DETAILED ACTION
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
Claims 1-5, 7-8, 10, 12-13, 19, 24-32 are pending.
Applicant’s election without traverse of Group I, drawn to delivery platform and its composition, along with the species of Compound 42b for targeting ligand and LP358b for PK/PD modulator in the reply filed on 06/16/2026 is acknowledged.
Claims 4, 5, 12, 13, 19, 24-26, 31, and 32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/16/2026.
Claims 1, 2, 3, 7, 8, 10, 27, 28-30 are examined here.
Priority
Benefit to provisional application 63/077,284, filed on 09/11/2020, via its CON of PCT ‘874, filed on 09/10/2021, is acknowledged.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed provisional application, Application No. 63/077,284, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. ‘284, filed on 09/11/2020 does not disclose the elected PK/PD modulator species LP358b. The PCT ‘874, with the filing date of 09/10/2021, discloses LP358b.
Thus, all claims examined except cl. 27 will enjoy the ‘284 filing date of 09/11/2020, while cl. 27 will enjoy the filing date of 09/10/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/25/2024 and 03/14/2025 were filed before the mailing date of instant action. The submission 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 § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 3, 10, 28-30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wong et al. (US20160348107, pub. 12/01/2016, “Wong”, also shares assignee but is outside the 1yr exception period, in IDS), as evidenced by Lee et al. (2026, J. Clin. Invest., 136, pg. 1-16, doi.org/10.1172/JCI195411) and Hong et al. (2024, Nat. Comm., 15, pg. 1-20, doi.org/10.1038/s41467-024-52002-4, “Hong”) and Williams et al. (2004, J. of Virol., 78, pg. 6967-6973).
Regarding instant cl. 1, 2, 3, 10, Wong discloses RNAi agent (aka RNAi trigger or trigger) to inhibit the expression of Hif2α gene, with unmodified RNAi comprising a sense strand of 19 nt. and an antisense strand of 19 nt. and the sense strand is fully complementary to the antisense strand (par. 6, e.g., sense strand SEQ ID NO: 285 and its complementary antisense strand SEQ ID NO: 478, par. 258). Wong discloses conjugating the RNAi to a delivery conjugate, which comprises a RGD (Arg-Gly-Asp) peptide and a PEG moiety, and were administered to mice (par. 262). The RGD is the targeting ligand linked to the RNAi and is an integrin-binding compound and is also conjugated to a delivery polymer or vehicle (par. 8-9). The RNAi trigger can include PEG groups/units (par. 74). PEG is considered a steric stabilizer, which prevents intramolecular or intermolecular interactions (par. 109), thus is considered a PK/PD (pharmacokinetic/pharmacodynamic) modulator, also as evidenced by instant specification (par. 61, corresponding to instant cl. 1, 10). Table 11 demonstrates RNAi trigger targeting Hif2α with various pegylated-RGD peptide results in inhibition in vivo of Hif2α expression (par. 262, 268, Ex. 16, corresponding to instant cl. 1, 2, 10).
As evidenced by Lee, Hif2α gene is also expressed in skeletal muscle (abstract).
As evidenced by Hong, αvβ6 integrin receptor is expressed on skeletal muscle cell (abstract).
As evidenced by Williams, RGD motif is the first integrin-binding sequence to be identified and is recognized by several integrins, including αvβ6 (pg. 6967, relevant to instant cl. 1, 3). Thus, the targeting ligand of RGD of Wong has an affinity for the αvβ6 integrin receptor, which is expressed on skeletal muscle cell.
Regarding instant cl. 28, the “RNAi agent inhibits expression of the mRNA of a human gene in a skeletal muscle cell” is the intended use of the RNAi targeting Hif2α and the disclosure of claim 1 meets all the structural limitation recited in the independent claim and, absent evidence to the contrary meets recited functional limitation or its intended use of the RNAi agent.
