DETAILED ACTION
Receipt of Arguments/Remarks filed on July 23 2026 is acknowledged. Claim 1 was amended. Claim 47 was added. Claims 1-47 are pending. Claims 4-5, 9, 11-17, 19-24 and 37-46 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 November 12 2025. Claims 1-3, 6-8, 10, 18, 25-36 and 47 are directed to the elected invention.
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 .
Withdrawn Objections/Rejections
The amendments filed July 23 2026 are sufficient to overcome the objection to the drawings and nucleotide and/or amino acid sequence disclosure.
The abandonment of copending ‘18170685 on April 21 2026 has rendered the rejection on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 9-10, 13-15, 17-18, 21, 25 and 41 of copending Application No. 18170685 (USPGPUB No. 20240167040) moot.
Maintained and Modified Rejection Based on Amendments in the reply filed on July 23 2026
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 6-8, 10, 18 and 25-36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 as currently written is vague and indefinite. The claim recites a guanosine analog of Formula I or II (shown below):
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. The scope of the structure is not clear. Specifically, it isn’t clear what the squiggly line is intended to mean. As taught by UCLA (see chem.ucla.edu, attached to this office action). A wavy line (squiggly line) means (1) a molecular structure beyond this point is unspecified or unimportant (aka it indicates a point of attachment) or (2) a mixture of isomers. It isn’t clear what the squiggly line in Formula I or II means. Neither the claims nor the specification provide a limiting definition. As set forth in Chem.UCLA.edu when it is intended to mean the point of attachment then the squiggly line crosses a bond:
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which does not appear to be the way the bond is used in the structure above. Therefore, the other interpretation is that it is a mixture of stereoisomers and the bond has a methyl (aka CH3) in either the R or S configuration. But the guanosine analogue is intended to be part of a polynucleotide in the claims so having a methyl group of unspecified configurations would not make sense as it pertains to the use in a larger molecule. Therefore, the claim is indefinite as it appears that this is supposed to be signifying the point of attachment but the squiggly line is not used in the conventional manner for this indication and nothing in the claims or specification clarify the meaning.
Claim 10 is also indefinite for the reasons set forth above for the squiggly line.
Claims 2-3, 6-8, 18 and 25-36 are included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
Response to Arguments
Applicants’ arguments filed July 23 206 have been fully considered but they are not persuasive.
Applicants argue that the preamble of claim 1 recites a polynucleotide. The definition of guanosine analogues at p. 5 shows the point of attachment of guanosine analogues. Points of attachment for guanosine analogues are shown on page 20. It is argued that the same subject was found acceptable and have been allowed in Japan. It is argued that the examiner interprets the claim correctly.
Regarding Applicants arguments, firstly, the allowance of similar claim in another case, let alone another count is immaterial. In re Giolito, 530 F. 2d 397, 188 USPQ 645 (CCPA 1976). Secondly, the sections in the specification pointed to by Applicants do not actually provide a limiting definition of the squiggly line as recited in the claims. Page 5 merely repeats the structure of the nucleobases 8-oxo-guanine and 7-deaza-8-aza-guanine. Page 20 recites the “dotted lines” and indicates that these represent the covalent bond between each nucleoside. However, this is NOT the structure claimed. For example, page 19 (which includes a structure which includes the dotted lines):
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This structure is NOT indefinite. This structure include convention nomenclature which is the dotted/dashed lines indicating point of attachment. But this is NOT the structure claimed, the structure claimed is a wavy line which standard nomenclature would indicate it means a bond of mixed stereochemistry which does not make sense. Therefore, Applicants arguments are not persuasive. Applicants can amend the structure to include the dashed lines which are 1) supported and 2) not indefinite.
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 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-2, 6-8, 10, 18, 26, 29-32 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Srivastava et al. (USPGPUB No. 20110137010) in view of Kutyavin et al. (Nucleic Acids Research, 2002, cited on PTO Form 1449) as evidenced by Aguilera et al. (WO2012144906).
