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 .
Claims 1-2, 4-11, 13-20 and 22-33 are pending.
Applicant’s election without traverse of a conjugate that read on (A) succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) as the species of maleimide group and (B) a combination of mutations L233A, L234A, and L327R as the combination of mutations in the heavy chain constant region in the reply filed on May 7, 2026 is acknowledged.
Claims 1-2, 4-11, 13-20 and 22-33, drawn to a conjugate that read on (A) succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) as the species of maleimide group and (B) a combination of mutations L233A, L234A, and L327R as the combination of mutations in the heavy chain constant region, are being acted upon in this Office Action.
Priority
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, or 365(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. 120 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 the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications 63/001,211, 17/214,525, 17/818,319 and 18/326,903, fail to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. The previously-filed applications do not disclose “L327R”, as in claims 7, 8, 16 and 17. Therefore for the purposes of applying prior art, the effective filing date of claims 7, 8, 16 and 17 is July 8, 2025, the date that the present application was filed. The invention of claims 1-6, 9-15 and 18-21 was described in applications 63/001,211, 17/214,525, 17/818,319 and 18/326,903. Therefore the effective filing date of claims 1-6, 9-15 and 18-21 is March 27, 2020, the date that application 63/001,211 was filed.
Should applicant disagree with the examiner’s factual determination above, applicant should point to evidence that shows that the invention of claims 1-2, 4-11, 13-20 and 22-33 in fact described in one or more of the previously-filed applications.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on December 30, 2025, November 21, 2025 and July 10, 2025 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Drawings
The drawings filed on July 8, 2025 are acceptable.
Specification
The substitute specification filed on Oct 2, 2025 has been entered.
Applicants should amend the first line of the specification to update the relationship between the instant application and U.S. Application No. 18/326,903, filed May 31, 2023, now U.S. Patent No. 12,427,202, U.S. Application No. 17/818,319, filed August 8, 2022, now U.S. Patent No. 11,707,532, which is a continuation of U.S. Application No. 17/214,525, filed March 26, 2021, now U.S. Patent No. 11,446,387.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7, 8, 16 and 17 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 applicant regards as the invention.
The claims are indefinite because claims 7, 8, 16 and 17 recite “L233A, L234A, and L327R”, but the claims fail to provide any frame of reference that would allow one of skill in the art to unambiguously identify the positions being referred to in the antibody. Amending the claims to recite “wherein the residues correspond to positions of SEQ ID NO: 39” would obviate this rejection, see specification at p. 53, para. [0177] to [0178].
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 7 and 16 are rejected under 35 U.S.C. 102 (a)(1)as being anticipated by US Patent No. 11,707,532 (issued July 25, 2023; PTO 892).
The effective filing date of claims 7, 8, 16 and 17 is July 8, 2025.
Claim 1 recites a conjugate comprising (i) an anti-transferrin receptor antibody or antigen binding fragment thereof, (ii) an siRNA molecule, which comprises a guide strand and a passenger strand, and (iii) a linker; wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises a variable heavy chain (VH) region, which comprises an HCDR1 comprising the sequence of SEQ ID NO: 17; an HCDR2 comprising the sequence of SEQ ID NO: 20; and an HCDR3 comprising the sequence of SEQ ID NO: 19; wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises a variable light chain (VL) region, which comprises a LCDR1 comprising the sequence of SEQ ID NO: 22; a LCDR2 comprising the sequence of SEQ ID NO: 23; and a LCDR3 comprising the sequence of SEQ ID NO: 24; and wherein the passenger strand of the siRNA comprises the sequence of SEQ ID NO: 1 and the guide strand of the siRNA comprises the sequence of SEQ ID NO: 2; and wherein the linker conjugates the anti-transferrin receptor antibody or antigen binding fragment thereof to a terminus of the guide strand or the passenger strand of the siRNA.
5. The conjugate of claim 1, wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is a full-length anti-transferrin receptor antibody.
7. The conjugate of claim 5, wherein the full-length anti-transferrin receptor antibody further comprises a mutation in the heavy chain constant region selected from the group consisting of L233A, L234A, and L327R.
