DETAILED ACTION
Election/Restrictions
Applicants’ election without traverse of Group I in the reply filed on July 24 2026 is acknowledged. Claims 1, 26-30, 33-34, 36-38, 44, 56-58, 62 and 69-72 are pending in the application and are being examined on the merits herein.
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 .
Priority
This application is a 371 of PCT/US2021/064581 (12/21/2021) which claims benefit of 63/129,126 (12/22/2020) as reflected in the filing receipt issued June 24 2024.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 1 2023 and July 24 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112-Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 72 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 72 as currently written is vague and indefinite. Firstly, claim 72 is incomplete as it depends on cancelled claim 47. Note MPEP 608.01(n)(V). Additionally, Claim 72 recites the limitation "The compound" and “the double-stranded RNA duplex” in line 1. There is insufficient antecedent basis for these limitations in the claim. In the interest of compact prosecution, the claim is interpreted as depending from claim 71 which provides antecedent basis to the claimed terminology.
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, 26-30, 33-34, 36-38, 44, 56-58, 62 and 69-72 are rejected under 35 U.S.C. 103 as being unpatentable over Debacker et al. (Molecular Therapy, 2010, cited on PTO Form 1449) in view of Li et al. (WO2018044350) and Keller et al. (WO2006016097, cited in the Office Action mailed on April 23 2026).
Applicant Claims
The instant application claims a compound represented by Formula I:
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wherein a specific compound claimed is:
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Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Debacker et al. is directed to the delivery of oligonucleotides to the liver with GalNAc. Figure 1 shows targeted delivery of siRNA and ASOs by GalNAc to achieve target mRNA and protein knockdown. It is taught that the attachment of the GalNAc moiety led not only to targeted delivery but also increased drug levels and a significant increase in potency in vivo (page 1759, right column; Fig. 2). It is taught that siRNA are double-stranded RNA with a sense and anti-sense strand (page 1760, left column; Fig. 4). Taught is the use of chemical modifications at the 2’ position of the nucleotides and to replace phosphodiester bonds with phosphorothioate (PS) bonds in order to achieve in vivo activity. These modifications give the conjugates enough nuclease stability to reach the liver after IV or subcutaneous injection (page 1761, left column; Fig. 3). As shown in Fig. 3 is a GalNAc conjugate:
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wherein X and Z are commonly ethylene glycol or alkyl spacers and Y is a multifunctional moiety allowing branching of the cluster. GalNAc-siRNA conjugates are generally made up of patterns of alternating 2’-O-methyl and 2’-fluoro nucleotides with insertion of PS bonds (page 1761, left column). Shown in Figure 3 are other modifications such as locked nucleic acids (LNA), cEt (constrained ethyl), 2’-MOE (methoxyethyl). Shown in Fig. 4 is a triantennary GalNAc conjugate wherein the GalNAc is attached at the 3’ of the sense strand.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Debacker et al. generically teaches the structure of a GalNAc conjugate and suggests that ethylene glycol spacers can be utilized, DeBacker et al. does not expressly teach the compounds claimed. However, this deficiency is cured by Li et al. and Keller et al.
Li et al. is directed to targeting ligands. Targeting ligands include a (targeting moiety-tether)n connected to a branch point group connected to a linker (claim 1). A specific targeting moiety-tether-branch point claimed is
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(page 203). In general, when the tether includes a PEG it has from 1 to 10 ethylene glycol units (page 35, lines 1-6). It is generally taught that the linker is a group of atoms linked to a branch point group on one end and linked to a therapeutic compound. The linker can be linked to a cleavable moiety which is then linked to an oligomeric compound. Cleavable moieties include phosphate groups (page 37, lines 19-32). Tethers include those with only alkyl groups as well as those with ethylene glycol groups (claim 6).
Keller et al. is directed to non-viral delivery vector comprising siRNA. Taught are coupling liposomes to one or more polymers wherein the liposome comprises an siRNA (claim 1). The polymer is PEG (claim 12). Taught is coupling lipids to one or more polymers and one or more agents (claim 15). Agents include a sugar/carbohydrate such as glucose (claims 16-17). Thus, a sugar linked to a polymer which is linked to an siRNA. The non-viral delivery vectors are serum resistant, less susceptible to degradation and dramatically stabilized against aggregation (page 11). Taught is a linker which is X which include PEG (page 36). Examples of X include a group of the following formula
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wherein n and m are independently from 0 to 6, more preferably 2, 3, or 4 and a highly preferred is m is 2 and n is 4. A specific PEG polymer taught is compound 3 (Scheme 1)
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which can be used for coupling. Polyethylene glycol has previously been used to modify the biophysical properties of drug delivery systems. It can be used to confer serum stability to gene delivery vectors (page 41). It was unexpectedly found that polymers such as peg with an siRNA dramatically stabilizes the liposomes against aggregation without impairing the power of the siRNA to downregulate the target gene (page 42).