Applicant Claims
The instant application claims a polynucleotide that comprises at least one phosphorothioate internucleoside linkage and at least a guanosine analogue which as elected is:
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Wherein the squiggly line is interpreted by the examiner as being the point of attachment to a sugar which would correspond to Structure IIb as elected:
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Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Srivastava et al. is directed to phosphoramidites for synthetic RNA in the reverse direction, efficient RNA synthesis and convenient introduction of 3’-end ligands, chromophores and modifications of synthetic RNA. Claimed is a compound of formula Ic:
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wherein J can be H, R6 is H or O-Z wherein Z is an acid labile protecting group (i.e. a group that gets cleaved for synthesis of the oligonucleotide) and Bn is a hydrogen or nucleobase selected from a list which includes 7-deaza-8-azaguanine (claim 1). It is taught that 7-deaza-2’-deoxy nucleosides can be incorporated within the RNA sequence in place of a dGuanosine base. This modification has many significant biological properties for diagnostic and therapeutic field of DNA and RNA (paragraph 0297-0298). RNA molecules which incorporate the compounds is claimed (claim 39). Exemplified oligonucleotides have phosphorothioate linkages (Figs 2A-2D; claim 29, 31; paragraph 0370). It is taught that the Reverse RNA synthesis can be used in RNAi (RNA interference) synthesis (paragraph 0376). The phosphoramidate oligos have been shown to help in design and efficacy of oligonucleotides for gene regulation, gene expression, antisense etc. (paragraph 0309). Incorporation of locked amino acids via reverse RNA synthesis is taught (paragraph 0309).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Srivastava et al. teaches 7-deaza-8-azaguanine, Srivastava et al. does not expressly provide motivation for selecting this base from the list taught. However, this deficiency is cured by Kutyavin et al.
Kutyavin et al. is directed to reduced aggregation and improved specificity of G-rich oligodeoxyribonucleotides containing pyrazole[3,4-d]pyrimidine guanine bases. It is taught that G-rich oligonucleotides (ODNs) can cause problems in DNA synthesis. Unwanted aggregation can plague studies that assume ODNs behave as single strand with predictable hybridization performance. Results show that PPG (8-aza-7-deazaguanine) when substituted for G can significantly reduce self-association. Data demonstrates improved mismatch discrimination properties of PPG-containing ODNs. The substitution of G with PPG could be beneficial in the case of relatively stable mismatches where G is involved (conclusions).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
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 teachings of Srivastava et al. and Kutyavin et al. and utilize PPG (aka 8-aza-7-deaxaguanine) as the base in the compound of formula Ic in Srivastava et al. One skilled in the art would have been motivated to choose PPG as it can reduce unwanted aggregation and/or self-association during synthesis and can be beneficial in forming relatively stable mismatches as taught by Kutyavin et al. One skilled in the art would have had a reasonable expectation of success as Srivastava et al. suggests that the base can be 8-aza-7-deaxaguanine. Therefore, to arrive at the claimed guanosine analogue one skilled in the art would have only needed to select 8-aza-7-deaxaguanine from a finite list of possible choices for the base.
Regarding the claimed polynucleotide, Srivastava et al. teaches incorporation of the compounds into polynucleotides. Exemplified oligonucleotides have phosphorothioate linkages. Therefore, incorporation of the compound Ic wherein the base is 8-aza-7-deazaguanine into the polynucleotide would result in the instantly claimed polynucleotide.
Regarding the claimed neurotoxicity, firstly, "A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim." Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1172 (Fed. Cir. 1993). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."). Note MPEP 2111.04.
In this case, claims 1 and 47 use the term "wherein", rather than "whereby", but it is concluded that the terms should be treated the same. Here, the wherein clause merely states the effect that is achieved when at least one guanosine analogue is incorporated into a polynucleotide. Therefore, Note: MPEP 2145: Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979); In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991); see also In re Woodruff, 919 F.2d 1575, 1577-78 (Fed. Cir. 1990) (obviousness rejection affirmed where using claimed elements in the manner suggested by the prior art necessarily resulted in claim-recited effect).