10. A conjugate comprising (i) an anti-transferrin receptor antibody or antigen binding fragment thereof, (ii) an siRNA, which comprises a guide strand and a passenger strand, and (iii) a linker; wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises the variable heavy chain (VH) sequence of SEQ ID NO: 30 and the variable light chain (VL) sequence of SEQ ID NO: 34; wherein the passenger strand of the siRNA comprises the sequence of SEQ ID NO: 1 and the guide strand of the siRNA the sequence of SEQ ID NO: 2; and wherein the linker conjugates the anti-transferrin receptor antibody or antigen binding fragment thereof to a terminus of the guide strand or the passenger strand of the siRNA.
14. The conjugate of claim 10, wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is a full-length anti-transferrin receptor antibody.
16. The conjugate of claim 14, wherein the full-length anti-transferrin receptor antibody further comprises a mutation in the heavy chain constant region selected from the group consisting of L233A, L234A, and L327R.
Regarding claim 7, the ‘532 patent teaches a conjugate comprising anti-TfR1 antibody or antigen binding fragment thereof conjugated to a DMPK siRNA, wherein the siRNA comprising a guide strand and a passenger strand via a linker comprising a maleimide group wherein the anti-TfR1 heavy chain variable region (VH) comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 20 and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 19, see Table 2, sequence alignment below:
ALIGNMENT:
Query Match 87.1%; Score 166.4; Length 116;
Best Local Similarity 41.8%;
Matches 33; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 YTFTNYWMH--------------EINPINGRSNYAEKFQG-------------------- 26
||||||||| |||||||||||||||||
Db 27 YTFTNYWMHWVRQAPGQGLEWMGEINPINGRSNYAEKFQGRVTLTVDTSSSTAYMELSSL 86
Qy 27 ------------GTRAMHY 33
|||||||
Db 87 RSEDTATYYCARGTRAMHY 105
And light chain variable region (VH) comprises an LCDR1 comprising the amino acid sequence of SEQ ID NO: 22, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 23 and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 24, see Table 3, sequence alignment below:
ALIGNMENT:
Query Match 83.1%; Score 121.3; Length 107;
Best Local Similarity 36.5%;
Matches 27; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 RTSENIYNNLA---------------AATNLAD--------------------------- 18
||||||||||| |||||||
Db 24 RTSENIYNNLAWYQQKQGKSPQLLVYAATNLADGVPSRFSGSGSGTQYSLKINSLQSEDF 83
Qy 19 -----QHFWGTPLT 27
|||||||||
Db 84 GNYYCQHFWGTPLT 97
The reference siRNA guide strand comprises the sequence of SEQ ID NO: 2, and a passenger strand comprises the sequence of SEQ ID NO: 1 (see sequences in Table 1, FIG. 2) and a linker comprising a maleimide group that conjugated to the cysteine residue of a full-length IgG anti-transferrin receptor antibody at a 5’ terminus of the passenger strand, see FIG. 1-2, in particular.
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342
510
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210
595
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, see entire document, col. 2, col. 5, lines 33-40, Example 1, Table 1, wherein the Fc region of the full-length IgG1 antibody comprises mutations at L233A and/or L234A, see col. 43, line 4-6.