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 Debacker et al., Li et al. and Keller et al. and utilize the targeting moiety-tether-branch point of Li et al. in combination with the linker of Keller et al. to couple the targeting moiety (i.e. GalNAc) to a siRNA. Debacker et al. generally teaches that siRNA conjugates are of the general formula:
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wherein X and Z are commonly ethylene glycol or alkyl spacers and Y is a multifunctional moiety allowing branching of the cluster. Li et al. teaches triantennary GalNAc with a branching point (which would correspond to the GalNAc3 wherein X is ethylene glycol moieties and Y is branching point of Debacker et al.) which have the following structure:
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. As taught by Keller et al., PEG polymers (ethylene glycol moieties) can be utilized to link a carbohydrate to an siRNA and include
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wherein n and m are independently from 0 to 6, more preferably 2, 3, or 4 and a highly preferred is m is 2 and n is 4.
Therefore, based on the teachings of Debacker et al., it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize any known ethylene glycol containing linkers as well as branching point tether sto conjugate a GalNAc to an siRNA. Since the linkers, branching points and tethers all serve the same purpose, one skilled in the art would have a reasonable expectation of success in substituting one for another absent a demonstration to the criticality.
Regarding claims 26-27, as set forth above, Li et al. teaches a branching point-tether-targeting moiety which is the same as present in claim 26. Regarding the linker, Keller et al. exemplifies 4 ethylene glycol groups, however, Keller et al. teaches that n can independently be 2, 3 or 4 (more preferably). Therefore, Keller et al. teaches an overlapping range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05. Furthermore, Debacker et al. teaches that the linker and tethers can be alkyl or ethylene glycol derived and Keller et al. teaches advantages of utilizing ethylene glycol (PEG) groups. Finally, Debacker et al. shows connection to the siRNA via a phosphate group.
Regarding claim 30, Debacker et al. expressly teaches in Fig. 4 a triantennary GalNAc conjugate wherein the GalNAc is attached at the 3’ of the sense strand.
Regarding claims 33-34 and 36-38, Debacker et al. teaches the use of chemical modifications at the 2’ position of the nucleotides and to replace phosphodiester bonds with phosphorothioate (PS) bonds in order to achieve in vivo activity. These modifications give the conjugates enough nuclease stability to reach the liver after IV or subcutaneous injection (page 1761, left column; Fig. 3). GalNAc-siRNA conjugates are generally made up of patterns of alternating 2’-O-methyl and 2’-fluoro nucleotides with insertion of PS bonds (page 1761, left column). Shown in Figure 3 are other modifications such as locked nucleic acids (LNA), cEt (constrained ethyl), 2’-MOE (methoxyethyl). Therefore, 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 Debacker et al., Li et al. and Keller et al. and utilize any of the specifically taught modifications in order to achieve the desired stability and activity as taught by Debacker et al. It would have been obvious to one of ordinary skill in the art to try any of the specifically taught modifications as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
Regarding claim 44 and 71, Debacker et al. teaches that siRNA are double-stranded RNA with a sense and anti-sense strand (page 1760, left column; Fig. 4).
Regarding claims 56-57, Debacker et al. teaches that the asiaoglycoprotein (ASGPR) receptor is expressed on all mammalian hepatocyte (liver) cell surfaces and is highly specific for N-acetylgalactosamine (GalNAc) (page 2194, first paragraph).
Regarding claim 58, as taught by Keller et al. pharmaceutical compositions will typically comprise any one or more of a pharmaceutically acceptable diluent, carrier or excipients and these are well known in the pharmaceutical art. The choice can be selected based on the intended route of administration and standard pharmaceutical practice (page 52).
Regarding claim 62, Debacker et al. clearly teaches that the conjugate results in gene knockdown (i.e. decrease the target mRNA). 50% knockdown is taught (page 1759).
Regarding claims 69-70 and 72, Debacker et al. shows in Fig. 4 a sense strand of 21 nt and antisense strand of 23 nt. Li et al. teaches an oligonucleotide which targets the F12 gene, this oligonucleotide includes a sense and antisense strand which include an AU pair (Duplex ID Ad02816, page 162). 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 Debacker et al., Li et al. and Keller et al. and utilize the dsRNA of Li et al. in order to inhibit expression of F12. One skilled in the art would have a reasonable expectation of success as Li et al. teaches that this sequence can inhibit F12 expression and includes a GalNAc attached at the 3’ end of the sense strand. The examiner notes that claim 72 just recites “a first base pair”. This is interpreted as being directed to the base pair at either the 3’ or 5’ end of the duplex.
Conclusion
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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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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