Regarding instant cl. 29, 30, Wong discloses that Hif2α RNAi trigger can be combined with one or more excipients to form pharmaceutical composition (par. 10, 141).
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:
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.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. (US20160348107, pub. 12/01/2016, “Wong”, also shares assignee but is outside the 1yr exception period, in IDS), as evidenced by Lee et al. (2026, J. Clin. Invest., 136, pg. 1-16, doi.org/10.1172/JCI195411) and Hong et al. (2024, Nat. Comm., 15, pg. 1-20, doi.org/10.1038/s41467-024-52002-4, “Hong”) and Williams et al. (2004, J. of Virol., 78, pg. 6967-6973) as applied to claims 1, 2, 3, 10, 28-30 above, and further in view of Li et al. (WO2019089765, pub. 05/09/2019, also shares assignee but is outside the 1yr grace period, in IDS).
Claim 7 recites formula II, enumerated below:
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Regarding instant cl. 7, disclosure of Wong, as evidenced by Williams, Hong, and Lee, is noted above regarding cl. 1, 2, 3, 10, 28-30. Wong discloses a RGD targeting ligand that targets an integrin receptor (par. 8-9).
Wong does not disclose the targeting ligand formula II.
Li discloses an αvβ6 integrin ligand of Formula IV:
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with n is an integer from 1 to 7 with R9 comprises a cargo molecule (par. 55).
In the instant formula II, the X is O, CR8R9, NR8, and R8 can be taken together with Rx or Ry to form a 4, 5, 6, 7, 8, 9 membered ring. Thus, forming a similar pyridyl ring of Li with additional 5 carbons, without the methyl group of Li. The structures are not patentably distinct, thus are an obvious variant of each other.
Li demonstrates that an αvβ6 integrin ligand (structure 1, par. 94, see illustration below) conjugated to a siRNA showed increased relative knockdown in vivo of an epithelial expression gene than a naked RNAi agent without a ligand (par. 533, Table 2). Li discloses a conjugate of siRNA with targeting ligands fused by linkers (e.g., par. 536).
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Li demonstrates in vivo inhibition with various similar ligand structures (e.g., structures 2, 5.1, 5.2, 6, 6.1, 6.2, see Table 4).
One of the KSR rationales that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the αvβ6-integrin targeting ligand of Wong in view of Li and arrive at the claimed invention with a reasonable expectation of success. Based on the success of Wong’s RGD-conjugated Hif2α-RNAi agent and of Li’s various structures of αvβ6 targeting ligand, a skilled artisan would reasonably expect success by substituting Wong’s RGD peptide on its Hif2α-RNAi agent with Li’s αvβ6 targeting ligand structures conjugated to the RNAi agent to inhibit expression of Hif2α in cells expressing Hif2α, including skeletal muscle cells. Thus, cl. 7 would be prima facie obvious.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. (US20160348107, pub. 12/01/2016, “Wong”), as evidenced by Lee et al. (2026, J. Clin. Invest., 136, pg. 1-16, doi.org/10.1172/JCI195411) and Hong et al. (2024, Nat. Comm., 15, pg. 1-20, doi.org/10.1038/s41467-024-52002-4, “Hong”) and Williams et al. (2004, J. of Virol., 78, pg. 6967-6973) and Li et al. (WO2019089765, pub. 05/09/2019) as applied to claims 1, 2, 3, 7, 10, 28-30 above, and further in view of DeMarco et al. (2016, Medicinal Research Review, 36, 389-424) and Bogdanowich-Knipp et al. (1998, J. of Peptide Research, pg. 530-541).
Elected structure of cl. 8 is 42b, illustrated below.
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Disclosure of Wong, as evidenced by Lee, Hong, Williams, and Li is noted above. Wong discloses that RGD ligand comprises guanidinium group linked to glycine-aspartate dipeptide (par. 103) and discloses several guanidinium motifs, schematic provided below (par. 105):
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Li discloses that αvβ6 ligand is stable in serum (par. 4).
