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 .
Election/Restrictions
Applicant's election with traverse of:
For (I), the oligonucleotide of formula (I):
a. n is 1;
b. W is N(RN) wherein RN is S(O)2-aryl and optional R20 is nitro;
c. V1 and V2 are both absent;
d. U is absent;
e. t is 1;
f. L is H.
For (II), the nucleobase variable “B” recited in formular (II) is uracil (“U”);
For (III), the 2’-modified nucleosides:
a. Formula (IIa); and
b. Within the elected formula: 1) X1 is OH; Z1 is D-Q, wherein D is O and Q is an oligonucleotide; and 2) Y1is O;
For (IV),
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for the 2’-modified nucleosides recited in claim 20, and
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for the 2’-modified nucleosides recited in claim 22;
For (V), ligand for L or H as elected in formula I above.
in the reply filed on 04/02/2026 was acknowledged in the non-final office action mailed 05/05/2026. The traversal was on the ground that the W groups are structurally very similar and all share N(RN). This is not found persuasive because the W variable as originally claimed was defined to be 0, S-S, N(RN), C(O)N(RN), N(RN)C(O), N(RN)S(O)2, or a biocleavable carbohydrate linker, which are not structurally very similar. Applicant has now amended W to be N(RN), C(O)N(RN), N(RN)C(O), or N(RN)S(O)2 and maintains the argument that the W groups are structurally very similar and all share N(RN). This is not found persuasive because the W variable as currently claimed are not structurally very similar, even though they all comprise N(RN). As previously and currently claimed, N(RN) is defined to be in its simplest form a secondary amine; whereas, C(O)N(RN) and N(RN)C(O) are amides, and N(RN)S(O)2 is a sulfonamide. Secondary amines, amides, and sulfonamides are not only completely different structures, but they each possesses completely different reactivities, solubilities, electronic makeup, geometry, and behaviors in drugs and materials. Furthermore, applicant’s argument pertains only to one of the numerous species elections required by the examiner and the applicant did not particularly point out error in the examiner’s requirement (even regarding variable W, applicant’s argument that all are structurally very similar does not establish an error in the requirement).
The requirement is still deemed proper and is therefore made FINAL.
Thus, claims 15-16 remain withdrawn as being drawn to non-elected species.
Status of Claims
Claims 3-5, 15-18, 20-21, 25, and 48-58 are pending. Claims 6-9 and 26-47 remain cancelled. Claims 1-2, 10-14, 19, and 22-24 have been cancelled in response to non-final. Claims 15-16 are remain withdrawn. Thus, claims 3-5, 17-18, 20-21, 25, 48-58 are currently under examination.
Withdrawn Rejections and/or Objections
Any rejection(s) and/or objection(s) not repeated herein are hereby withdrawn.
Claim Interpretation
The claims contain limitations preceded by the term “optional”. All claim limitations recited as “optional” are interpreted as not required. As such, prior art can be applied to teach these limitations, but does not need to be applied.
New Rejection(s) and/or objection(s) Necessitated by Amendment
Specification
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claim 55 is objected to because of the following informalities: “overhangs” in line 3 should be spelled “overhang”. Appropriate correction is required.
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.
Claim 51 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.
Claim 51 recites “the antisense strand contains one or more 2’-modified nucleosides at one or more positions selected from the group consisting of positions 2, 6, 8, 9, 14, and 16 of the 5’-end of the antisense strand.” It is indefinite how a nucleoside (if only the antisense strand contains only one 2’-modified nucleoside) can be at more than one position. Likewise, it is indefinite how more than one 2’-modified nucleoside can be at the one position in an antisense strand.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 3 does not depend on a claim previously set forth. In accordance with 35 U.S.C. 112(d), or pre-AIA 35 U.S.C. 112, fourth paragraph, a claim in dependent form shall contain:
(i) a reference to a claim previously set forth, and
(ii) then specify a further limitation of the subject matter claimed.” See MPEP 608.01(n).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 3-5, 17-18, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Cook et. al., (US 20040048826 A1) in view of Manoharan M. et. al., (US 20030113769 A1), Fukuyama, T et. al., (Tetrahedron Letters 38 (1997): 5831-5834), and Mercurio ME, et. al., (J Org Chem. 2016 Dec 2;81(23):11612-11625).
