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
This action is written in response to applicant’s correspondence received 02/28/2025. Claims 1, 14, 20, 22-28, 30-31, 33-44, 46-55, 57-62, 64-65 and 67-69 are currently pending. Claims 47, 49, 52-53, 58-60 and 67-69 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1, 14, 20, 22-28, 30-31, 33-44, 46, 48, 50-51, 54-55, 57, 61-62 and 64-65 are examined herein. Applicant elected the invention of Group I, a species from Group A which is a trisaccharide of N-acetylgalactosamine, and a species from Group B which is a 2’-OMe modification without traverse in the reply filed 07/26/2024.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Objections
Claim 1 is objected to for minor informalities. Claim 1 recites (p. 3, bottom) “said second and third nucleic together”. This appears to be a typographical error and is grammatically incorrect. It is believed that applicant’s intent was for the claim to read, “said second and third nucleic acid sequences together”, and the claim is interpreted accordingly. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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, 14, 20, 22-28, 30-31, 33-44, 46, 48, 50-51, 54-55, 57, 61-62 and 64-65 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 recites the limitations "said first and fourth nucleic acid portions" and “said second and third nucleic acid portions” (p. 4 ln 9-11). There is insufficient antecedent basis for this limitation in the claim. The claim previously recites first, second, third and fourth nucleic acid sequences but does not recite nucleic acid portions. The dependent claims are rejected for failing to remedy the lack of antecedent basis. The first through fourth nucleic acid portions are interpreted as referring to the first through fourth nucleic acid sequences previously recited in the claim. If that interpretation is correct, then amending the claim to replace the term “portions” with “sequences”, as was done in e.g., line 3 of claim 1 in the amendments of 02/28/2025, would obviate this rejection.
Claim 1 recites wherein the first sequence is directly linked at its 3’ end to the 5’ end of a second nucleic acid sequence, and wherein the first and fourth sequences form a duplex region, but also recites wherein 2 to 6 nucleotides at the 3’ end of the first sequence form a linker moiety that remains single-stranded. The same direct linkage combined with a single-stranded linker applies to the third and fourth sequences, while the second and third sequences also form a duplex. This language is considered indefinite because it is unclear whether the linker is located within the 3’ terminus of the first and third sequences, or whether it is appended to the 3’ terminus of those sequences. If the linker is appended to the 3’ terminus, then the first and third sequences cannot, by definition, be directly linked, because there is a linker moiety between them. If the linker is part of the 3’ terminus, then the first and third sequences may be directly linked. However, the claim also requires the first/fourth and second/third sequences to form duplexes. Because the claim does not specify the required level of complementarity in the duplexes, it encompasses both full and partial complementarity. If the linker moiety is part of the first and third sequences, and the linker must be single-stranded, then the first/fourth and second/third sequences cannot form fully complementarity duplexes. Per the claim language, the last 2-6 nt must be excluded from the duplex for the linker to remain single-stranded. Therefore, at least in some embodiments, the single-stranded linker moiety and fully complementary duplexes appear to be mutually exclusive structures. Given these contradictions, the ordinary artisan would not be apprised of the metes and bounds of the claimed structures.
Claim 20 recites the term “said one or more ligands”. There is insufficient antecedent basis for this limitation in the claim because claim 1, from which claim 20 depends, does not recite one or more ligands. It is relevant to note that claim 14 presently recites one or more ligands. Either amending claim 20 to depend from claim 14, or amending claim 1 to recite the subject matter of claim 14, would obviate this rejection.
Claim Rejections - 35 USC § 102
This rejection has been modified as necessitated by the amendments to the claims of 02/28/2025.
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, 14, 25-28, 30, 31, 33-34, 43, 44, 46, 48, 50-51, 54-55, 57, 61-62, 64 and 65 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2007/091269 A2 to Aygun (of record, herein “Aygun”), as evidenced by Shukla ((2010) “Exploring Chemical Modifications for siRNA Therapeutics: A Structural and Functional Outlook”. ChemMedChem, 5: 328-349.).