Finally, as evidenced by Aguilera et al., incorporation of modified bases such as 8-aza-7-deazaguianine are expected to provide a compound or an oligonucleotide with improved RNA binding kinetics and/or thermodynamic properties, provide a compound or an oligonucleotide with a decreased or acceptable level of toxicity and/or immunogenicity (pages 10-11, lines 30-32 and 1-22). Therefore, the expectation would be that incorporation of a modified base such as 8-aza-7-deazaguanine would have reduced toxicity and Applicants have not established a specific unexpected effect.
Regarding claims 6-8, 10 and18 as set forth above compound 1c with the 8-aza-7-deazaguanine base would result in a locked nucleic acid, specifically, beta-D-oxy LNA: compound IIb.
Regarding claims 2, 26 and 29-32, exemplified sequences include those with phosphorothioates and contain multiple G nucleotides (paragraph 0440). 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 teachings of Srivastava et al. and Kutyavin et al. and utilize PPG (aka 8-aza-7-deazaguanine) with all the G located in the particular oligonucleotide sequence. One skilled in the art would have been motivated to replace all the G nucleotides (e.g. 1, 2, 3, 4 or more) with PPG in order to reduce aggregation and improved specificity of G-rich oligodeoxyribonucleotides as taught by Kutyavin et al.
Claims 2-3, 25-29 and 32-36 are rejected under 35 U.S.C. 103 as being unpatentable over Srivastava et al. in view of Kutyavin et al. as evidenced by Aguilera et al. (WO2012144906) as applied to claims 1-2, 6-8, 10, 18, 26, 29-32 and 47 above and in further view of Costa et al. (USPGPUB No. 20170191064).
Applicant Claims
The instant application claims the polynucleotide is an antisense oligonucleotide. The instant application claims the antisense oligonucleotide is a gapmer. The instant application claims a pharmaceutical formulation comprising the polynucleotide and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant. The instant application claims the formulation is suitable for administration to the central nervous system or for treatment of a neurological disorder. The instant application claims the formulation is suitable for administration via intrathecal injection.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Srivastava et al. and Kutyavin et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Srivastava et al. suggests incorporation into oligonucleotides and teaches the phosphoramidate oligos have been shown to help in design and efficacy of oligonucleotides for gene regulation, gene expression or antisense, Srivastava et al. does not expressly teach an antisense gapmer or pharmaceutical composition comprising the oligonucleotides. However, these deficiencies are cured by Costa et al.
Costa et al. is directed to oligonucleotides for inducing paternal ube3a expression. Claimed is an antisense oligonucleotide which comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 98% complementarity to position 25278410 to 25419462 on human chromosome 15 (claim 1). The oligonucleotides comprises one or more modified nucleosides (claim 5). The modifications are a LNA nucleoside (claim 8; paragraph 0053-0054). The oligonucleotide is a gapmer (claim 12). Sequences specifically taught (Table 3) include:
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Claimed is a pharmaceutical composition comprising the oligonucleotide and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant (claim 16). The oligonucleotides can be administered via intrathecal administration (paragraph 026-0268). The oligonucleotide can comprise one or more modified nucleosides or nucleotides (paragraph 0016; 0031). Nuclease resistant linkages, such as phosphorothioate linkages, are useful in oligonucleotide regions capable of recruiting nuclease when forming a duplex with the target nucleic acid, such as region G for gapmers (paragraph 0028).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
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 teachings Srivastava et al., Kutyavin et al. and Costa et al. and utilize the compound of Srivastava et al. with the PPG (aka 8-aza-7-deaxaguanine) nucleobase in the oligonucleotide of Costa et al. One skilled in the art would have been motivated to utilize this oligonucleoside as Srivastava et al. suggests it use in the synthesis of oligonucleotides. Since Costa et al. teaches the inclusion of modified nucleobases as well as modified sugars and specifically teaches the use of a locked nucleic acid (LNA) there is a reasonable expectation of success. Since the nucleoside is a guanine, it would be obvious to use the modified nucleoside at any G in the oligonucleotide sequence of Costa et al.
Regarding the claimed phosphorothioate internucleoside linkage, Costa et al. teaches nuclease resistant linkages, such as phosphorothioate linkages, are useful in oligonucleotide regions capable of recruiting nuclease when forming a duplex with the target nucleic acid, such as region G for gapmers. Since Srivastava et al. also teaches phosphorothioate linkages, there is a reasonable expectation of success.
