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 .
DETAILED ACTION
Applicant’s amendments and remarks filed on October 15, 2025 are acknowledged. Claims 3, 9, 11-14, 16-18, 20-22, 24-26, 28, 29, 31, 32, 35-38, 41, 42, 44, 45, 47, 49-53, 55, 56, 59-61, 63, and 65 have been canceled. Claims 1, 2, 7, 8, 23, 27, 30, and 33 were amended. Claim 64 was withdrawn. Claims 1, 2, 4-8, 10, 15, 19, 23, 27, 30, 33, 34, 39, 40, 43, 46, 48, 54, 57, 58, 62, 64, and 66 are pending.
Claims 1, 2, 4-8, 10, 15, 19, 23, 27, 30, 33, 34, 39, 40, 43, 46, 48, 54, 57, 58, 62, and 66 are examined on the merits herein.
It is noted that the amendment to the claims filed on October 15, 2025 does not comply with the requirements of 37 CFR 1.121(c) because the amended claims do not reflect changes relative to the immediate prior version of the claims. For example, claim 1 recites part (a)(i) two times. The second instance of “(i)” should be “(ii)” as recited in the claims filed on October 11, 2022. In addition, the first instance of part “(i)” in claim 1 recites “first variable domain”; however, claim 1 part i. filed on October 11, 2022 recites “a first variable domain” (emphasis added). In addition, claim 15 is missing the word “comprises” after “strand”. However, in the interest of compact prosecution, the amendment to the claims has been entered.
Priority
This application claims priority to PCT/US2020/038475 filed on June 18, 2020 which claims priority to U.S. provisional application 62/864,755 filed on June 21, 2019.
Withdrawn Objections
In view of Applicant’s amendments and response, the claim objections and drawing objections are withdrawn.
In view of Applicant’s amendments and response, the objections to the specification are withdrawn. It is noted that the clean substitute specification has markings in reference to the correction made for the objection to paragraph [0017] (“Error! Bookmark not defined.”).
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 112(b) rejections are withdrawn.
Drawings
The drawings were received on October 15, 2025. These drawings are found acceptable by the examiner.
Specification
The substitute specification filed on September 12, 2022 has been entered.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because of the use of legal phraseology ("e.g." stands for "exempli gratia", and should be removed or replaced with a non-Latin version, such as "for example"). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because of the following informalities:
Paragraph [0043]: reads “is synthetic scheme a synthetic scheme”…“of of” and should read “is a synthetic scheme” and there should only be one (1) instance of the word “of”.
Paragraph [0044]: there should only be one (1) instance of the phrase “a synthetic scheme” and one (1) instance of the word “of”.
Appropriate correction is required.
Claim Objections
Claims 1 and 15 are objected to because of the following informalities:
There are two (2) instances of part “(i)” in claim 1.
Claim 1 part (B) recites in part “ora light chain comprising” and should recite “or a light chain comprising”.
Claim 15 recites in part “wherein the sense strand 2 to 5 2’-fluoro modifications”. It appears based on the immediate prior version of the claims that the word “comprises” is missing after “strand”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 1, 2, 4-8, 10, 15, 19, 23, 27, 30, 33, 34, 39, 40, 43, 46, 48, 54, 57, 58, 62, and 66 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 as currently written requires at least 80% identity to the recited sequences for the heavy and light chains of the Ig. Thus, the claim allows for variability in the CDR regions which are critical for antigen binding.
