 100% identity to the known WT sequence of the human SOS2 gene. The first 384 nucleotides aligned are shown below. Regarding claim 17 specifically, Grupe teaches where based on the SNP information disclosed herein, antisense oligonucleotides can be produced that specifically target mRNA molecules that contain one or more particular SNP nucleotides (see pg. 91, line 26). Regarding claim 19, Grupe teaches where the present invention specifically contemplates isolated nucleic acid molecules that are about 18-26 nucleotides in length and the use of these nucleic acid molecules for RNAi (see pg. 92, line 20).
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Regarding claim 24, Grupe teaches where the present invention encompasses nucleic acid analogs that contain modified, synthetic, or non-naturally occurring nucleotides or structural elements or other alternative/modified nucleic acid chemistries known in the art (see pg. 37, line 17). Grupe also teaches where nucleic acid molecules that are about 18-26 nucleotides in length and the use of these nucleic acid molecules for RNAi (see pg. 92, line 20).
Regarding claim 25, Grupe teaches where the modified nucleoside comprises a locked nucleic acid (LNA) (see pg. 91, line 8-9), wherein Grupe states “exemplary blockers include peptide nucleic acids, morpholinos, locked nucleic acids, and methylphosphonates”.
Regarding the claims listed above, Grupe does not specifically teach the effects of administration as recited in claims 1 and 2, such as increases an estimated glomerular filtration rate, or decreases in creatinine, blood urea nitrogen, etc. However, these limitations of the claim are directed towards the intended use or functions of the composition. Looking to MPEP § 2112.01 (I-II) for guidance, for product and apparatus claims, when the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent. This is directly stated in MPEP 2112; "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable.
As claim 1 broadly recites an oligonucleotide that targets SOS2 and Grupe teaches antisense oligonucleotides and siRNA that targets SOS2, which anticipates the composition of claimed 1, therefore the claimed functions of administering the composition is presumed to be inherent in the teachings of Grupe.
In view of the foregoing, claims 1-2, 13-19, and 24-25 are rejected under U.S.C. 102(a)(1) as being anticipated by Grupe.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 20, 21, 22, 29, is/are rejected under 35 U.S.C. 103 as being unpatentable over Grupe et al. (WO 2012151305 A2, published 11/8/2012) in view of Praveen et al. (US 20200231965 A1, published 7/23/2020).
Regarding claims 20-22 and 29, the teachings of Grupe teaches the composition of claim 1, as recited in claims 20-22 and 29, as described above.
Regarding claims 20-22, and 29, Grupe does not explicitly teach where the oligonucleotide comprises a modified internucleoside linkage (claims 20-22), or where the modified nucleoside comprise of one or more 2’-fluoro modified nucleosides or 2’-O-alkyl modified nucleosides (claim 29).
Regarding claims 20-22, Praveen teaches methods and oligonucleotide compositions of treating patients having an ophthalmic condition associated with SOS2 (see abstract, paragraph 0046, and 0419), wherein the oligonucleotide comprises a modified internucleoside linkage as evidenced by “modified phosphate moieties include, but are not limited to, those that can be modified so that the linkage between two nucleotides contain a phosphorothioate” (see paragraph 0338).
Regarding claim 29, Praveen teaches where examples of non-natural nucleotides include, but are not limited to, dideoxynucleotides, biotinylated, alkylated, and fluorophore-labeled nucleotides (see paragraph 0335).
It would have been obvious to one with ordinary skill in the art, before the effective filing date, to combine the teachings of Grupe and Praveen to arrive at an antisense oligonucleotide where the oligonucleotide comprises modified internucleoside linkages, specifically phosphorothioate linkages and 2’-fluoro or 2’-O-alkyl modified nucleosides.
One would expect a reasonable chance of success as Praveen already discloses modified oligonucleotides to target the SOS2 gene, and wherein the modified oligonucleotides comprise of internucleoside linkages and modified nucleotides (see paragraph 0335 and 0338).
One would be motivated to do so as internucleoside linkages and modified nucleotides are known in the art to support oligonucleotide stability. This is evidenced by Clave et al. (Modified internucleoside linkages for nuclease-resistant oligonucleotides, RSC Chemical Biology, Volume 2, Issue 1, all pages, published 12/8/2020), where Clave teaches numerous chemical modifications of oligonucleotides have been developed in order to improve resistance to nuclease digestion (see introduction of Clave). Therefore, by incorporating these elements, one would be motivated to combine in order to formulate an oligonucleotide composition, as disclosed in Grupe, with greater stability, such as the oligonucleotide composition taught by Praveen.