Regarding claims 10 and 16, the ‘532 patent teaches the anti-transferrin receptor antibody or antigen binding fragment thereof comprises a heavy chain variable sequence of SEQ ID NO: 30, see reference SEQ ID NO: 30, sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 617; Length 116;
Best Local Similarity 100.0%;
Matches 116; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWMHWVRQAPGQGLEWIGEINPINGRSNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWMHWVRQAPGQGLEWIGEINPINGRSNY 60
Qy 61 AEKFQGRVTLTVDTSSSTAYMELSRLRSDDTAVYYCARGTRAMHYWGQGTLVTVSS 116
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AEKFQGRVTLTVDTSSSTAYMELSRLRSDDTAVYYCARGTRAMHYWGQGTLVTVSS 116
and a light chain variable sequence of SEQ ID NO: 34, see reference SEQ ID NO: 34, sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 568; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRTSENIYNNLAWYQQKPGKSPKLLIYAATNLADGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRTSENIYNNLAWYQQKPGKSPKLLIYAATNLADGVPS 60
Qy 61 RFSGSGSGTDYTLTISSLQPEDFATYYCQHFWGTPLTFGGGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDYTLTISSLQPEDFATYYCQHFWGTPLTFGGGTKVEIK 107
Thus, the reference teachings anticipate the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 8 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 11,707,532 (issued July 25, 2023; PTO 892) in view of US Patent No. 10,913,800, claimed earliest priority to 62/784,181 filed December 21, 2018; PTO 892).
The effective filing date of claims 7, 8, 16 and 17 is July 8, 2025.
The teachings of the ‘532 patent have been discussed supra.
The ‘532 patent does not teach the full-length anti-transferrin receptor antibody further comprises L233A, L234A and L327R mutation in the constant region as per claims 8 and 17.
However, the ‘800 patent teaches full-length anti-transferrin receptor antibody wherein the Fc region comprises L233A, L234A and L327R (col. 17, lines 50-59, in particular) to reduce or eliminate Fc effector functions such as Fcγ receptor binding, antibody-dependent cellular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC), see col., 16, lines 33-42, col, 17, lines 63 to col. 18, line 7, in particular. This minimizes unwanted immune activation, e.g., ADCC or CDC that might cause off-target effects and improve safety in patients. The reference anti-transferrin receptor antibody is conjugated to siRNA, see para. [12], FIG. 20.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of the ‘532 patent and the ‘800 patent by modifying the Fc region of ‘532 patent’s anti-transferrin receptor antibody conjugated to the passenger strand of siRNA comprises SEQ ID NO: 1 with the ‘800 patent’s L233A, L234A and L327R to arrive at the claimed invention with a reasonable expectation of success, e.g., to reduce or eliminate Fc effector functions such as Fcγ receptor binding, antibody-dependent cellular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC), see para. [12], FIG. 20.
One of ordinary skill in the art would have been motivated to do so in order to minimize unwanted immune activation, e.g., ADCC or CDC that might cause off-target effects and improve safety in patients because the ‘800 patent teaches that L233A, L234A and L327R substitution eliminates Fc effector functions such as Fcγ receptor binding, antibody-dependent cellular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC).
One of ordinary skill in the art would have been motivated to do so because the ‘532 patent teaches that targeting the guide strand or the passenger strand of the siRNA that hybridizes to a target sequence of DMPK is useful for treating muscle atrophy, e.g., myotonic dystrophy type 1 or DM1 (see Summary of invention, col. 4, lines 32-40) and conjugating the guide strand or the passenger strand of the siRNA to an anti-transferrin receptor (TfR) antibody or antigen binding fragment thereof is expected to bind TfR on cells, internalized, and delivers the siRNA into the intracellular compartment where it can engage RISC and silence DMPK, thereby increase target specificity and/or reduce off-target effects, see col. 8, line 4-15, in particular.
“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-2, 4-11, 13-20 and 22-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,446,387. Although the claims at issue are not identical, they are not patentably distinct from each other because while the ‘387 patent issued from the application which served as the great grandparent for the present case, the examined application was filed as a CON, not a DIV, and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here.
Issued claim 1 recites a small interfering RNA (siRNA) molecule conjugate comprising an anti-transferrin receptor antibody or antigen binding fragment thereof conjugated to a siRNA molecule that hybridizes to a target sequence of DMPK mRNA; wherein the sense strand of the siRNA comprises the sequence selected from the group consisting of SEQ ID NOs: 3, 5, 7, 9, 11, 13, and 15, and the antisense strand of the siRNA comprises the sequence selected from the group consisting of SEQ ID NOs: 4, 6, 8, 10, 12, 14, and 16; and wherein the siRNA molecule conjugate mediates RNA interference against DMPK.