Claim 57 is drawn to a genus of second variable domains of Ig that comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 9, 10, 11, 12, 13, 14, and any combinations thereof. Thus, the claim encompasses a large genus of second variable domains defined solely by function.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification discloses that a conjugate of the invention comprises a dual variable domain immunoglobulin molecule or an antigen-binding fragment thereof, and a double-stranded RNA molecule linked together via a linker. The dual variable domain immunoglobulin molecule comprises a first variable domain that binds to a binding target and a second variable domain that comprises a reactive residue where the linker is covalently conjugated to the reactive residue [0008]. The specification envisions that the amino acid sequences of a first variable domain region, which provides antigen binding functionality, can include chimeric, humanized, or human amino acid sequences. Further, any suitable combination of such sequences can be incorporated into a first variable domain of the DVD immunoglobulin molecule [00222]. The specification also envisions that the DVD immunoglobulin molecule comprises a second variable domain from a 38C2 antibody which includes a reactive lysine residue [00225]. The specification discloses that the DVD immunoglobulin molecule includes a light chain variable domain sequence of a humanized 38C2 antibody (SEQ ID NO: 9 and 15) and a heavy chain variable domain sequence of a humanized 38C2 antibody (SEQ ID NO: 10 and 16) [00234-00235]. The specification discloses in paragraphs [00254] through [00260] that the DVD immunoglobulin comprises SEQ ID NO: 18 and/or 19; SEQ ID NO: 20 and/or SEQ ID NO: 21; SEQ ID NO: 22 and/or SEQ ID NO: 23; SEQ ID NO: 24 and/or SEQ ID NO: 25; SEQ ID NO: 26 and/or SEQ ID NO: 27, light chain and heavy chain, respectively. Paragraph [00261] discloses that the DVD immunoglobulin comprises SEQ ID NO: 28 (a first heavy chain), and/or SEQ ID NO: 29 (a second heavy chain), and/or SEQ ID NO: 30 (a light chain). No description is provided of any other combinations of second variable domain sequences as recited in claim 57.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claim with regard to structure and function, the examples are only representative of a small group of the second variable domains. The results are not necessarily predictive of other second variable domains falling within the broadly claimed genus. Thus, it is impossible for one to extrapolate from the limited examples described herein those second variable domains that would necessarily meet the structural/functional characteristics of the rejected claim.
Mariuzza et al. (Ann. Rev. Biophys. Biophys. Chem. 1987) reviews the structural basis of antigen-antibody recognition and teach that naturally occurring conventional antibodies comprise two polypeptides, the so-called light and heavy chains. Mariuzza et al. also teaches that the complementarity-determining regions (CDRs) of the heavy (H) and light (L) polypeptide chains of immunoglobulins determine, by their hypervariable sequences, the antigen-binding specificity of antibody molecules [page 140, first paragraph]. Therefore, changing the CDR sequence will alter the specificity of the antibody.
Wu et al. (Nature Biotechnology 2007) teaches the design of a DVD-Ig which can be engineered from any two mAbs of distinct specificities [page 1290, right column, first paragraph]. Figure 1a (reproduced below) shows a DVD-Ig protein design with two variable domains linked in tandem in each heavy and light chain.
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One of skill in the art would have recognized the unpredictability of providing a functional DVD-Ig protein without the specification of both the heavy and light chains.
Nanna et al. (Nature Communications 2017) teaches that a DVD is composed of variable domains of trastuzumab, h38C2 with reactive Lys, and constant domains (as shown in Figure 1a and reproduced below). Nanna et al. also teaches that to harness the Lys reactivity of h38C2 for drug attachment and enable tumor targeting, dual-variable-domains (DVDs) were engineered to combine the variable domains of h38C2 and trastuzumab. DVDs are tetravalent IgG-like molecules composed of two heavy and two light chains [page 3, right column, last paragraph bridging to page 4, left column].
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The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a genus of second variable domains that comprise a reactive residue that bind antigen.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1, 2, 4-8, 10, 15, 19, 23, 27, 30, 33, 34, 39, 40, 43, 46, 48, 54, 57, 58, 62, and 66.
Response to Arguments
Applicant's arguments filed October 15, 2025 have been fully considered but they are not persuasive.
Applicant asserts that amending claim 1 to recite specific amino acid sequences for the light and heavy chains for the DVD-Ig overcomes the 35 U.S.C. 112(a) written description rejection. Claim 1 as currently written requires at least 80% identity to the recited sequences for the heavy and light chains of the Ig thus allowing for variability in the CDR regions which are critical for antigen binding. However, Mariuzza et al. taught that changing the CDR sequence will alter the specificity of the antibody. Therefore, the Examiner is maintaining the 35 U.S.C. 112(a) written description rejection.
Claim Rejections - 35 USC § 103
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.
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.
Claims 1, 4-8, 10, 15, 19, 23, 27, 30, 33, 34, 39, 40, 43, 46, 48, 54, 57, 58, 62, and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Rader et al. (WO 2017/049139; reference cited by Applicant) in view of Maier et al. (US 2017/0275626; reference cited by Applicant).