For the purposes of comparison to the prior art, the nucleic acid portions recited in claim 1 and all of its dependents will be interpreted to encompass structures including but not limited to those comprising portions of or the whole of siRNA molecules, within the broader context of a multimeric siRNA construct, wherein the first and fourth sequences are or are a component of one siRNA molecule wherein the first sequence is the antisense or guide strand and the fourth sequence is the sense or passenger strand, and the second and third sequences are likewise interpreted as a second siRNA molecule wherein the second sequence is the antisense or guide and the third sequence is the sense or passenger strand. The claims require that the first/fourth and second/third sequences each form a duplex. Additionally, please note that claim 1 recites “nucleotides” but does not recite any particular type of nucleotides, i.e., RNA, DNA, nucleotide analogs, etc. Therefore, the broadest reasonable interpretation of the claimed nucleotides encompasses RNA and DNA nucleotides as well as any nucleotide analogs. The claim also requires a 2-6 nucleotide linker at the 3’ ends of the first and third nucleic acid sequences. Because the claim specifies that the 3’ end of the first sequence is directly linked to the second sequence, and likewise for the third and fourth sequences, the linkers are interpreted as being part of the first and third sequences.
Regarding claim 1, Aygun teaches a nucleic acid construct comprising a first continuous nucleic acid strand comprising a first sequence that is complementary to a sequence transcribed from a first target gene, wherein said first sequence is directly linked at its 3’ end to the 5’ end of a second nucleic acid sequence a second continuous nucleic acid strand comprising a third sequence that is complementary to a sequence transcribed from a second target gene, which target gene is different to said first target gene, wherein said third sequence is different to said first target gene, wherein said third sequence is directly linked at the 3’ end to the 5’ end of a fourth nucleic acid sequence, wherein said first and fourth nucleic acid sequences together form a first nucleic acid duplex region and said second and third nucleic together form a second nucleic acid duplex region:
the present invention discloses tandem oligoribonucleotides which encode two inhibitory RNA molecules such as siRNAs, wherein each siRNA may be specific for a different gene (or wherein both siRNAs are specific for the same gene)…It is also within the scope of the present invention to provide for oligonucleotides which encode three, four or even five inhibitory RNAs which target the same or as many as five different genes. [p. 6 ln. 2-5 and 10-12]
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Please note that the above shows structures and descriptions in which the first and second sequences are continuous and directly linked wherein 2 to 6 nucleotides (e.g., the 2-4 nucleotides seen in any of structures 9-11, which exemplify the generic linkers shown in structure 17) at the 3’ end of the first or third sequences form a linker moiety. Also note that, in certain embodiments, the linker moieties have nucleotide sequences which are not capable of base pairing, such as the 5’-dTsdT-3’ (i.e., 5’-TT-3’ if only the base sequence is shown), and would therefore each be single-stranded, forming a loop or bubble. See also below, in which Aygun shows structures with a “minimal loop linker” in which the linkers do not base pair, and further describes the loop linker:
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The first strand and the second strand may be linked by a loop structure…the loop structure may be comprised of a nucleic acid. (p. 21 ln 2-4)
Note that in the above structures, dT or T indicate desoxyribothymidine (DNA); s indicates phosphorothioate (PO3S instead of PO4); U, A, G, and C indicate 2'-O-Methyl-Ribouridine (RNA), 2'-O-Methyl-Riboadenosine (RNA), 2'-O-Methyl-Riboguanosine (RNA) and 2'-0- 15 Methyl-Ribocytidine (RNA) respectively; U, A, G and C indicate ribouridine (RNA), riboadenosine (RNA), riboguanosine (RNA) and ribocytidine (RNA) respectively (p. 37 ln 11-16)
Here, it is relevant to note that while Aygun’s exemplary embodiments, shown above, show the first and second sequences in the order, from 5’ to 3’, of sense-antisense rather than the claimed antisense-sense order, Aygun states that the order of the sense and antisense may be altered such that any conformation is possible (p. 11 ln 1-3), and therefore also teaches the claimed order:
Further, with respect to molecules containing any of the linkers as presented in structures 7-15 above, it is to be noted that the order of the sense and antisense strands may be altered, such that any conformation is possible
Further regarding claim 1, Aygun teaches wherein each of the sequences are independently 15 to 23 bases, which overlaps the claimed range of 10 to 18 (p. 20 ln 9-12):
The length of the double-stranded structure of the siRNA is typically from about 17 to 21 and 10 more preferably 18 or 19 bases. Further, the length of said first strand and/or the length of said second strand may independently from each other be selected from the group comprising the ranges of from about 15 to about 23 bases, 17 to 21 bases and 18 or 19 bases.