Wong and Li do not disclose the structure of 42b targeting ligand.
DeMarco discloses that integrin-receptors bind to RGD peptide and disclose a RGD peptide structure (pg. 391, see below). Below is the comparison of Marco and instant structures.
Marco’s RGD structure
Instant 42b
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The difference is that the instant structure 42b includes a biphenyl-naphthalene ring structure and PEG moieties conjugated to aspartic acid.
It is known that a non-modified linear RGD peptide is sensitive to degradation. Bogdanowich-Knipp et al. (1998, J. of Peptide Research, pg. 530-542) disclose that the aspartic acid residue within the RGD peptide is a “highly susceptible to chemical degradation and leads to the loss of the biological activity” (abstract). Thus Bogdanowich-Knipp compared a linear RGD peptide to a cyclic RGD peptide, by introducing a disulfide bond cyclization within the peptide, and demonstrated that first the aspartic acid is sensitive to degradation in both linear and cyclic RGD peptide and that the cyclic peptide appeared to be 30-fold more stable than the linear peptide (abstract).
One of the KSR’s rationales for supporting conclusion of obviousness is “obvious to try,” requiring the following three findings: (1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem; (2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem; (3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Based on the recognized problem that a linear RGD peptide is sensitive to degradation and based on the finite number of phenyl-naphthalene ring structures adjoined to the RGD-mimic peptides of Li, which are stable in serum, Li and DeMarco provide finite number of structures as a solution to counter the degradation issue associated with aspartic acid.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have tried modifying the Marco’s RGD peptide that binds to integrin receptor in view of Bogdanowich-Knipp and Li to have arrived at the claimed invention with a reasonable expectation of success. Based on the known property of RGD peptide to bind to integrin receptor as disclosed by Marco, and Bogdanowich-Knipp demonstrates that aspartic acid (D) of the RGD peptide is sensitive to degradation, and based on Li’s disclosure of a serum-stable αvβ6 targeting ligand and when conjugated to siRNA results in inhibition of target gene, a skilled artisan would reasonably expect success to try modifying the RGD structure of Marco with the phenyl-naphthalene ring structures with PEG moieties of Li, resulting in a RGD structure modified with phenyl-naphthalene and PEG moeity of Li which are stable and compatible for RNAi-based inhibition.
Thus, cl. 8 would be prima facie obvious.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. (US20160348107, pub. 12/01/2016, “Wong”, also shares assignee but is outside the 1yr exception period, in IDS), as evidenced by Lee et al. (2026, J. Clin. Invest., 136, pg. 1-16, doi.org/10.1172/JCI195411) and Hong et al. (2024, Nat. Comm., 15, pg. 1-20, doi.org/10.1038/s41467-024-52002-4, “Hong”) and Williams et al. (2004, J. of Virol., 78, pg. 6967-6973) as applied to claims 1, 2, 3, 10, 28-30 above, and further in view of Tai (2019, Molecule, 24, pg. 1-25).
Disclosure of cl. 1, 2, 28-30 is noted above. Wong discloses various delivery groups conjugated to RNAi agent, TEG-cholesterol at the 5’ end of the oligomer (par. 157), various amphipathic membrane active polyamines termed “100A, 006, 064, and 126 (Ex. 2, par. 164-185, Ex. 3, par. 186-192) and demonstrates their successful inhibition in vivo (Table 6, 7; par. 259, par. 260-261)
Wong and Li do not disclose the elected LP358b of claim 27.