2. The siRNA molecule conjugate of claim 1, wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises a humanized antibody or antigen binding fragment thereof, a chimeric antibody or antigen binding fragment thereof, or a multi-specific antibody or antigen binding fragment thereof.
3. The siRNA molecule conjugate of claim 2, wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises an IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, triple body, mini-antibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, F(ab′)2, F(ab′)2-scFv2, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, diabody-Fc, tandem scFv-Fc, or intrabody.
4. The siRNA molecule conjugate of claim 1, wherein the anti-transferrin receptor antibody or antigen binding fragment thereof specifically binds to human transferrin receptor (TfR).
5. The siRNA molecule conjugate of claim 1, wherein the siRNA molecule conjugate comprises a linker connecting the anti-transferrin receptor antibody or antigen binding fragment thereof to the siRNA molecule.
6. A pharmaceutical composition comprising: a. the siRNA molecule conjugate of claim 1; and b. a pharmaceutically acceptable excipient.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is formulated for parenteral, oral, intranasal, buccal, rectal, intrathecal, or transdermal administration.
8. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is formulated for intravenous administration.
9. The siRNA molecule conjugate of claim 1, wherein siRNA comprises the sense strand comprising SEQ ID NO:3 and the antisense sequence comprising SEQ ID NO: 4.
10. The siRNA molecule conjugate of claim 1, wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is conjugated to the siRNA molecule via a linker.
11. The siRNA molecule conjugate of claim 10, wherein the linker comprises a 4-(N-maleimidomethyl) cyclohexane-1-amidate linker.
12. The siRNA molecule conjugate of claim 10, wherein the linker is conjugated with the sense strand of the siRNA molecule.
13. The siRNA molecule conjugate of claim 12, wherein the linker is conjugated with the 5′ end of the sense strand of the siRNA molecule.
11,446,387
19/263,372
SEQ ID NO: 17
YTFTNYWMH
YTFTNYWMH
SEQ ID NO: 20
EINPINGRSNYAEKFQG
EINPINGRSNYAEKFQG
SEQ ID NO: 19
GTRAMHY
GTRAMHY
SEQ ID NO: 22
RTSENIYNNLA
RTSENIYNNLA
SEQ ID NO: 23
AATNLAD
AATNLAD
SEQ ID NO: 24
QHFWGTPLT
QHFWGTPLT
SEQ ID NO: 1
cccuagaacugucuucgaa
cccuagaacugucuucgaa
SEQ ID NO: 2
uucgaagacaguucuaggguu
uucgaagacaguucuaggguu
SEQ ID NO: 34
SEQ ID NO: 34
SEQ ID NO: 30
SEQ ID NO: 30
SEQ ID NO: 48
SEQ ID NO: 48
SEQ ID NO: 63
SEQ IDNO: 63
The issued patent teaches that the linker comprises SMCC, see col. 56, line 25-27 or Sulfo-MCC, see col. 75, line 2-3. The issued patent teaches that the antibody comprises a mutation in the heavy chain constant region L233A and/or L234A, see col. 44, line 14-24. The issued patent teaches that linker is conjugated to a cysteine residue of the anti-transferrin receptor antibody, see col. 4, lines 20-23. The issued patent teaches that ratio between the polynucleic acid molecule and anti-transferrin receptor antibody or antigen binding fragment there of is about 1:1, 2:1, 3:1 or 4:1, see col. 4, line 25-28, in particular.
A person of skill in the art, reading the claims of the ‘387 patent, would look to the patent and follow the ‘387 patent’s express instruction on how to make the product within a sample, e.g., Examples 1, 3, 4, Table 11 thereby arriving at the conjugate of the examined claims.
Claims 1-2, 4-11, 13-20 and 22-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,707,532. Although the claims at issue are not identical, they are not patentably distinct from each other because while the ‘532 patent issued from the application which served as the grandparent for the present case, the examined application was filed as a CON, not a DIV, and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here.