Regarding claim 3 and 25, Costa et al. teaches the oligonucleotides are antisense gapmers.
Regarding claims 27-28 and the claimed sequences of claim 33, as set forth above Costa et al. teaches the use of oligonucleotides of 10 to 30 nucleotides in length with at least 98% complementarity to position 25278410 to 25419462 on human chromosome 15. Table 3 teaches specific oligonucleotides and their corresponding position on the chromosome.
As set forth above instantly claimed SEQ ID NO: 6 (Qy) has 100% identity to SEQ ID NO: 95 (Db) of Costa et al.
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And SEQ ID No: 10 (Qy) has 100% identity to SEQ ID No: 100 (Db) of Costa et al.
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The sequences contain the same sequence identity as well as the same capital letters which Costa et al. teaches represent beta-D-oxy-LNA nucleosides, lowercase letters present DNA nucleosides and all LNA C are 5-methyl cytosine (0416) which is the same definition as claim 33. Therefore, replacement of the G in the sequence, which is obvious for the reasons set forth above, would result in the same sequence.
Regarding claim 34-36, Costa et al. expressly claims a pharmaceutical composition comprising the oligonucleotide and a diluent, solvent, carrier, etc. 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 teachings Srivastava et al., Kutyavin et al. and Costa et al. and utilize a composition, specifically a carrier and the oligonucleotide, in order to formulate a composition which can be delivered intrathecally. Therefore, all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2143 KSR International Co. v. Teleflex Inc., 550 US 398, 82 USPQ 2d 1385 (2007).
Furthermore, regarding claims 35-36, these claims are directed to the intended use of the pharmaceutical formulation. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Note: MPEP 2111.02 and MPEP 2145. Costa et al. teaches the pharmaceutical composition with a carrier and that the composition can be administered intrathecally. Therefore, it is clearly taught as being suitable for administration to the CNS and suitable for administration via intrathecal injection.
Response to Arguments
Applicants’ arguments filed July 23 2026 have been fully considered but they are not persuasive.
Applicants argue that the instant invention is based upon the finding that the proportion of natural, i.e. unmodified guanosine nucleobases, within a polynucleotide sequence is directly correlated to the likelihood that a polynucleotide is neurotoxic. The instant inventors have identified that the substitution of unmodified G nucleobase with PPG or 8-oxo-dG bases in a phosphorothioate antisense or siRNA alleviates neurotoxicity in vivo as well as in in vitro neurotoxicity assays. It is argued that none of the cited reference address neurotoxicity. It is argued that this reduced neurotoxicity is unexpected. It argued that the examples show that replacement of one of the natural guanosines with either 8-aza-7-deaza-guanine or 8-oxo-deoxyguanosine showed reduced or zero toxicity.
Regarding Applicants’ arguments, firstly, the previously cited prior art is silent to any toxicity. Therefore, the examiner cannot agree that the expected in the prior art is that these sequences would be toxic. Newly cited Aguilera et al. suggests that incorporation of modified bases would be expected to have the same or reduced toxicity. Applicants have not shown an unexpected effect with the specifically claimed modified nucleobase (i.e. comparison to other modified nucleobases). Secondly, the data shows that replacement of any g with either of the claimed guanosine analogue results in reduced activity. Therefore, the data shows mere incorporation results in reduced neurotoxicity. Both Srivastava et al. and Kutyavin et al. provide strong motivation to include PPG in the oligonucleotides. Therefore, the data in the specification is not sufficient to establish an unexpected effect. The state of the prior art establishes that incorporation of modified bases would be expected to reduce toxicity. Kutyavin et al. clearly discloses advantages of using PPG resulting in a strong case of obviousness. Applicants’ results merely show that the claimed PPG possess properties that were not previously appreciated. Note: MPEP 2145: Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979); In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991); see also In re Woodruff, 919 F.2d 1575, 1577-78 (Fed. Cir. 1990) (obviousness rejection affirmed where using claimed elements in the manner suggested by the prior art necessarily resulted in claim-recited effect).
Conclusion
Applicants’ 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 ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ABIGAIL VANHORN/ Primary Examiner, Art Unit 1636
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