Tai in its review titled “Current aspects of siRNA bioconjugate for in vitro and in vivo delivery” discloses the following:
To overcome the barriers during delivery, delivery systems generally have to harness the potentials of several different components for a safe and effective delivery of siRNA to target cells. As for a polymer–siRNA bioconjugate system, these essential components may include the ligand for targeting, the endosomolytic component for endosomal escape, siRNA as cargo, PEG chain to elongate blood retention, and potentially a hydrophobic lipid for better interaction with cell membrane. To yield this multiconjugate system, scientists generally subsequently couples all these components step by step into a polymeric backbone that contains many conjugate sites (such as polylysine). The conjugate reaction on the backbone is dynamic and it is hard to precisely control the conjugate position or the conjugate extent, which therefore has been named ‘dynamic polyconjugate’. However, the bioconjugate molecule generally is quick, small in size, and can be purified, chemically defined, and well-characterized, thus showing less heterogeneity than the cationic polymer/siRNA complex. (pg. 12)
Tai discloses various siRNAs with each component individually conjugated to a siRNA: e.g., targeting peptide ligand RGD (Fig. 3, pg. 5), PEGylated and hydrophobic siRNA (see Fig. 5, e.g., anandamide siRNA conjugate with both PEG and unsaturated carbon chain, while docosanoic acid (DCA) siRNA conjugate has a saturated 22 carbon chain, pg. 10). Tai discloses amide linkage between hydrophobic and PEG group (e.g., see anandamide siRNA conjugate Fig. 5; also see Fig. 4B, pg. 10, 9).
Also, use of 5 or 6 membered ring structures linking siRNA to various functional components is known in the art as well: Tai discloses in Fig. 6A a two ring HBFC linkage of siRNA to targeting peptide (pg. 11) and in Fig. 7B a triazole (a 5 membered ring with 3 nitrogens) linking 24 PEGs to targeting peptide to siRNA via a disulfide linkage (pg. 13).
Use of divalent lipid structure joined by an amino group is known in the art; see Tai’s PC-docosanoic acid (PC-DCA) siRNA conjugate to alter bio-distribution to target to muscle, fat and adrenal gland (Fig. 5, pg. 10).
Thus, although Tai does not disclose the elected structure of LP358b, Tai discloses the individual elements of each structure and its purpose, as noted above.
One of the KSR’s rationale for supporting conclusion of obviousness is “obvious to try,” requiring the following three findings: (1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem; (2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem; (3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Here, Tai discloses the problem that “[i]n the preclinical studies, the siRNA delivery strategy has moved away from the complicate lipid or polymer nanoparticles that contain multicomponents for functionalities to the chemically well-defined siRNA bioconjugates that possess a more homogenous, stable, and biocompatible structure” (pg. 1). Tai discloses the various elements that are within the instant LP358b, a terminal hydrophobic chain (here it is a saturated 15 carbon chain), various PEG groups linked by an amide group; a dual ring structure linking the siRNA to the functional group. Tai discloses “[a]s for a polymer–siRNA bioconjugate system, these essential components may include the ligand for targeting, the endosomolytic component for endosomal escape, siRNA as cargo, PEG chain to elongate blood retention, and potentially a hydrophobic lipid for better interaction with cell membrane” (pg. 12).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have tried modifying a backbone structure, i.e. cholesterol or polymer, of the RNAi-trigger targeting Hif2α of Wong in view of Tai to have arrived at the claimed invention with a reasonable expectation of success. Based on the success of RNAi triggers targeting Hif2α of Wong and Tai discloses that a siRNA-bioconjugate comprising PEG, targeting ligand and hydrophobic structure is a more homogenous, stable and biocompatible structure and provides various elements example of each; a skilled artisan would reasonably expect success by trying to modify the RNAi-trigger of Wong with a hydrophobic structure, a PEG structure, and a mono- or bi-valent structure for lipid moiety of Tai to target a desired cell in vivo. Thus, cl. 27 would be prima facie obvious.
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.