In view of the foregoing, claims 20-22, and 29 are rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Grupe et al. (WO 2012151305 A2, published 11/8/2012) in view of Pallan et al. (Structure and nuclease resistance of 2’, 4’-constrainted 2’-O-methoxyethyl (cMOE) and 2’-O-ethyl (cEt) modified DNAs, ChemComm, Volume 48 Issue 66, published 8/25/2012).
Regarding claim 28, Grupe teaches the composition of claim 24, dependent on claim 1, as described above.
Regarding claim 28, Grupe does not teach where the modified nucleoside is one recited in claim 28.
Regarding claim 28, Pallan teaches antisense oligonucleotide modifications that yield highly nuclease resistant oligonucleotides (abstract), wherein the modified nucleoside comprises a 2’-O-methyl nucleoside (see abstract) and locked nucleic acid antisense AONs modifications yield the highly nuclease resistant-constrained MOE nucleic acids (see introduction).
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Grupe and Pallan, to arrive at the claimed invention of an oligonucleotide composition comprising modified nucleosides comprising a 2’-O-methyl nucleoside.
One would expect a reasonable chance of success as Pallan teaches these modifications used in antisense oligonucleotides for the use of improving oligonucleotide stability.
One would be motivated to do so as Pallan teaches where these modifications can be used to formulate antisense oligonucleotides with greatly enhanced nuclease stability profile (see introduction of Pallan).
In view of the foregoing, claim 28 is rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
Claims 31-32 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Grupe et al. (WO 2012151305 A2, published 11/8/2012) in view of O’Loughlin et al. (Functional Delivery of Lipid-Conjugated siRNA by Extracellular Vesicles, Molecular Therapy, Volume 25, Issue 7, pgs. 1580-1587, published 4/6/2017).
Regarding claims 31-32, and 34, the composition of claim 31, an oligonucleotide composition comprising modified nucleosides, is taught by the art of Grupe, as described above.
Regarding claims 31-32, and 34, Grupe does not disclose wherein the oligonucleotide composition comprises a lipid attached at the 3’ or 5’ end, the lipid composition, or the type of ligand.
Regarding claim 31, O’Loughlin teaches optimized methods to load extracellular vesicles with cholesterol-conjugated siRNAs (see abstract), wherein the oligonucleotide comprises a lipid attached to the 3’ or 5’ terminus of the oligonucleotide (see abstract).
Regarding claim 32, O’Loughlin teaches wherein the lipid comprises cholesterol (see abstract).
Regarding claim 34, O’Loughlin teaches where the oligonucleotide comprises a cholesterol ligand (see abstract).
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Grupe and O’Loughlin to arrive at an oligonucleotide composition targeting SOS2 with a lipid or cholesterol attached to the oligonucleotide.
One would expect a reasonable chance of success as O’Loughlin teaches siRNA oligonucleotides conjugated to lipids or cholesterols (see abstract).
One would be motivated to combine the teachings above as O’Loughlin teaches RNA delivery of lipid-conjugated molecules, therefore, one would combine the composition of Grupe with the delivery method of O’Loughlin in order to deliver the RNAi as a treatment to an individual.
In view of the foregoing, claims 31-32, and 34 are rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
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 1-2, 13-22, 24-25, 28-29, 31-32, and 34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 50-64 of copending Application No. 18/866,499. Although the claims at issue are not identical, they are not patentably distinct from each other because both application are drawn to an oligonucleotide that targets SOS2.
Regarding claims 1-2 of the instant application and claim 50 of the copending application, both applications recite the same effects resulting from the intended use of a composition with identical scope. While the copending application does recite more effects than those listed in the instant application, as the claims are drawn to a composition, if the structure of the composition are the same, then the effects of administration are presumed to be inherent, see MPEP § 2112.01.
Regarding the structure of the composition, both applications recite the same structural limitations including nucleoside sequence length (12-30 nucleosides), modifications to the sense and antisense strand, modified nucleosides, and a lipid ligand.
In view of the foregoing, it is obvious to one with ordinary skill in the art that, that the scope of the claimed invention is patentably indistinct between the instant application and the copending application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID YU whose telephone number is (571)272-1118. The examiner can normally be reached Monday-Friday 7:30 am -5 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.T.Y./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
Prosecution Insights