Regarding claims 3-5, 17-18, and 20-21, Cook teaches oligonucleotides comprising one or more 2’-O modified guanine (G) nucleosides that meet the limitations of formula (IIa) of claims 3-5. For example, Cook recites in claim 10: “an oligomer comprising at least one subunit having the structure:
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wherein X is R1—(R2)n;
R1 is C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl;
R2 is halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, imidazole, N-phthalimido, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, a group that enhances the pharmacodynamic properties of oligonucleotides, or a group that enhances the pharmacokinetic properties of oligonucleotides;
T3 and T5 independently are OH or a further subunit of said oligomer that is joined to said structure; and
n is an integer from 0 to about 6.”
When selecting, for example, “C1” for R1 (i.e., methylene or -CH2-) and NH-alkyl for R2, one skill in the art would arrive at 2’-O-CH2-NH-(alkyl) and when an ethyl group is selected as the alkyl group, an artisan would arrive at 2’-O-CH2-NH-CH2 -CH3; thereby, satisfying formula IIa recited in instant claim 4 and formula
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recited in instant claim 5. Cook therefore expressly teaches a 2’O-modified oligonucleotide subunit having an alkylene-containing substituent with an amino/N-alkyl functionality. The C1 member of Cook’s expressly recited alkyl range provides a one-carbon alkylene segment, i.e., a methylene segment, in the 2’-O scaffold. Selection of Cook’s NH-alkyl provides the amino-bearing 2’-O-alkylene scaffold corresponding to the nitrogen-containing W alternative, N(RN), required by claim 4. Cook’s teachings of the scaffold 2’-O-CH2-NH-alkyl, wherein the alkyl group inherently encompasses an ethyl group, reads on the elected species in current claims 17-18 and 20-21 minus the S(O2)-aryl protecting group on the nitrogen.
Cook does not explicitly disclose a 2-nitrobenzenesulfonyl (oNBS) protecting group (i.e., an S(O2)-aryl) on the nitrogen.
Manoharan teaches aminooxy functionalized oligomers, optionally with nitrogen protecting groups useful during synthesis. Specifically, Manoharan teaches “an oligomer comprising a plurality of nucleotide units of the structure:
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wherein:
Bx is a purine or pyrimidine heterocyclic base;
each T1 and T2 is, individually, OH, a protected hydroxyl, a nucleotide, a nucleoside or an oligonucleotide;
T3 is H, OH, a protected hydroxyl or a sugar substituent group; said oligomer further comprising at least one group, R, therein; said R group occurring at the 5′-end, the 3′-end, in lieu of at least one T3 or as a substituent on at least one Bx; said R group having one of the formulas:
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wherein: each Z is, independently, a single bond, O or a phosphate; each Q is, independently, H, C1-C10 alkyl or a nitrogen protecting group; each T0 is, independently, a bond or a linking moiety; each L is, independently, a chemical functional group, a conjugate group or a solid support material; or Q, T0 and L, together, are a chemical functional group; each m is, independently, an integer from 1 to about 10; and each n is, independently, an integer from 1 to about 6.” Manoharan further teaches that a protecting group “renders a chemical functionality of a molecule inert to specific reaction conditions and can later be removed from such functionality in a molecule without substantially damaging the remainder of the molecule,” see [0078]. For example, “the aminooxy functionality is masked with a protecting group…” see [0057].
Mercurio teaches the use of the oNBS group as a switchable protecting group for amines specifically within the context of modified nucleopeptide synthesis on solid phase resin, see pgs. 11614 last paragraph and 11615 first paragraph.
