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 .
1. Claims 2, 4-28, 31-35, 37-58, 60-63, 65-72, 74-89, 91-104, 106-119, 121-167, and 169-238 have been cancelled. Claims 1, 29, 30, and 64 have been amended.
Claims 1, 3, 29, 30, 36, 59, 64, 73, 90, 105, 120, 168, and 239-244 are pending and under examination.
2. All rejections/objections pertaining to claim 2 are moot because the claim was cancelled with the reply filed on 04/13/2026.
The objection to claims 1 and 3 is withdrawn in response to applicant’s arguments.
The nonstatutory double patenting rejection over the claims of copending Application No. 17/770,504 is moot because Application No. 17/770,504 gas been cancelled.
The rejection of claim 29 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph us withdrawn in response to applicant’s arguments and the amendment to claim 1 to specify that the distribution of DMAEMA, PAA, and BMA monomers within the block is random.
Specification
3. The claim listing is objected to because claim 30 is improperly identified as “currently amended”. Since the claim has not been amended, the correct status identifier is “previously presented”.
Claim Objections
4. Claim 30 is objected to because of the recitations: (1) “each RA is independently selected from”; and (2) “C1-10 alkyl C2-10 alkenyl”.
Correction to (1) “RA is independently selected from”; and (2) “C1-10 alkyl, C2-10 alkenyl” is required.
The objection is maintained because the claim has not been amended as stated by the applicant.
Double Patenting
5. 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.
6. Claims 1, 3, 29, 30, 36, 59, 64, 73, 90, 105, 120, 168, and 239-244 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 9 of U.S. Patent No. 11,427,823, in view of Prieve et al. (WO 16/118697). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets encompass the same nucleic acid conjugates comprising N-acetyl galactosamine (NAG) as a targeting ligand. The nucleic acid conjugate recited in the patent claim 1 is
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; the nucleic acid is an siRNA, which anticipates the genus of nucleic acids recited in the instant claims. This compound also anticipates the genus of compounds set forth by formulas X, I, and XXX recited in the instant claims 1-3, 30, 36, and 64; and also anticipates the genus of compounds encompassed by the formula recited in the instant claim 168.
The patent claims do not recite a membrane destabilizing polymer, nor do they recite a method. Prieve et al. teach that, since the delivery of siRNA conjugates is inefficient, large doses are needed for eliciting the desired biological effect (see [4]). Prieve et al. teach using a membrane destabilizing polymer to enhance the delivery of siRNAs to the cell cytoplasm; the membrane destabilizing polymer comprises NAG as a ligand for targeted delivery to the liver. Prieve et al. teach using compositions comprising siRNAs and the membrane destabilizing polymer for delivering therapeutic siRNA to subjects. The membrane destabilizing polymer is a block copolymer having the structure:
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, where
NAG is:
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PEG12 is a linker of 12 ethylene glycol units, which could have the structure
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PEGMA is polyethyleneglycol methacrylate with 2-20 ethylene glycol units;
HMA is hexyl methacrylate (i.e., C6 alkyl-methacrylate);
D is DMAEMA (dimethylaminoethyl methacrylate);
P is PAA (propyl acrylic acid);
B is BMA (butyl methacrylate; i.e., a C4 alkyl-methacrylate);
m and n are each a mole fraction greater than 0, wherein m is greater than n and m + n = 1; q is a mole fraction of 0.2 to 0.75; r is a mole fraction of 0.05 to 0.6; s is a mole fraction of 0.2 to 0.75; q + r + s = 1; v is 1 to 25; w is 1 to 25 (see Abstract; [7]; [12]-[13]; [15]; [24]; [26]-[27]; [30]; [37]; [49]; [80]; [109]; [0168]; [0172], formula Vi on p. 59; [191]; [194]-[195]; [203]; [213]; [220]; [245]-[246]). Thus, the membrane destabilizing polymer of Prieve et al. is identical to the one recited in in the instant claims 1-3, 29, and 239-244).