It is relevant to note that here, Aygun refers to first and second strands in the context of a double-stranded siRNA, i.e., wherein the first and second strands are the guide and passenger strands. Therefore, the first and second strands of Aygun are interpreted as analogous to the first and fourth or second and third duplexed sequences.
Further regarding claim 1, Aygun teaches wherein the construct comprises modified nucleotides and/or modified internucleotide linkages that are resistant to in vivo cleavage, and includes unmodified nucleotides at the 3’ of the first and third sequences. See for example Variant 1f, shown above, which has linkers comprising both DNA nucleotides with phosphorothioate linkages (dTsdT) as well as unmodified ribouridines, wherein the linkers are not complementary and would therefore form a single-stranded loop or bubble. As evidenced by Shukla, unmodified ribonucleotides in siRNAs are inherently vulnerable to nuclease degradation (i.e., cleavage by nucleases), whereas modifications such as phosphorothioate backbone modifications or 2’-O-methyl sugar modifications have the inherent property of being more resistant to nuclease cleavage:
Unmodified siRNAs have a half-life of less than ∼15 min in serum…the guide strand is more susceptible to degradation by exonucleases and the passenger strand is preferentially degraded by endonucleases…The most viable method to address the nuclease vulnerability of siRNAs is the use of various chemical modifications (§4.1 Imparting nuclease resistance without loss of RNAi activity p. 336)
Broadly speaking, chemical modifications used in siRNAs fall into four classes: backbone, sugar, base, and terminal modifications…The backbone modifications involve alterations to the phosphate ester linkages in the nucleic acid (Figure 4 a). One of the more common modifications of this type is the phosphorothioate (PS) modification, in which one of the non-bridging phosphate oxygen atoms is replaced by sulfur to give a PS group…This modification is widely used in antisense oligonucleotide therapeutics and is now being employed in siRNAs, as it provides improved nuclease resistance (§4.1 Imparting nuclease resistance without loss of RNAi activity p. 336)
The 2′-OMe modification has been shown to improve nuclease resistance (§4.1 Imparting nuclease resistance without loss of RNAi activity p. 337)
Therefore, insofar as Aygun teaches PS and 2’-O-methyl modifications, and teaches unmodified nucleotides present in the linker, and Shukla evidences that modified and unmodified nucleotides and backbones inherently have greater or lesser nuclease resistance, Aygun teaches that the modified nucleotides would be protected from nuclease degradation while the unmodified nucleotides would be vulnerable to nuclease cleavage, such that after in vivo administration the constructs would be cleaved by endogenous nucleases at the unmodified nucleotides and form two sets of nucleic acid targeting molecules comprising the first/fourth and second/third sequence duplexes.