Fukuyama teaches that the oNBS group is the preferred reagent for the selective and efficient N-alkylation of amines to form secondary amines (e.g., N-ethyl amines), see pg. 5831.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to modify the 2’-O-scaffold of Cook, i.e., the 2-O-CH2-NH-CH2CH3, with a oNBS protecting group taught by Fukuyama and Mercurio to arrive at the species comprising the nitrobenezenesulfonamide of claims 17-18 and 20-21. Manoharan provides the specific motivation to use nitrogen protecting groups in oligonucleotide synthesis, teaching that such groups render a chemical functionality inert to certain reaction conditions and are used specifically to mask amino-based functionalities. A PHOSTITA would follow this teaching to protect the amine in Cook during iterative steps of oligonucleotide synthesis because the amino functionality of Cook’s modified subunit is susceptible to undesired reactions during multistep oligonucleotide synthesis. Moreover, as evidenced by Mercurio, the oNBS group is recognized as an effective protecting group for amines in the field of oligonucleotide chemistry on solid phase. A PHOSITA would be motivated to attach the oNBS group to the nitrogen during the assembly of oligonucleotides to prevent side reactions with phosphoramidite reagents. The combination involves the application of a known nitrogen protecting group to a known oligonucleotide modification for its established purpose of masking the amine functionality, thereby preventing side reactions. A PHOSITA would have had a reasonable expectation of success to produce stable, protected 2’-amino modified oligonucleotides.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Cook et. al., (US 20040048826 A1) in view of Manoharan M. et. al., (US 20030113769 A1), Fukuyama, T et. al., (Tetrahedron Letters 38 (1997): 5831-5834), and Mercurio ME, et. al., (J Org Chem. 2016 Dec 2;81(23):11612-11625) as applied to claim 4 above, and further in view of Tachas G. et. al., (US20060178325A1).
Neither Cook, Manoharan, Fukuyama, or Mercurio explicitly teach the 2’modified oligonucleotides can be single- or double-stranded.
Tachas teaches that 2’-modified oligonucleotides “may be introduced in the form of single-stranded, double-stranded, circular or hairpin oligomeric compounds and may contain structural elements such as internal or terminal bulges or loops,” see [0044]. Tachas further teaches that single-stranded antisense compounds which are “DNA-like” elicit RNAse H,” and that “activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide-mediated inhibition of gene expression,” see [0044]. Tachas further teaches that “in many species the introduction of double-stranded structures, such as double-stranded RNA (dsRNA) molecules, has been shown to induce potent and specific antisense-mediated reduction of the function of a gene or its associated gene products,” see [0045].
It would have been obvious to a PHOSITA before the effective filing date to make the 2-modified oligonucleotides of Cook in view of Manoharan, Fukuyama, and Mercurio as either single or double stranded. One would have been motivated to do so in order to enhance the efficacy oligonucleotide-mediated inhibition of gene expression. One would have had a reasonable expectation of success because Tachas successfully employed both single- and double-stranded oligonucleotides.
Claims 4-5, 25, and 48-58 are rejected under 35 U.S.C. 103 as being unpatentable over Cook et. al., (US 20040048826 A1) in view of Hu B, et al.,(Therapeutic siRNA: state of the art. Signal Transduct Target Ther. 2020 Jun 19;5(1):101).
Regarding claims 4-5, the teachings of Cook are incorporated herein by reference to the 103 rejection above.
Cook does not teach the modified oligonucleotide is double stranded or the additional limitations set forth in claims 48-58.
Hu teaches double stranded modified siRNA, and that being modified and double stranded improves “siRNA accumulation and residence time in tissue and enhances siRNA potency in vivo by elevating Argonaute-2 binding,” see pages 2, as well as pages 4-8 and Fig 3.
It would have been obvious to a PHOSITA before the effective filing date to make the 2-modified oligonucleotides of Cook as either single or double stranded. One would have been motivated to do so in order to enhance the efficacy oligonucleotide-mediated inhibition of gene expression. One would have had a reasonable expectation of success because Hu teaches double stranded siRNA are routinely and successfully deployed with efficacious results.