Based on the teachings of Prieve et al., one of skill in the art would have reasonably concluded that the membrane destabilizing polymer would enhance the efficiency of the siRNA conjugate recited in the patent claims. One of skill in the art would have found obvious to modify the patent claims by adding the membrane destabilizing polymer of Prieve et al. with the reasonable expectation that doing so would enhance the activity of the siRNA conjugate. One of skill in the art would have also found obvious to deliver the resulting composition to a subject, when siRNA therapy was needed.
With respect to the instant claim 29, the second block of the copolymer of Prieve et al. is [DMAEMA-PAA BMA] and not
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(i.e., [DMAEMA-BMA-PAA]. However, the essential elements (i.e., DMAEMA, BMA, and PAA) are taught by the prior art. Moreover, Prieve et al. teach that DMAEMA, BMA, and PAA could be a randomly arranged within the block (see [17]-[18]; [67]). One of skill in the art would readily recognized that each of DMAEMA, BMA, and PAA performs its function regardless of the arrangement and would have found obvious to use routine experimentation and vary the arrangement, yielding no more than what have been expected from such an arrangement. A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties.” In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
Thus, the patent claims and the instant claims are obvious variants.
7. Claims 1, 3, 29, 30, 36, 59, 64, 73, 90, 105, 120, 168, and 239-244 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, and 5 of U.S. Patent No. 12,033,843, in view of Prieve et al. Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets encompass the same nucleic acid conjugates comprising N-acetyl galactosamine (NAG) as a targeting ligand and the same method for delivering the conjugate to a subject. The compound recited in the patent claim 1 compound anticipates the genus of compounds set forth by formulas X, I, and XXX recited in the instant claims 1-3, 30, 36, and 64; and anticipates the genus of compounds encompassed by the formula recited in the instant claim 168. The patent specification discloses that the compound could be in the stereoisomeric form recited in the instant claim 168 (see columns 71-72, last compound).
The patent claims do not recite a membrane destabilizing polymer, nor do they recite a method. Prieve et al. teach that, since the delivery of siRNA conjugates is inefficient, large doses are needed for eliciting the desired biological effect (see [4]). Prieve et al. teach using a membrane destabilizing polymer to enhance the delivery of siRNAs to the cell cytoplasm; the membrane destabilizing polymer comprises NAG as a ligand for targeted delivery to the liver. Prieve et al. teach using compositions comprising siRNAs and the membrane destabilizing polymer for delivering therapeutic siRNA to subjects. The membrane destabilizing polymer is a block copolymer having the structure:
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, where
NAG is:
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72
96
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PEG12 is a linker of 12 ethylene glycol units, which could have the structure
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83
384
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PEGMA is polyethyleneglycol methacrylate with 2-20 ethylene glycol units;
HMA is hexyl methacrylate (i.e., C6 alkyl-methacrylate);
D is DMAEMA (dimethylaminoethyl methacrylate);
P is PAA (propyl acrylic acid);
B is BMA (butyl methacrylate; i.e., a C4 alkyl-methacrylate);
m and n are each a mole fraction greater than 0, wherein m is greater than n and m + n = 1; q is a mole fraction of 0.2 to 0.75; r is a mole fraction of 0.05 to 0.6; s is a mole fraction of 0.2 to 0.75; q + r + s = 1; v is 1 to 25; w is 1 to 25 (see Abstract; [7]; [12]-[13]; [15]; [24]; [26]-[27]; [30]; [37]; [49]; [80]; [109]; [0168]; [0172], formula Vi on p. 59; [191]; [194]-[195]; [203]; [213]; [220]; [245]-[246]). Thus, the membrane destabilizing polymer of Prieve et al. is identical to the one recited in in the instant claims 1-3, 29, and 239-244).
Based on the teachings of Prieve et al., one of skill in the art would have reasonably concluded that the membrane destabilizing polymer would enhance the efficiency of the siRNA conjugate recited in the patent claims. One of skill in the art would have found obvious to modify the patent claims by adding the membrane destabilizing polymer of Prieve et al. with the reasonable expectation that doing so would enhance the activity of the siRNA conjugate. One of skill in the art would have also found obvious to deliver the resulting composition to a subject, when siRNA therapy was needed.