Finally, regarding claim 1, Aygun teaches wherein the nucleic acid targeting molecules derived from the construct modulate expression of the target by inducing cleavage of the target sequence (mRNA):
An siRNA is a double-stranded RNA molecule which down-regulates or silences (prevents) the expression of a gene/ mRNA of its endogenous or cellular counterpart. RNA interference is based on the ability of dsRNA species to enter a specific protein complex, where it is then targeted to the complementary cellular RNA and specifically degrades it. Thus the RNA interference response features an endonuclease complex containing an siRNA, commonly referred to as an RNA-induced silencing complex (RISC), which mediates cleavage of single-stranded RNA having sequence complementary to the antisense strand of the siRNA duplex…longer dsRNAs are digested into short (17-29 bp) dsRNA fragments (also referred to as short inhibitory RNAs - "siRNAs") by type III RNases…These fragments and complementary mRNA are recognized by the RISC protein complex. The whole process is culminated by endonuclease cleavage of target mRNA. [p. 2 ln 14-27]
Regarding claim 14, Aygun teaches a construct comprising one or more ligands conjugated to the 3’ end of the first nucleic (acid) strand and/or the second nucleic acid strand:
Terminal modifications on the 5' and/or 3' part of the tandem oligonucleotides are also possible. Such terminal modifications may be lipids, peptides, sugars or other molecules. [p. 7 ln 6-8]
Regarding claim 25, it has been noted above that Aygun teaches wherein each of the siRNA strands (i.e., sequences) are independently selected from the group comprising the ranges of about 15 to about 23 bases. Assuming a sequence length of 15 bases and a linker length of 2, then each full tandem siRNA strand would be 32 nt long, which falls within the claimed range.
Regarding claim 26, Aygun teaches linker moieties which are 4 nucleotides in length (see e.g., Variant 1f, above).
Regarding claims 27-28, 30-31 and 43, Aygun (p. 35) teaches wherein the construct comprises one or more phosphorothioate internucleotide linkages (relevant to claim 27); 1 to 17 phosphorothioate internucleotide linkages (relevant to claim 28), comprises PS linkages between at least two adjacent nucleotides of the linker moiety (relevant to claim 30) and/or each adjacent nucleotide that is present in the linker moiety (relevant to claim 31), and/or a plurality of adjacent commonly modified nucleotides are located in the linker moiety:
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Please note that ‘s’ denotes a PS linkage and the linkage in Variant Ie has a PS linkage between each adjacent nucleotide in the linker. Additionally, please note that “commonly modified nucleotides” is interpreted as encompassing any nucleotide modification, including both backbone and sugar modifications. Under that interpretation, the dTsdT modifications taught by Aygun also teach that a plurality (2 or more) of adjacent commonly nucleotides are located in the linker moiety.
Regarding claims 33, 34, 44, 46, 48 and 57, Aygun teaches wherein at least one nucleotide of any nucleic acid portion is modified (relevant to claim 33); wherein one or more of the odd or even nucleotides starting from the 5’ region is modified (relevant to claim 34); wherein one or more of the modified nucleotides of the first or second nucleic acid portions do not have a common modification present in the corresponding nucleotide of the corresponding passenger strand/duplex region (relevant to claim 44); wherein the modified nucleotide is a 2’-O-methyl modification in a ribose moiety (relevant to claims 46 and 48); wherein all the nucleotides other than unmodified nucleotides contain 2’O-methyl modifications in ribose moieties (relevant to claim 57) (see Variant If above and the key below):
Note that in the above structures…U, A, G, and C indicate 2'-O-Methyl-Ribouridine (RNA), 2'-O-Methyl-Riboadenosine (RNA), 2'-O-Methyl-Riboguanosine (RNA) and 2'-0- 15 Methyl-Ribocytidine (RNA) respectively [p. 37 ln 11-15]
Regarding claim 50, Aygun teaches wherein the nucleotides at any of positions 2 and 14 downstream from the first nucleotide of the 5’ region of the first and/or second nucleic acid sequences do not contain 2’-O-methyl modifications in ribose moieties (emphasis added for clarity). See Variants 1e-f above, where e.g. the nucleotides at positions 3 and 5 downstream from the first nucleotide of the 5’ region of the first nucleic acid sequences are unmodified.