U.S. Patent 11,845,937
Claims 1, 2, 3, 27-30 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 5, 8, 11, 15, 18 of U.S. Patent No. 11,845,937, issued 12/19/2023. Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant cl. 1, 2, 3, 28, Claim 1 of ‘937 teaches a RNAi agent for inhibiting DUX4 gene, comprising an antisense and sense strand, SEQ ID NO: 99 and 147, respectively. SEQ ID NO: 99 and 147 lie within the recited range of respective strand, thus read on RNAi agent. Claim 18 of ‘937 teaches a method of inhibiting DUX4 gene expression in one or more of triceps, biceps, etc., thus corresponding to a gene expressed in skeletal muscle cells. Claim 15 teaches a method of DUX4 gene expression is inhibited by at least 40% in the skeletal muscles of the subject. Claim 4 of ‘937 discloses that RNAi agent of cl. 1, is linked to PK/PD modulator. Claims 2, 5 discloses a targeting ligand of Peptide 1 is linked to the 5’ terminal end of the sense strand. Claim 8 teaches αvβ6-peptide 1, which inherently has an affinity for αvβ6 integrin receptor.
Regarding instant cl. 27, claim 8 teaches that LP29b represents:
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.
The below instant LP358 PK/PD modulator identifies differences from LP29b of ‘937.
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The differences are 1) a 3 isopropyl moiety bound to tertiary amine in LP358b, 2) the parentheses locations of 24 PEG repeats (regardless, there are still 24 PEG units and structurally represents the same carbon chain length in between the amide groups), and 3) LP29b uses a one 5-membered ring.
MPEP 2144.09(I) states that “[a] prima facie case of obviousness may be made when chemical compounds have very close structure similarities and similar utilities.” The LP29b and LP358b are both PK/PD modulator that are conjugated to a siRNA to aids in it delivery. The LP29b is also structurally similar to LP358b: LP29b has bivalent strands, with each strand having a terminal seven carbon chain, three repeating PEG units, each of equal lengths (23, 24, and 4) and all are interlinked by amide groups, and the bivalent strands branching off a secondary amine. Thus, LP29b has a close structural similarity to LP358b, thus corresponding to structure of LP358b of instant cl. 27.
Cl. 11 of ‘937 teaches a pharmaceutical composition comprising RNAi agent of cl. 1 and comprising pharmaceutical acceptable excipient, corresponding to instant cl. 29, 30.
Application No. 18/178,242 (‘242): Issued a notice of allowance
Claims 1, 2, 3, 10, 27-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26, 27, 134, 135-136 of copending Application No. 18/178,242 (‘242) in view of Wong et al. (US20160348107, pub. 12/01/2016, “Wong”, also shares assignee but is outside the 1yr exception period, in IDS), as evidenced by Lee et al. (2026, J. Clin. Invest., 136, pg. 1-16, doi.org/10.1172/JCI195411) and Hong et al. (2024, Nat. Comm., 15, pg. 1-20, doi.org/10.1038/s41467-024-52002-4, “Hong”) and Williams et al. (2004, J. of Virol., 78, pg. 6967-6973) for cl. 1, 3.
This is a provisional nonstatutory double patenting rejection; however, the application has been issued a notice of allowance.
Claim 26 teaches a compound having the structure of LP238b:
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The difference between LP238b and instant LP358b is pointed out by the arrow, i.e. the instant LP358b has an isopropyl group bound to the amine group. Although parentheses locations of LP238b are different from instant LP358b in representing the PEG unit, it is still a PEG unit and has the same number of repeating PEG units (23 and 24) as instant LP358b. MPEP 2144.09(I) states that “[a] prima facie case of obviousness may be made when chemical compounds have very close structure similarities and similar utilities.” The LP238b and LP358b are both PK/PD modulator that are conjugated to a siRNA to aids in it delivery. The LP238b is also structurally similar to LP358b: LP29b has bivalent strands, with each strand having a terminal seven carbon chain, three repeating PEG units, each of equal lengths (23, 24, and 4) and all are interlinked by amide groups, the bivalent strands branch off a secondary amine, and two ring structure linker to the siRNA is the same. Thus, LP238b has a close structural similarity to LP358b, and corresponds to structure of LP358b of instant cl. 27. Thus, ‘242 teaches a PK/PD modulator.