With respect to the instant claim 29, the second block of the copolymer of Prieve et al. is [DMAEMA-PAA BMA] and not
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(i.e., [DMAEMA-BMA-PAA]. However, the essential elements (i.e., DMAEMA, BMA, and PAA) are taught by the prior art. Moreover, Prieve et al. teach that DMAEMA, BMA, and PAA could be a randomly arranged within the block (see [17]-[18]; [67]). One of skill in the art would readily recognized that each of DMAEMA, BMA, and PAA performs its function regardless of the arrangement and would have found obvious to use routine experimentation and vary the arrangement, yielding no more than what have been expected from such an arrangement. A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties.” In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
Thus, the patent claims and the instant claims are obvious variants.
8. Claims 1, 3, 29, 30, 36, 59, 64, 73, 90, 105, 120, 168, and 239-244 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24-36 of copending Application No. 17/782,901 (reference application), in view of Prieve et al. Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets encompass the same siRNA-ligand conjugate and the same method for delivering the conjugate to a subject. The specific species of siRNA recited in the application claim 1 anticipate the genus of nucleic acids recited in the instant claim 1.
The application claims do not recite a membrane destabilizing polymer. Prieve et al. teach that, since the delivery of siRNA conjugates is inefficient, large doses are needed for eliciting the desired biological effect (see [4]). Prieve et al. teach using a membrane destabilizing polymer to enhance the delivery of siRNAs to the cell cytoplasm; the membrane destabilizing polymer comprises NAG as a ligand for targeted delivery to the liver. Prieve et al. teach using compositions comprising siRNAs and the membrane destabilizing polymer for delivering therapeutic siRNA to subjects. The membrane destabilizing polymer is a block copolymer having the structure:
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, where
NAG is:
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72
96
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PEG12 is a linker of 12 ethylene glycol units, which could have the structure
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83
384
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PEGMA is polyethyleneglycol methacrylate with 2-20 ethylene glycol units;
HMA is hexyl methacrylate (i.e., C6 alkyl-methacrylate);
D is DMAEMA (dimethylaminoethyl methacrylate);
P is PAA (propyl acrylic acid);
B is BMA (butyl methacrylate; i.e., a C4 alkyl-methacrylate);
m and n are each a mole fraction greater than 0, wherein m is greater than n and m + n = 1; q is a mole fraction of 0.2 to 0.75; r is a mole fraction of 0.05 to 0.6; s is a mole fraction of 0.2 to 0.75; q + r + s = 1; v is 1 to 25; w is 1 to 25 (see Abstract; [7]; [12]-[13]; [15]; [24]; [26]-[27]; [30]; [37]; [49]; [80]; [109]; [0168]; [0172], formula Vi on p. 59; [191]; [194]-[195]; [203]; [213]; [220]; [245]-[246]). Thus, the membrane destabilizing polymer of Prieve et al. is identical to the one recited in in the instant claims 1-3, 29, and 239-244).
Based on the teachings of Prieve et al., one of skill in the art would have reasonably concluded that the membrane destabilizing polymer would enhance the efficiency of the siRNA conjugate recited in the patent claims. One of skill in the art would have found obvious to modify the application claims by adding the membrane destabilizing polymer of Prieve et al. with the reasonable expectation that doing so would enhance the activity of the siRNA conjugate. One of skill in the art would have also found obvious to deliver the resulting composition to a subject, when siRNA therapy was needed.
With respect to the instant claim 29, the second block of the copolymer of Prieve et al. is [DMAEMA-PAA BMA] and not
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(i.e., [DMAEMA-BMA-PAA]. However, the essential elements (i.e., DMAEMA, BMA, and PAA) are taught by the prior art. Moreover, Prieve et al. teach that DMAEMA, BMA, and PAA could be a randomly arranged within the block (see [17]-[18]; [67]). One of skill in the art would readily recognized that each of DMAEMA, BMA, and PAA performs its function regardless of the arrangement and would have found obvious to use routine experimentation and vary the arrangement, yielding no more than what have been expected from such an arrangement. A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties.” In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
Thus, the application claims and the instant claims are obvious variants.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
9. Claims 1, 3, 29, 30, 36, 59, 64, 73, 90, 105, 120, 168, and 239-244 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 197- 211 of copending Application No. 18/734,444 (reference application), in view of Prieve et al. Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets encompass the same siRNA-ligand conjugate and the same method for delivering the conjugate to a subject. The species of siRNA recited in the application claim 197 anticipates the genus of nucleic acids recited in the instant claim 1.