Issued claim 1 recites a method of treating muscular dystrophy in a subject comprising administering to the subject a therapeutically effective amount of a small interfering RNA (siRNA) conjugate comprising an anti-transferrin receptor antibody or antigen binding fragment thereof conjugated to an siRNA that hybridizes to a target sequence of Dystrophia Myotonica Protein Kinase (DMPK) mRNA, said siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a sequence selected from the group consisting of SEQ ID NOs: 3, 5, 7, 9, 11, 13, and 15, and the antisense strand comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 6, 8, 10, 12, 14, and 16; and wherein the siRNA conjugate mediates RNA interference against DMPK, thereby treating muscular dystrophy in said subject.
2. The method of claim 1, wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises a humanized antibody, a chimeric antibody or an antigen binding fragment thereof.
3. The method of claim 2, wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises an IgG-scFv, nanobody, diabody, DART, TandAb, scDiabody, scDiabody-CH3, triple body, mini-antibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, F(ab′)2, F(ab′)2-scFv2, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, diabody-Fc, tandem scFv-Fc, or intrabody.
4. The method of claim 1, wherein the anti-transferrin receptor antibody or antigen binding fragment thereof specifically binds to human transferrin receptor (TfR).
5. The method of claim 1, wherein the siRNA conjugate comprises a linker connecting the anti-transferrin receptor antibody or antigen binding fragment thereof to the siRNA.
6. The method of claim 1, wherein the siRNA conjugate is administered parenterally, orally, intranasally, buccally, rectally, intrathecally, intravenously or transdermally.
7. The method of claim 6, wherein the siRNA conjugate is administered intravenously.
8. The method of claim 1, wherein the sense strand comprises the sequence of SEQ ID NO: 3 and the antisense strand comprises the sequence of SEQ ID NO: 4.
9. The method of claim 1, wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is conjugated to the siRNA via a linker.
10. The method of claim 9, wherein the linker comprises a 4-(N-maleimidomethyl) cyclohexane-1-amidate linker.
11. The method of claim 9, wherein the linker is conjugated with the sense strand.
12. The method of claim 11, wherein the linker is conjugated with a 5′ end of the sense strand.
13. The method of claim 9, wherein the linker comprises a 6-amino-1-hexanol linker.
14. The method of claim 1, wherein the muscular dystrophy is myotonic dystrophy type 1 (DM1).
A person of skill in the art, reading the claims of the ‘532 patent, would look to the patent and follow the ‘532 patent’s express instruction on how to make the product within a working sample, e.g., Examples 1, 3, 4, Table 11, Fig. 1-2, thereby arriving at the conjugate of the examined claims.
11,727,532
19/263,372
SEQ ID NO: 17
YTFTNYWMH
YTFTNYWMH
SEQ ID NO: 20
EINPINGRSNYAEKFQG
EINPINGRSNYAEKFQG
SEQ ID NO: 19
GTRAMHY
GTRAMHY
SEQ ID NO: 22
RTSENIYNNLA
RTSENIYNNLA
SEQ ID NO: 23
AATNLAD
AATNLAD
SEQ ID NO: 24
QHFWGTPLT
QHFWGTPLT
SEQ ID NO: 1
cccuagaacugucuucgaa
cccuagaacugucuucgaa
SEQ ID NO: 2
uucgaagacaguucuaggguu
uucgaagacaguucuaggguu
SEQ ID NO: 34
SEQ ID NO: 34
SEQ ID NO: 30
SEQ ID NO: 30
SEQ ID NO: 48
SEQ ID NO: 48
SEQ ID NO: 63
SEQ IDNO: 63
The ‘532 patent teaches that the linker comprises SMCC, see col. 56, line 25-27 or Sulfo-MCC, see col. 75, line 2-3. The issued patent teaches that the antibody comprises a mutation in the heavy chain constant region L233A and/or L234A, see col. 44, line 14-24. The issued patent teaches that linker is conjugated to a cysteine residue of the anti-transferrin receptor antibody, see col. 4, lines 24-26. The issued patent teaches that ratio between the polynucleic acid molecule and anti-transferrin receptor antibody or antigen binding fragment thereof is about 1:1, 2:1, 3:1 or 4:1, see col. 4, line 28-32, in particular.