Claim 26 teaches that Rz represents an oligonucleotide-based agent. Claim 27 of ‘242 teaches oligonucleotide-based agent is an RNAi agent. Claim 134 of ‘242 teaches oligonucleotide-based agent comprises a linker conjugated to a targeting ligand.
Claim 135 of ‘242 teaches a pharmaceutical composition comprising the compound of cl. 134, with cl. 136 teaching that composition further comprises saline, which is known as an excipient, corresponding to instant cl. 29, 30.
‘242 does not teach RNAi agent with antisense strand complementary to mRNA of a skeletal muscle gene, nor sense strand, nor a targeting ligand with affinity to receptor of a skeletal muscle cell.
Briefly, Wong discloses RNAi agent (aka RNAi trigger or trigger, comprising a 19-nt. sense and antisense strands) to inhibit the expression of Hif2α gene; the RNAi agent conjugated to a RGD targeting-ligand peptide and a PEG moiety and were administered to mice (par. 262). RGD-peptide is an integrin-binding compound. Table 11 demonstrates RNAi trigger targeting Hif2α with various pegylated-RGD peptide results in inhibition in vivo of Hif2α expression (par. 268, Ex. 16).
As evidenced by Lee, Hif2α gene is also expressed in skeletal muscle (abstract), corresponding to instant cl. 1, 2, 28. As evidenced by Hong, αvβ6 integrin receptor is expressed on skeletal muscle cell (abstract). As evidenced by Williams, RGD motif is the first integrin-binding sequence to be identified and is recognized by several integrins, including αvβ6 (pg. 6967, relevant to instant cl. 1, 3). Thus, the targeting ligand of RGD of Wong has an affinity for the αvβ6 integrin receptor, which is expressed on skeletal muscle cell.
Thus, a skilled artisan would reasonably expect success by substituting the RNAi agent and targeting ligand of ‘242 with RNAi agent targeting Hif2α and RGD targeting ligand of Wong. Thus, cl. 1, 2, 10, 27-30 would be prima facie obvious.
Claim 7 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26, 27, 134, 135-136 of copending Application No. 18/178,242 (‘242) and Wong et al. (US20160348107, pub. 12/01/2016, “Wong”, also shares assignee but is outside the 1yr exception period, in IDS), as evidenced by Lee et al. (2026, J. Clin. Invest., 136, pg. 1-16, doi.org/10.1172/JCI195411) and Hong et al. (2024, Nat. Comm., 15, pg. 1-20, doi.org/10.1038/s41467-024-52002-4, “Hong”) and Williams et al. (2004, J. of Virol., 78, pg. 6967-6973) for cl. 1, 3 in view of Li et al. (WO2019089765, pub. 05/09/2019).
This is a provisional nonstatutory double patenting rejection, although a notice of allowance has been issued.
Disclosure of ‘242 and Wong, as evidenced by Lee, Hong, and Williams, is noted above.
‘242 and Wong do not disclose the structure of Formula II of cl. 7.
Li discloses an αvβ6 integrin ligand of Formula IV:
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with n is an integer from 1 to 7 with R9 comprises a cargo molecule (par. 55).
The genus of the instant formula II includes a species where the X is O, CR8R9, NR8, and R8 can be taken together with Rx or Ry to form a 4, 5, 6, 7, 8, or 9 membered ring. Thus, forming a similar pyridyl ring of Li with additional 5 carbons, without the methyl group of Li.
MPEP 2144.09(I) states that “[a] prima facie case of obviousness may be made when chemical compounds have very close structure similarities and similar utilities.” The Formula IV and species of formula II are both a targeting ligand for αvβ6 integrin receptor and in targeting the siRNA to a particular cell. They are structurally very similar, thus there is a prima facie case of obviousness.