The application claims do not recite a membrane destabilizing polymer. The patent claims do not recite a membrane destabilizing polymer, nor do they recite a method. Prieve et al. teach that, since the delivery of siRNA conjugates is inefficient, large doses are needed for eliciting the desired biological effect (see [4]). Prieve et al. teach using a membrane destabilizing polymer to enhance the delivery of siRNAs to the cell cytoplasm; the membrane destabilizing polymer comprises NAG as a ligand for targeted delivery to the liver. Prieve et al. teach using compositions comprising siRNAs and the membrane destabilizing polymer for delivering therapeutic siRNA to subjects. The membrane destabilizing polymer is a block copolymer having the structure:
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, where
NAG is:
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72
96
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PEG12 is a linker of 12 ethylene glycol units, which could have the structure
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83
384
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PEGMA is polyethyleneglycol methacrylate with 2-20 ethylene glycol units;
HMA is hexyl methacrylate; i.e., C6 alkyl-methacrylate;
D is DMAEMA (dimethylaminoethyl methacrylate);
P is PAA (propyl acrylic acid);
B is BMA (butyl methacrylate; i.e., a C4 alkyl-methacrylate);
m and n are each a mole fraction greater than 0, wherein m is greater than n and m + n = 1; q is a mole fraction of 0.2 to 0.75; r is a mole fraction of 0.05 to 0.6; s is a mole fraction of 0.2 to 0.75; q + r + s = 1; v is 1 to 25; w is 1 to 25 (see Abstract; [7]; [12]-[13]; [15]; [24]; [26]-[27]; [30]; [37]; [49]; [80]; [109]; [0168]; [0172], formula Vi on p. 59; [191]; [194]-[195]; [203]; [213]; [220]; [245]-[246]). Thus, the membrane destabilizing polymer of Prieve et al. is identical to the one recited in in the instant claims 1-3, 29, and 239-244).
Based on the teachings of Prieve et al., one of skill in the art would have reasonably concluded that the membrane destabilizing polymer would enhance the efficiency of the siRNA conjugate recited in the patent claims. One of skill in the art would have found obvious to modify the patent claims by adding the membrane destabilizing polymer of Prieve et al. with the reasonable expectation that doing so would enhance the activity of the siRNA conjugate. One of skill in the art would have also found obvious to deliver the resulting composition to a subject, when siRNA therapy was needed.
With respect to the instant claim 29, the second block of the copolymer of Prieve et al. is [DMAEMA-PAA BMA] and not
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(i.e., [DMAEMA-BMA-PAA]. However, the essential elements (i.e., DMAEMA, BMA, and PAA) are taught by the prior art. Moreover, Prieve et al. teach that DMAEMA, BMA, and PAA could be a randomly arranged within the block (see [17]-[18]; [67]). One of skill in the art would readily recognized that each of DMAEMA, BMA, and PAA performs its function regardless of the arrangement and would have found obvious to use routine experimentation and vary the arrangement, yielding no more than what have been expected from such an arrangement. A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties.” In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
Thus, the application claims and the instant claims are obvious variants.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 103
10. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The 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.
11. Claims 1, 3, 29, 30, 36, 59, 64, 73, 90, 105, 120, 168, and 239-244 are rejected under 35 U.S.C. 103 as being unpatentable over Heyes et al. (WO 17/177326; published on 10/19/2017), in view of Prieve et al. (WO 16/118697).