Claims 1-2, 4-11, 13-20 and 22-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12,427,202. Although the claims at issue are not identical, they are not patentably distinct from each other because while the ‘387 patent issued from the application which served as the parent for the present case, the examined application was filed as a CON, not a DIV, and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here.
1. A polynucleic acid molecule that hybridizes to a target sequence of DMPK mRNA comprising: a sense strand comprising the nucleic acid sequence of SEQ ID NO: 1; and an antisense strand comprising the nucleic acid sequence of SEQ ID NO: 2, wherein the antisense strand comprises 2′-F modified nucleotides at positions 2, 6, 14, and 16 from the 5′-end.
2. The polynucleic acid molecule of claim 1, wherein the antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-end.
3. The polynucleic acid molecule of claim 1, wherein the antisense strand comprises two phosphorothioate internucleotide linkages at the 3′-end.
4. The polynucleic acid molecule of claim 1, wherein the sense strand comprises three consecutive 2′-F modified nucleotides.
5. The polynucleic acid molecule of claim 4, wherein the three consecutive 2′-F modified nucleotides are at positions 7, 8, and 9 from the 5′-end.
6. The polynucleic acid molecule of claim 1, wherein the sense strand comprises two phosphorothioate internucleotide linkages at the 5′-end.
7. The polynucleic acid molecule of claim 1, wherein the sense strand comprises two phosphorothioate internucleotide linkages at the 3′-end.
8. The polynucleic acid molecule of claim 1, wherein all nucleotides of the sense strand are 2′-F modified nucleotides or 2′-OMe modified nucleotides.
9. A method for treating muscular dystrophy in a subject in need thereof, comprising: providing a pharmaceutical composition comprising the polynucleic acid molecule of claim 1; and administering the pharmaceutical composition to the subject in need thereof to treat the muscular dystrophy, wherein the polynucleic acid molecule reduces a quantity of the mRNA transcript of human DMPK.
A person of skill in the art, reading the claims of the ‘202 patent, would look to the patent and follow the ‘202 patent’s express instruction on how to make the product within a working sample, e.g., Examples 1, 3, 4, Table 11, Fig. 1-2, thereby arriving at the conjugate of the examined claims.
12,427,202
19/263,372
SEQ ID NO: 17
YTFTNYWMH
YTFTNYWMH
SEQ ID NO: 20
EINPINGRSNYAEKFQG
EINPINGRSNYAEKFQG
SEQ ID NO: 19
GTRAMHY
GTRAMHY
SEQ ID NO: 22
RTSENIYNNLA
RTSENIYNNLA
SEQ ID NO: 23
AATNLAD
AATNLAD
SEQ ID NO: 24
QHFWGTPLT
QHFWGTPLT
SEQ ID NO: 1
cccuagaacugucuucgaa
cccuagaacugucuucgaa
SEQ ID NO: 2
uucgaagacaguucuaggguu
uucgaagacaguucuaggguu
SEQ ID NO: 34
SEQ ID NO: 34
SEQ ID NO: 30
SEQ ID NO: 30
SEQ ID NO: 48
SEQ ID NO: 48
SEQ ID NO: 63
SEQ IDNO: 63
The ‘202 patent further teaches that the linker comprises SMCC, see col. 4, line 24-26, col. 56, line 25-27 or Sulfo-MCC, see col. 75, line 2-3. The issued patent teaches that the antibody comprises a mutation in the heavy chain constant region L233A and/or L234A, see col. 6, lines 18-20, col. 44, lines 20-24. The issued patent teaches that linker is conjugated to a cysteine residue of the anti-transferrin receptor antibody, see col. 4, lines 26-30. The issued patent teaches that ratio between the polynucleic acid molecule and anti-transferrin receptor antibody or antigen binding fragment thereof is about 1:1, 2:1, 3:1 or 4:1, see col. 4, line 33-35, in particular.