Regarding claims 1, 4-8, 10, 15, 19, 23, 27, 30, 33, 34, 54, and 66, Rader et al. teaches an immunoconjugate having the formula Ig-(L-D)n, where: Ig is a dual variable domain immunoglobulin molecule, or an immunoglobulin-fragment (antigen-binding fragment) thereof, where the dual variable domain immunoglobulin molecule comprises a first variable domain that binds to a binding target, and a second variable domain that comprises a reactive residue; L is a linker that is covalently conjugated to the reactive residue of the second variable domain of Ig; and D is a drug moiety [0010]. Further, Rader et al. teaches that the second variable domain comprises a reactive lysine residue [0011]. Rader et al. teaches that the drug moiety is an expression modifying moiety such as a siRNA of about 20 to about 25 base pairs, or hairpin double strand RNA (hairpin dsRNA) [00177] and [00186]. In addition, Rader et al. teaches that tumor-associated binding targets that can be targeted by the first variable domain of a subject DVD immunoglobulin molecule include HER2, CD 138, and BCMA [00141]. Rader et al. teaches SEQ ID NO: 5 is an amino acid sequence of a light chain variable region of an HER2-h38C2-DVDl immunoglobulin [0015]. SEQ ID NO: 5 (designated as Db below) has a match to instant SEQ ID NO: 26 (designated as Qy below) as shown in the alignment below.
Query Match 84.3%; Score 1593; DB 1; Length 332;
Best Local Similarity 93.4%;
Matches 310; Conservative 6; Mismatches 16; Indels 0; Gaps 0;
Qy 21 DQQLTQSPSSLSASVGDRVTITCRASQSIGSWLSWYQQKPGKAPKLLIYGASNLASGVPS 80
| |:||||||||||||||||||||||| : : ::||||||||||||||| || | |||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPS 60
Qy 81 RFSGSRSGTDYTLTISSLQPEDFATYYCLGASPNGWAFGQGTKVEIKASTKGPELQMTQS 140
||||||||||:||||||||||||||||| |||||||||||||||||||||||
Db 61 RFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKASTKGPELQMTQS 120
Qy 141 PSSLSASVGDRVTITCRSSQSLLHTYGSPYLNWYLQKPGQSPKLLIYKVSNRFSGVPSRF 200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PSSLSASVGDRVTITCRSSQSLLHTYGSPYLNWYLQKPGQSPKLLIYKVSNRFSGVPSRF 180
Qy 201 SGSGSGTDFTLTISSLQPEDFAVYFCSQGTHLPYTFGGGTKVEIKRTVAAPSVFIFPPSD 260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SGSGSGTDFTLTISSLQPEDFAVYFCSQGTHLPYTFGGGTKVEIKRTVAAPSVFIFPPSD 240
Qy 261 EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS 320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS 300
Qy 321 KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 352
||||||||||||||||||||||||||||||||
Db 301 KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 332
Rader et al. teaches SEQ ID NO: 6 is an amino acid sequence of a heavy chain variable region of an HER2-h38C2-DVDl immunoglobulin [0016]. SEQ ID NO: 6 (designated as Db below) has a match to instant SEQ ID NO: 27 (designated as Qy below) as shown in the alignment below.