Regarding claim 48, Hu teaches that the oligonucleotide contains at least one 2'- modified nucleoside at the antisense strand, sense strand, or both strands of the oligonucleotide, see Fig. 3.
Regarding claim 49-50, Hu teaches that the oligonucleotide contains at least one 2'- modified nucleoside at the first two positions of the 5'-end or 3'-end of a strand and the oligonucleotide contains at least one 2'- modified nucleoside at the first two positions of the 5'-end of the antisense strand, see Fig. 3.
Regarding claims 51-52, Hu teaches “2′-F modifications are positioned at sites 7, 9, 10 and 11 in the sense strand and sites 2, 6, 8, 9, 14 and 16 in the antisense strand (all from the 5′-ends of the strands),” see page 7 second column.
Regarding claim 53, Hu teaches the sense strand contains one or two 2'- modified nucleosides at positions 9, 10, or 11, counting from 5'-end of the sense strand, see Fig. 3.
Regarding claim 54, Hu teaches the sense strand further comprises one or two 2'-deoxy modifications within positions 7, 8, 9, 10, 11, 12, or 13, counting from 5'-end of the sense strand, see Fig. 3 Inclisiran/ALN-PCSsc.
Regarding claim 55, Hu teaches that the sense strand is 21 nucleotides in length, and the antisense strand is 23 nucleotides in length, wherein the strands form a double-stranded region of 21 consecutive base pairs having a 2-nucleotide long single-stranded overhangs at the 3'-end, see Fig. 3 ESC Plus (ESC+).
Regarding claim 56, Hu teaches that the oligonucleotide further comprises one or more 2'-0 modifications selected from the group consisting of 2'-deoxy, 2'-0-methoxyalkyl, 2'- 0-methyl, 2'-0-allyl, 2'-C-allyl, 2'-fluoro, 2'-0-N-methylacetamido (2'-0-NMA), 2'-0- dimethylaminoethoxyethyl (2'-0-DMAEOE), 2'-O-aminopropyl (2'-O-AP), and 2'-ara-F, see Fig. 3 all examples.
Regarding claim 57, Hu teaches that the sense and the antisense strands comprise: no more than ten 2'-fluoro modified nucleotides; and/or at least 50%, at least 60%, or least 70% of 2'-OMe modified nucleotides, see Fig. 3.
Regarding claim 58, Hu teaches that the sense strand comprises at least two phosphorothioate linkages at the 5'-end or the 3'-end, see Fig. 3 GivlaariTM/Givosiran.
REGARDING APPLICANT’S ARGUMENTS PERTAINING TO § 103 BASED ON COOK
Applicant's arguments filed 08/05/2026 have been fully considered but they are not persuasive.
1. No reference teaches the claimed combination of features
Applicant’s argument that no individual reference teaches the claimed combination is not persuasive because the rejection is based on the combined teachings of the references under 35 U.S.C. § 103. Cook teaches the relevant 2′-O–alkylene–amino oligonucleotide framework; Fukuyama teaches the nitrobenzenesulfonamide protection/N-alkylation technique; Manoharan teaches the use of nitrogen protection in oligonucleotide synthesis; and Mercurio supports the predictable use of nitrobenzenesulfonyl protection chemistry in a solid-phase synthesis involving nucleic-acid components. The rejection provides an articulated rationale with a reasonable expectation of success for combining these teachings.
2. Cook is an expansive generic framework/vast number of possible selections
Applicant’s argument that Cook discloses a broad genus is not persuasive. A broad disclosure does not preclude an obviousness determination where the prior art identifies the relevant structural framework and teaches a predictable modification. Cook expressly recites a 2′-O-modified oligomer subunit having a C1-C20 alkylene group and NH-alkyl functionality. Applicant characterizes Cook as providing a generic framework with multiple possible substituents. MPEP 2123, Rejection Over Prior Art’s Broad Disclosure Instead of Preferred Embodiments, states that “[a] reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments.” The relevant issue is not whether Cook expressly prefers every possible species within its genus, but whether the cited references provide a reasoned and predictable route to the claimed nitrogen-containing species. For the reasons set forth above, they do.