Claims 1-2, 4-11, 13-20 and 22-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 19/263,325 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims are drawn to a conjugate comprising (i) an anti-transferrin receptor antibody or antigen binding fragment thereof, (ii) an siRNA molecule, which comprises a guide strand and a passenger strand, and (iii) a linker; wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises a variable heavy chain (VH) region, which comprises an HCDR1 comprising the sequence of SEQ ID NO: 17; an HCDR2 comprising the sequence of SEQ ID NO: 20; and an HCDR3 comprising the sequence of SEQ ID NO: 19; wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises a variable light chain (VL) region, which comprises a LCDR1 comprising the sequence of SEQ ID NO: 22; a LCDR2 comprising the sequence of SEQ ID NO: 23; and a LCDR3 comprising the sequence of SEQ ID NO: 24; and wherein the passenger strand of the siRNA comprises the sequence of SEQ ID NO: 3 and the guide strand of the siRNA comprises the sequence of SEQ ID NO: 4; and wherein the linker comprises a maleimide group that conjugates the anti-transferrin receptor antibody or antigen binding fragment thereof to a terminus of the guide strand or the passenger strand.
Instant claim 1 recites a conjugate comprising (i) an anti-transferrin receptor antibody or antigen binding fragment thereof, (ii) an siRNA molecule, which comprises a guide strand and a passenger strand, and (iii) a linker; wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises a variable heavy chain (VH) region, which comprises an HCDR1 comprising the sequence of SEQ ID NO: 17; an HCDR2 comprising the sequence of SEQ ID NO: 20; and an HCDR3 comprising the sequence of SEQ ID NO: 19; wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises a variable light chain (VL) region, which comprises a LCDR1 comprising the sequence of SEQ ID NO: 22; a LCDR2 comprising the sequence of SEQ ID NO: 23; and a LCDR3 comprising the sequence of SEQ ID NO: 24; and wherein the passenger strand of the siRNA comprises the sequence of SEQ ID NO: 1 and the guide strand of the siRNA comprises the sequence of SEQ ID NO: 2; and wherein the linker conjugates the anti-transferrin receptor antibody or antigen binding fragment thereof to a terminus of the guide strand or the passenger strand of the siRNA.
A person of skill in the art, reading the claims of the reference, would look to the reference and follow the reference’s express instruction on how to make the product within a working sample, e.g., Examples 1, 3, 4, Table 1, Fig. 1-2, thereby arriving at the conjugate of the examined claims.
19/263,325 (reference)
19/263,372
SEQ ID NO: 17
YTFTNYWMH
YTFTNYWMH
SEQ ID NO: 20
EINPINGRSNYAEKFQG
EINPINGRSNYAEKFQG
SEQ ID NO: 19
GTRAMHY
GTRAMHY
SEQ ID NO: 22
RTSENIYNNLA
RTSENIYNNLA
SEQ ID NO: 23
AATNLAD
AATNLAD
SEQ ID NO: 24
QHFWGTPLT
QHFWGTPLT
SEQ ID NO: 1
cccuagaacugucuucgaa
cccuagaacugucuucgaa
SEQ ID NO: 2
uucgaagacaguucuaggguu
uucgaagacaguucuaggguu
SEQ ID NO: 34
SEQ ID NO: 34
SEQ ID NO: 30
SEQ ID NO: 30
SEQ ID NO: 48
SEQ ID NO: 48
SEQ ID NO: 63
SEQ IDNO: 63
2. The conjugate of claim 1, wherein the maleimide group is selected from the group consisting of succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) and sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-SMCC), which corresponds to instant claim 3.
3. The conjugate of claim 1, wherein the linker conjugates the anti-transferrin receptor antibody or antigen binding fragment thereof to a 5′ end terminus of the passenger strand, which corresponds to instant claim 4.
4. The conjugate of claim 1, wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is a full-length anti-transferrin receptor antibody, which corresponds to instant claim 5.
5. The conjugate of claim 4, wherein the full-length anti-transferrin receptor antibody is a humanized anti-transferrin receptor antibody or a human anti-transferrin receptor antibody, which corresponds to instant claim 6.