Heyes et al. teach a method to deliver an oligonucleotide or siRNA to the liver in a subject; the method comprises delivering to the subject a conjugate set forth by formula I:
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, where R1 is a targeting ligand; L1 and L2 are each absent or a linking group; R2 is a nucleic acid; Ring A is absent, a 3-20 membered cycloalkyl, a 5-20 membered aryl, a 5-20 membered heteroaryl, or a 3-20 membered heterocycloalkyl; RA is independently selected from the group consisting of hydrogen, hydroxy, CN, F, Cl, Br, I, -C1-2-alkyl-ORB, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl; wherein the C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl are optionally substituted with one or more groups independently selected from halo, hydroxy, and C1-3 alkoxy; RB is hydrogen, a protecting group, a covalent bond to a solid support, or a bond to a linking group that is bound to a solid support; and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as encompassed by claims 1 and 3 and as recited in claim 30 (see Abstract; p. 1, line 23 through p. 2, line 13; p. 7, lines 8-11; p. 33, lines 4-6; claims 1, 2, 32, and 47).
In formula (I), R1 is:
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, where
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and where T3-T6 are
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(n = 1, 2, or 3), and B1-B3 are
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(claims 64, 73, 90, 105, and 120) (see p. 48, line 18 through p. 49,
line 14).
The conjugate of formula (I) could be compound 231 where the saccharide targeting ligand is N-acetyl galactosamine (NAG):
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i.e., same as elected compound 520 except that, in the linkers, n=3 (not 2) as in compound 520 (see p. 58). However, as per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, there is no evidence of record indicating that linkers where n=2 provides any unexpected properties as compared to linkers where n=3. Furthermore, Heyes et al. teach that linkers where n=2 could be used to obtain structurally similar conjugates (see conjugate 218 on p. 57). One of skill in the art would have found obvious to modify conjugate 231 by using linkers having n=2 with the reasonable expectation that doing so would result in a compound suitable to deliver oligonucleotides to the subject (claims 59, 64, and 168).
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties.” In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
In addition to the above, Heyes et al. teach delivering nucleic acid conjugates set by formula (XX):
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where R1 is targeting ligand; L1 is absent or a linking group; L2 is absent or a linking group; R2 is a nucleic acid; B is
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where the valence marked with * is attached to L1 or is attached to R1 if L1 is absent; and the valence marked with ** is attached to L2 or is attached to R2 if L2 is absent (claim 36) (see p. 47-48).
Heyes et al. do not teach co-delivering the membrane destabilizing polymer set forth by formula XX (claims 1 and 3). Prieve et al. teach using a membrane destabilizing polymer to enhance the delivery of LNPs encapsulating oligonucleotides (such as siRNAs) to the cell cytoplasm; the LNPs and the membrane destabilizing polymer both comprise a ligand targeting the cell of interest; the ligand is N-acetyl galactosamine (NAG) for targeted delivery to the liver. Prieve et al. teach using compositions comprising siRNAs and the membrane destabilizing polymer for delivering therapeutic siRNA to subjects. The membrane destabilizing polymer is a block copolymer having the structure:
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, where
NAG is:
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PEG12 is a linker of 12 ethylene glycol units, which could have the structure
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83
384
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PEGMA is polyethyleneglycol methacrylate with 2-20 ethylene glycol units;
HMA is hexyl methacrylate (i.e., C6 alkyl-methacrylate);
D is DMAEMA (dimethylaminoethyl methacrylate);
P is PAA (propyl acrylic acid);
B is BMA (butyl methacrylate; i.e., a C4 alkyl-methacrylate);
m and n are each a mole fraction greater than 0, wherein m is greater than n and m + n = 1; q is a mole fraction of 0.2 to 0.75; r is a mole fraction of 0.05 to 0.6; s is a mole fraction of 0.2 to 0.75; q + r + s = 1; v is 1 to 25; w is 1 to 25 (see Abstract; [7]; [12]-[13]; [15]; [24]; [26]-[27]; [30]; [37]; [49]; [80]; [109]; [0168]; [0172], formula Vi on p. 59; [191]; [194]-[195]; [203]; [213]; [220]; [245]-[246]). Thus, the membrane destabilizing polymer of Prieve et al. is identical to the one recited in claims 1, 3, and 239-244.