Thus, a skilled artisan would reasonably expect success by substituting a targeting ligand of ‘242 with targeting ligand of Li to target αvβ6 integrin receptor. Thus cl. 7 would be prima facie obvious.
Application No. 18/181,340
Claims 1, 2, 3, 7, 8, 28, 29, 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 8, 16, 22, 23, 24, 26, 27, 30, 32, 34, 35 of copending Application No. 18/181,340 (‘340). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1 of ‘340 teaches a compound of Formula I, which corresponds to instant Formula II, corresponding to instant cl. 7. Claims 2, 5, 8, 16, and 22 of ‘340 teach formulas that read on instant Formula II, corresponding to instant cl. 7. Claim 23 teaches a compound number 42b, which is identical to instant elected 42b, corresponding to instant cl. 8. Claims 24 and 26 teach that cargo molecule of Formula I of ‘340 is a RNAi agent bound to a 5’-end of sense strand. Claim 27 teaches formula Ip, which corresponds to instant formula II. Claim 30 teaches various species that read on instant formula I and one species is a compound “42p” (see below for image), which appears to be similar to instant elected 43b compound number. The one difference is that 42p has a terminal N3 bound to the PEG moiety. Based on MPEP2144.09(I), due to structural similarity between 42p and instant 42b with similar ligand function to target the αvβ6 integrin receptor, there is a prima facie case of obviousness between the structures.
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Claim 34 of ‘340 teaches a composition and a pharmaceutical acceptable excipient, corresponding to instant cl. 29, 30.
Claim 35 of ‘340 teaches a RNAi agent targeting a gene located in a skeletal muscle cell, corresponding to instant cl. 1, 28.
Regarding defining RNAi agent, the specification of ‘340 discloses the structural features of RNAi agent (par. 113) and provides sense and antisense strands can be 16 to 49 nt. in length, which overlap with instant structural limitation of sense and antisense strands, corresponding to instant cl. 1.
And PEG is considered a PK/PD modulator and since various targeting ligand species discloses PEG moieties, then inherently has PK/PD modulator conjugated to siRNA, corresponding to instant cl. 1.
Further instant specification discloses the structure of Formula I and species of 42b compound bind to integrin receptor, specifically integrin αvβ6 integrin receptor, corresponding to instant cl. 2, 3.
Application No. 18/178,179
Claims 1, 2, 3, 10, 27-30 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 23, 47, 48, 51, 52 of copending Application No. 18/178,179 (‘179). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1 of ‘179 teaches a delivery vehicle inhibiting expression of a gene expressed in skeletal muscle cells comprising a) an RNAi agent comprising antisense strand of 17-49 nt. with at least 15 nt. complementary to a mRNA of a gene expressed in skeletal muscle cells and a sense strand of 16-49 nt. in length, b) a targeting ligand with affinity for a receptor present on the surface of a skeletal muscle cell, and c) a PK/PD modulator and RNAi agent in linked to the targeting ligand and to the PK/PD modulator via linker, corresponds to instant cl. 1. Linked is interpreted as conjugated.
Claims 2, 3 of ‘179 teach targeting ligand has affinity for an integrin receptor, specifically αvβ6 integrin receptor, respectively, corresponds to instant cl. 2, 3.
Claim 23 of ‘179 teaches PK/PD modulator with at least one PEG unit, corresponds to instant cl. 10.
Claim 47 of ‘179 teaches PK/PD modulator is the elected LP358b, corresponding to instant cl. 27.
Claim 48 of ‘179 teaches RNAi agent inhibits expression of mRNA of a human gene in a skeletal muscle cell, corresponding to instant 28.
Claims 51 and 52 teach a composition and pharmaceutical composition and pharmaceutical excipient, correspond to instant cl. 29, 30, respectively.
Conclusion
No claim allowed.
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/KEYUR A VYAS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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