6. The conjugate of claim 4, wherein the full-length anti-transferrin receptor antibody further comprises a mutation in the heavy chain constant region selected from the group consisting of L233A, L234A, and L327R, which corresponds to instant claim 7.
7. The conjugate of claim 4, wherein the full-length anti-transferrin receptor antibody further comprises a mutation in the heavy chain constant region selected from the group consisting of L233A, L234A, and L327R, which corresponds to instant claims 7-8.
8. The conjugate of claim 1, wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is selected from the group consisting of monovalent Fab′, divalent Fab2, and single chain variable fragment (scFv), which corresponds to instant claim 9.
9. A conjugate comprising (i) an anti-transferrin receptor antibody or antigen binding fragment thereof, (ii) an siRNA, which comprises a guide strand and a passenger strand, and (iii) a linker; wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises the variable heavy chain (VH) sequence of SEQ ID NO: 30 and the variable light chain (VL) sequence of SEQ ID NO: 34; wherein the passenger strand of the siRNA comprises the sequence of SEQ ID NO: 3 and the guide strand of the siRNA comprises the sequence of SEQ ID NO: 4; and wherein the linker comprises a maleimide group that conjugates the anti-transferrin receptor antibody or antigen binding fragment thereof to a terminus of the guide strand or the passenger strand, which corresponds to instant claim 10.
10. The conjugate of claim 9, wherein the maleimide group is selected from the group consisting of succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) and sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-sMCC) , which corresponds to instant claim 12.
11. The conjugate of claim 9, wherein the linker conjugates the anti-transferrin receptor antibody or antigen binding fragment thereof to a 5′ end of the passenger strand, which corresponds to instant claim 13.
12. The conjugate of claim 9, wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is a full-length anti-transferrin receptor antibody, which corresponds to instant claim 14.
13. The conjugate of claim 12, wherein the full-length anti-transferrin receptor antibody is a humanized anti-transferrin receptor antibody or a human anti-transferrin receptor antibody, which corresponds to instant claim 15.
14. The conjugate of claim 12, wherein the full-length anti-transferrin receptor antibody further comprises a mutation in the heavy chain constant region selected from the group consisting of L233A, L234A, and L327R, which corresponds to instant claim 16.
15. The conjugate of claim 12, wherein the full-length anti-transferrin receptor antibody further comprises the L233A, L234A and L327R mutations in the heavy chain constant region, which corresponds to instant claim 17.
16. The conjugate of claim 9, wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is selected from the group consisting of monovalent Fab′, divalent Fab2, and single chain variable fragment (scFv) , which corresponds to instant claim 18.
17. A conjugate comprising (i) an anti-transferrin receptor antibody, (ii) an siRNA molecule, which comprises a guide strand and a passenger strand, and (iii) a linker; wherein the anti-transferrin receptor antibody comprises two heavy chains, each of which comprises SEQ ID NO:48, and two light chains, each of which comprises SEQ ID NO:63; wherein the passenger strand of the siRNA comprises the sequence of SEQ ID NO: 3 and the guide strand of the siRNA comprises the sequence of SEQ ID NO: 4; and wherein the linker comprises a maleimide group that conjugates the anti-transferrin receptor antibody to a 5′ end terminus of the passenger strand of the siRNA, which corresponds to instant claim 19.
18. The conjugate of claim 17, wherein the maleimide group is selected from the group consisting of succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) and sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-sMCC) , which corresponds to instant claim 21.
The copending application also teaches that the linker comprises SMCC, see para [12]. The issued patent teaches that the antibody comprises a mutation in the heavy chain constant region L233A and/or L234A, see para. [0178]. The reference teaches that linker is conjugated to a cysteine residue of the anti-transferrin receptor antibody, see para. [12]. The reference teaches that ratio between the polynucleic acid molecule and anti-transferrin receptor antibody or antigen binding fragment thereof is about 1:1, 2:1, 3:1 or 4:1, see para. [12], in particular.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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