Although Prieve et al. do not specifically teach using the membrane destabilizing polymer in conjunction with siRNA conjugates, Prieve et al. do teach that the delivery of siRNA conjugates is inefficient and that large doses are needed for eliciting the desired biological effect (see [4]).
Based on the teachings in Prieve et al., one of skill in the art would have reasonably concluded that the membrane destabilizing polymer would also enhance the efficiency of the siRNA conjugates, including the conjugate taught by Heyes et al. One of skill in the art would have found obvious to modify the method of Heyes et al. by administering the conjugate together with the membrane destabilizing polymer of Prieve et al., with the reasonable expectation that doing so would enhance the activity of the siRNA.
With respect to claim 29, Prieve et al. teach [DMAEMA-PAA BMA] as the second block and not:
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(i.e., [DMAEMA-BMA-PAA]. However, there is no evidence on the record that the claimed arrangement results in an unexpected property. The arrangement is not significant if it does not provide a novel feature. The essential elements (i.e., DMAEMA, BMA, and PAA) are taught by Prieve et al. Moreover, Prieve et al. teach that DMAEMA, BMA, and PAA could be randomly arranged within the second block (see [17]-[18]; [67]). One of skill in the art would readily recognized that each of DMAEMA, BMA, and PAA performs its function regardless of the arrangement and would have found obvious to use routine experimentation and vary the arrangement, yielding no more than what would have been expected from such an arrangement. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties.” In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
12. Double patenting
The applicant is right in pointing out that the 12,043,843 patent is drawn to a subject matter which has no relationship to the claimed invention. However, this was a typographical error, the examiner meant the 12,043,833 patent; the correct patent number is provided in the rejection. The examiner regrets any inconvenience that this may have caused the applicant.
The applicant argues that Prieve teaches a composition comprising LNPs encapsulating the therapeutic agent and the membrane-destabilizing polymer. The applicant argues that, since Prieve teaches LNP as a critical element.
This is not found persuasive. Prieve teaches that it is the membrane-destabilizing polymer which is critical for the enhanced delivery to cytosol. In the paragraph indicated by the applicant ([109]), Prieve discloses that the membrane-destabilizing polymer functions to enhance the delivery of the therapeutic agent into the cytosol by improving endosomal escape of the LNP from the endosome. The combination of LNP and membrane-destabilizing polymer demonstrates enhanced delivery activity (100-fold improvement) as compared to the use of LNPs alone (see also [262] on p. 97). Thus, Prieve provides evidence that the membrane-destabilizing polymer itself is the enhancing agent.
One of skill in the art would have reasonably concluded that the membrane-destabilizing polymer would similarly enhance transfection for delivery compositions other than LNPs, including the ones recited in the patent/application claims.
The applicant argues that Prieve is silent with respect to a combining the membrane-destabilizing polymer and unencapsulated therapeutic agent.
However, Prieve does not have to teach every claim limitation. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In this case, the combination of the cited references suggests modifying Heyes to arrive at the claimed invention.
The argument of surprising results, as supported by Holland, is not found persuasive. Heyes teaches that the bivalent conjugates 179 and the tetravalent conjugates 206 administered at 1 mg/kg mediate efficient silencing for 28 days in mice (see p. 108; p.117; Example 25; Fig. 8). Based on Prieve, one of skill in the art would have reasonably expected that adding the membrane-destabilizing polymer would enhance silencing by two orders of magnitude.
It is also noted that the silencing levels in Heyes are similar to those observed for the bivalent and tetravalent conjugates (1 mg/kg) in Holland (compare Fig. 8 in Heyes with Fig. 2A in Holland). It follows that adding the membrane-destabilizing polymer to Prieve’s compounds would result in silencing levels similar to those shown in Holland’s Fig. 2A.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
35 U.S.C. 103
The arguments are the same as for the double patenting rejections. They are not found persuasive for the reasons set forth above.
Conclusion
13. THIS ACTION IS MADE FINAL. 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 ILEANA POPA whose telephone number is (571)272-5546. The examiner can normally be reached 8:00 am to 4:30 pm.
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/ILEANA POPA/Primary Examiner, Art Unit 1633
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