Regarding claim 51, Aygun teaches wherein the nucleotides of the third or fourth nucleic acid sequences that correspond in position to any of the nucleotides of positions 11 to 13 downstream from the first nucleotide of the 5’ region of the first or second nucleic acid portions do not contain 2’-O-methyl modifications in ribose moieties (emphasis added for clarity). See Variants 1e-f above, where, for example, the positions in Seq03-as corresponding to positions 11 and 13 of Seq03-s are unmodified.
Regarding claims 54-55, Aygun teaches the construct which comprises one or more unmodified nucleotides (relevant to claim 54; see e.g. Variants 1e-f of Aygun above), wherein said one or more unmodified nucleotides can replace any unmodified nucleotide (relevant to claim 55):
underlined nucleotides were modified, but it is envisaged that unmodified nucleotides may also be used.[p. 48 ln 3-4]
Regarding claims 61 and 62, Aygun teaches wherein the construct is either blunt-ended (relevant to claim 61) or one of the nucleic acid sequences has an overhang (relevant to claim 62):
The double stranded structure of the siRNA may be blunt ended, on one or both sides. [p. 20 ln 1]
at least one of the two strands may have an overhang of at least one nucleotide at the 5'-end; the overhang may consist of at least one deoxyribonucleotide. At least one of the strands may also optionally have an overhang of at least one nucleotide at the 3'-end.[p. 20 ln 6-8]
Regarding claims 64-65, Aygun teaches the construct and a physiologically acceptable excipient (relevant to claim 64) for use in the treatment of a disease or disorder (relevant to claim 65):
the compound can be administered…alone or as an active ingredient in combination with pharmaceutically acceptable carriers, solvents, diluents, excipients [p. 56 ln 30-32]
Response to Arguments
Applicant's arguments filed 02/28/2025 have been fully considered but they are not persuasive.
Applicant argues that, “almost all of the molecules described in Aygun contain discontinuities”. This argument is not persuasive because, as discussed in the previous rejection of the claims under 35 U.S.C. 102 as well as the modified rejection above, Aygun teaches continuous structures as well as structures with gaps. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (MPEP 2123).
Applicant also argues that “Aygun contains only vague descriptions of bispecific siRNA molecules where the sense and antisense portions on each strand are joined together by some hypothetical and unspecified DNA or RNA sequence, where these descriptions lack any detail and would provide the person of ordinary skill with no guidance at all regarding the specific nature of the linkers”. This argument is not persuasive because Aygun, as discussed previously, discussed above, and as stated by Applicant on p. 16 of the Remarks of 02/28/2025, exemplifies specific linker sequences. See e.g., page 9 in examples 9-11 as well as pages 34-35, Variants 1a-f. Applicant also argues that the “linkers contain irrelevant DNA residues”. However, Applicant has not supported the argument that the DNA residues are irrelevant with any citations to, evidence from, or explanations of the prior art or specification. As such, Applicant's remarks have been considered in accordance with MPEP 716.01(C) ("The arguments of counsel cannot take the place of evidence in the record.”).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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 20 and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2007/091269 A2 to Aygun (of record) in view of Rajeev et al. (of record).
Aygun teaches the construct according to claim 1, from which claims 20 and 22-24 depend.
Aygun does not teach the construct wherein one or more ligands comprise the elected species of one or more N-Acetyl-Galactosamine moieties (relevant to claims 20, 22).
Aygun does not teach the construct wherein the one or more ligands are attached in a linear or branched configuration (relevant to claim 23), or wherein the ligands are attached as a triantennary configuration, or as a configuration based on single ligands.
Rajeev teaches siRNAs conjugated to branched triantennary N-Acetylgalactosamine moieties and/or siRNAs conjugated to N-Acetylgalactosamine ligands arranged in a linear, trivalent configuration based on single ligands (see Figure 1; the trivalent configuration is interpreted as equivalent to the claimed configuration based on single ligands, because the trivalent configuration comprises three individual, or single, N-acetylgalactosamine ligands attached in a series).