3. The Office used improper hindsight to choose C1/methylene
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
4. Cook prefers longer alkyl groups and thus motivates toward longer alkylene groups
Applicant’s argument that Cook expresses a preference for certain longer alkyl groups and thus one skilled in the art would have been motivated towards longer alkyl chain linkers is not persuasive. MPEP, Rejection Over Prior Art’s Broad Disclosure Instead of Preferred Embodiments, states that “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments.” A preference for one disclosed embodiment does not constitute a teaching away from another expressly recited alternative absent criticism, discrediting, or discouragement of that alternative. Cook expressly includes methylene linker within the disclosed range. Applicant has not identified a teaching in Cook that the methylene member is inoperative or unsuitable for the amino-containing 2′-O-modified oligonucleotide framework relied upon in the rejection.
5. Manoharan contains O–N, not the claimed 2′-O–CH2–N linkage
Applicant’s argument regarding the O–N linkage in Manoharan is not persuasive because Manoharan is not relied upon to teach the claimed 2′-O–CH2–N linkage. Cook is relied upon for the 2′-O–alkylene–amino structural framework. Manoharan is relied upon for its teaching that amino functionality may be masked with a nitrogen-protecting group during oligonucleotide synthesis.
6. Fukuyama and Mercurio are not directed to 2′-O nucleosides/oligonucleotide synthesis
Applicant’s argument that Fukuyama and Mercurio do not disclose the exact claimed 2′-O-modified nucleoside is not persuasive. A reference or combination thereof need not disclose the identical final product to be relevant for an obviousness determination. MPEP 2144.06, Art Recognized Equivalence for the Same Purpose, states that “[a]n express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious.”. Fukuyama teaches nitrobenzenesulfonamide protection and N-alkylation of amines to prepare secondary amines, and Mercurio supports the use of nitrobenzenesulfonyl amine-protection chemistry in a solid-phase synthesis involving nucleic-acid components. These teachings are relevant to the specific chemical problem presented by Cook’s amino-functionalized 2′-O-modified oligonucleotide scaffold: controlling the amino functionality during synthesis and/or N-alkylation. Thus, oNBS protection is an equivalent used in analogous synthesis and constitutes an obvious selection for protecting amine functionality.
7. No motivation to consult amine/diamine or nucleopeptide art
Applicant’s argument that a skilled artisan would not consult Fukuyama or Mercurio is not persuasive. The relevant inquiry is whether the references address the same chemical problem, not whether they have the identical final end product. MPEP 2141.01(a) Analogous and Nonanalogous art, states that “[a] reference is analogous art to the claimed invention if: (1) the reference is from the same field of endeavor as the claimed invention (even if it addresses a different problem); or (2) the reference is reasonably pertinent to the problem faced by the inventor (even if it is not in the same field of endeavor as the claimed invention). Cook provides an amino-functionalized 2′-O-modified oligonucleotide scaffold. Fukuyama teaches a known means to protect and selectively N-alkylate an amine, and Manoharan identifies protection of amino functionality as useful during oligonucleotide synthesis. Mercurio further supports the compatibility of nitrobenzenesulfonyl amine-protection chemistry in a solid-phase synthesis involving nucleic-acid components. The references therefore provide an articulated, chemistry-based reason to combine their teachings. Thus, the cites references are reasonably pertinent and analogous art to the instantly claimed invention.
8. Tachas does not cure Cook
Tachas is used to provide the teaching of double stranded oligonucleotides, not any alleged deficiencies of Cook regarding the 2’-O modifications. Thus, applicant’s argument that Tachas is irrelevant regarding the claimed oligonucleotide structure having a specific combination of features (i) and (ii) is irrelevant in itself and not persuasive.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to COREY LANE BRETZ whose telephone number is (571)272-7299. The examiner can normally be reached M-F 7:30am - 6:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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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/COREY LANE BRETZ/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