Rajeev further provides a teaching, suggestion or motivation to conjugate N-acetylgalactosamine moieties to siRNAs in either a triantennary or trivalent configuration:
sequential covalent conjugation of three simple GalNAc moieties through non-nucleosidic linkers to the 3’-end of oligonucleotides are well recognized
by the ASGPR, which in turn facilitates robust, tissue-specific delivery of therapeutic oligonucleotides to liver. The uptake efficiency of the siRNAs with the simplified trivalent GalNAc display was comparable to that of siRNAs conjugated
to the triantennary GalNAc ligand. [p. 906]
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the construct as taught by Aygun to comprise the N-Acetyl-Galactosamine ligands as taught by Rajeev, in any of the configurations taught by Rajeev. The skilled artisan would have been motivated to do so based on Rajeev’s teachings that utilizing either configuration would yield equivalent and predictable outcomes of a siRNA construct with robust, tissue-specific delivery of therapeutic oligonucleotides to the liver.
Claims 35-42 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2007/091269 A2 to Aygun (cited on the IDS received 09/14/2022; herein Aygun) in view of WO Patent Publication 2016201301 A1 to Borodovsky (cited on the attached PTO-892; herein Borodovsky).
Aygun teaches the construct according to claims 1 and 33, from which claims 35-42 depend.
Aygun does not teach:
wherein one or more of the odd numbered nucleotides starting from the 3’ region of the third or fourth nucleic acid sequences are modified by a modification that is different from the modification of odd numbered nucleotides starting from the 5’ region of the first or second nucleic acid portions, respectively. This is interpreted to mean that the passenger and guide strands must have a modification to at least one odd-numbered nucleotide, starting from the 3’ end of the passengers and 5’ end of the guides, but that this at least one modification in the passenger strand must be a different type of modification relative to the modification of an odd numbered nucleotide on the guide strand (relevant to claim 35)
wherein one or more of the even numbered nucleotides starting from the 3’ region of the third or fourth nucleic acid sequence are modified by a modification that is different from the modification of odd numbered nucleotides of those sequences. This is interpreted to mean that the third and fourth nucleic acid sequences must have different alternating modifications in an “a-b-a-b-a-b…” pattern starting from the 3’ end. (relevant to claim 36)
wherein at least one of the modified even numbered nucleotides of the first and/or second and/or third and/or fourth nucleic acid sequence is adjacent to at least one or more differently modified odd numbered nucleotides of those portions. This is interpreted to require essentially the same pattern of modifications as described in b) above, but applied to the first and second nucleic acid sequences. (relevant to claims 37, 38)
wherein a plurality of adjacent nucleotides of the first and/or second and/or third and/or fourth nucleic acid sequences are modified by a common modification (relevant to claims 39, 40), wherein the plurality of adjacent nucleotides are 2-4 adjacent nucleotides (relevant to claim 41), wherein the plurality of adjacent nucleotides are in the 5’ region of the third or fourth nucleic acid sequence (relevant to claim 42)
Borodovsky teaches limitations a, b and c above (relevant to claims 35-38):
the RNAi agent of the invention comprises the modification pattern for the alternating motif on the sense strand relative to the modification pattern for the alternating motif on the antisense strand is shifted. The shift may be such that the modified group of nucleotides of the sense strand corresponds to a differently modified group of nucleotides of the antisense strand and vice versa. For example, the sense strand when paired with the antisense strand in the dsRNA duplex, the alternating motif in the sense strand may start with “ABABAB” from 5’-3’ of the strand and the alternating motif in the antisense strand may start with “BABABA” from 5’-3’of the strand within the duplex region. [p. 64 ln 14-24]
the RNAi agent comprises the pattern of the alternating motif of 2'-O-methyl modification and 2’-F modification on the sense strand initially has a shift relative to the pattern of the alternating motif of 2'-O-methyl modification and 2’-F modification on the antisense strand initially, i.e., the 2'-O-methyl modified nucleotide on the sense strand base pairs with a 2'-F modified nucleotide on the antisense strand and vice versa. The 1 position of the sense strand may start with the 2'-F modification, and the 1 position of the antisense strand may start with the 2'- O-methyl modification. [p. 64 ln 25-31]
every nucleotide in the sense strand and the antisense strand of the RNAi agent, including the nucleotides that are part of the motifs are modified nucleotides. In one embodiment each residue is independently modified with a 2’-O-methyl or 3’-fluoro, e.g., in an alternating motif.
It is relevant to note that if every nucleotide in a given strand, sense or antisense, is modified in an alternating pattern, then the alternating pattern may be said to begin at both the 5’ and 3’ ends of the nucleic acid construct. In addition, when combined with the teachings in ¶64 above regarding alternating 2’-F and 2’-O-methyl modifications starting at position 1 of the sense and antisense strands, respectively, Borodovsky further teaches the above limitations.
Borodovsky further teaches wherein a plurality of adjacent nucleotides of the first and/or second and/or third and/or fourth nucleic acid portions are modified by a common modification (relevant to claims 39, 40), wherein the plurality of adjacent nucleotides are 2-4 adjacent nucleotides (relevant to claim 41), wherein the plurality of adjacent nucleotides are in the 5’ region of the third or fourth nucleic acid portion (relevant to claim 42):
The alternating nucleotide may refer to one per every other nucleotide or one per every three nucleotides, or a similar pattern. For example, if A B and C each represent one type of modification to the nucleotide, the alternating motif can be "ABABABABABAB ... ," 5 "AABBAABBAABB .. .," "AABAABAABAAB ... ," "AAABAAABAAAB ... ," "AAABBBAAABBB ... ," or "ABCABCABCABC ... ," etc.
Borodovsky further provides a teaching, suggestion or motivation to modify RNAi molecules according to the patterns disclosed above:
when the sense strand and antisense strand of the double stranded RN Ai agent are completely modified to have one or 10 more motifs of three identical modifications on three consecutive nucleotides at or near the cleavage site of at least one strand of an RN Ai agent, the gene silencing activity of the RNAi agent was superiorly enhanced. [p. 58 ln 8-12]
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the construct as taught by Aygun according to the modification patterns taught by Borodovsky, to achieve the predictable outcome of an RNAi construct with enhanced gene silencing activity compared to a similar construct without said modification patterns.
Response to Arguments
Applicant's arguments filed 02/28/2025 have been fully considered but they are not persuasive.
Applicant argues that, “The deficiencies of Aygun are set forth above. Desaulnier is cited only as teaching non- nucleotide spacer linkers. Rajeev is cited only as teaching use of GalNAc ligands. Borodovsky is cited as teaching only certain modification patterns. For the reasons set forth above in the response to the rejections under § 102, nothing in Aygun teaches or suggests simple, short, molecules of the type defined in the instant claims and the secondary references fail to remedy these deficiencies.” This argument is not persuasive because, as discussed above in the modified rejections of the claims under 35 U.S.C. 102, Aygun teaches the limitations of amended claims 1, 14, 27-28, 30, 33-34, 44, 46, 48, 50-51, 54-55, 57 and 61-62.
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 1-13, 25-31, 33, 46-49 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of copending Application No. 18/170,971 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims recite a generic nucleic acid construct comprising the same generic structural elements, including linkers and base and backbone modifications, as the specific construct, with specific target genes and specific SEQ ID NOs: which anticipate the generic structures.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 02/28/2025 have been fully considered but they are not persuasive. Applicant requests that the rejection be held in abeyance pending an indication of allowable subject matter. Per MPEP 804(I)(B)(1), a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional. As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. Only compliance with objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated.
Conclusion
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 AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
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/A.M.Z./Examiner, Art Unit 1636
/RICHARD A SCHNIZER/Primary Examiner, Art Unit 1635