Query Match 90.7%; Score 2837.5; Length 574;
Best Local Similarity 94.1%;
Matches 540; Conservative 11; Mismatches 18; Indels 5; Gaps 3;
Qy 21 EQQVVESGGGLVQPGGSLRLSCAVSGFSLNSYGVIWVRQAPGKGLEYVS-IIGSSGNTYY 79
| |:||||||||||||||||||| |||:: : |||||||||||:|: | ::| | |
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRY 60
Qy 80 ASSVKGRFTISRDTRLNTVYLQMNSLRAEDTAVYFCARYYGDSGF---DSWGQGTLVTVS 136
| ||||||||| || || |||||||||||||||:|:|: || || | ||||||||||
Db 61 ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGD-GFYAMDYWGQGTLVTVS 119
Qy 137 SASTKGPEVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMSWVRQSPEKGLEWVSEIRL 196
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 120 SASTKGPEVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMSWVRQSPEKGLEWVSEIRL 179
Qy 197 RSDNYATHYAESVKGRFTISRDNSKNTLYLQMNSLRAEDTGIYYCKTYFYSFSYWGQGTL 256
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 180 RSDNYATHYAESVKGRFTISRDNSKNTLYLQMNSLRAEDTGIYYCKTYFYSFSYWGQGTL 239
Qy 257 VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA 316
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 240 VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA 299
Qy 317 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAP 376
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 300 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAP 359
Qy 377 ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 436
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 360 ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 419
Qy 437 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP 496
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 420 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP 479
Qy 497 PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 556
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 480 PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 539
Qy 557 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 590
||||||||||||||||||||||||||||||||||
Db 540 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 573
Regarding claim 39, Rader et al. teaches that the first variable domain of Ig is positioned closer to an N-terminus than a second variable domain [00209].
Regarding claim 40, Rader et al. teaches that the Ig can be a bispecific immunoglobulin molecule [00209].
Regarding claim 43, Rader et al. teaches that the amino acid sequences of a first variable domain region, which provides antigen binding functionality, can include humanized sequences [00142].
Regarding claim 46, Rader et al. teaches that a binding target is a tumor cell surface antigen [00210].
Regarding claim 48, Rader et al. teaches that L is a reversible linker, an irreversible linker, a cleavable linker, a non-cleavable linker, a branched linker, or a linear linker [00212].
Regarding claim 57, Rader et al. teaches SEQ ID NO: 4 which is an amino acid sequence of a heavy chain variable region of a humanized 38C2 (h38C2) antibody [0014]. Rader et al. also teaches that the second variable domain of Ig comprises the amino acid sequence of SEQ ID NO: 4 [00209]. SEQ ID NO: 4 (designated as Db below) has a 100% match to instant SEQ ID NO: 10 (designated as Qy below) as shown in the alignment below.
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Regarding claim 58, Rader et al. teaches that the first and second variable domain are linked along their light chain or heavy chain by a peptide linker sequence [00138].
Regarding claim 62, Rader et al. teaches that immunoconjugates can be formulated into pharmaceutical compositions for therapeutic uses. The compound can be administered to a subject in an appropriate carrier [00205].
However, Rader et al. does not teach that the expression modifying dsRNA molecule is capable of inhibiting the expression of a target gene where the antisense strand has sufficient complementarity to the target sequence to mediate RNA interference. Rader et al. does not explicitly teach that the sense strand is covalently conjugated with the linker. In addition, Rader et al. does not teach the structural limitations of the dsRNA as recited in the dependent claims. Rader et al. also does not teach a ligand.
Maier et al. teaches a double-stranded RNA (dsRNA) agent for inhibiting the expression of a target gene wherein the dsRNA agent comprises a sense strand and an antisense strand, each strand having 14 to 40 nucleotides [0011]. Maier et al. teaches that the dsRNA agent may comprise only a single overhang, which can strengthen the interference activity of the dsRNA, without affecting its overall stability wherein the overhang is located at the 3′-terminal end of the antisense strand (claim 8). Further, the dsRNA may also have a blunt end at the 5’-end of the antisense strand (claim 7). The asymmetric blunt end at the 5′-end of the antisense strand and 3′-end overhang of the antisense strand favor the guide strand loading into RISC process [0268]. Maier et al. teaches that the dsRNA agents further comprise a thermally destabilizing modification at position 7 counting from the 5′-end of the antisense strand [0222] (claim 30). Maier et al. teaches that the sense strand and antisense strand typically form a duplex dsRNA wherein the duplex region may be 12-40 nucleotide pairs in length [0264] (claims 5-6). In addition, each residue of the sense strand and antisense strand is independently modified with 2′-O-methyl or 2′-fluoro [0281] (claims 4, 15, 23, and 34). Maier et al. teaches that the dsRNA agent can comprise a 5’-end vinylphosphonate (5’-VP) at the 5’-end of the antisense strand [0052] (claim 33). Maier et al. teaches that the dsRNA may comprise at least one phosphorothioate internucleotide linkage on the sense strand or antisense strand or both (e.g., the internucleotide linkage modification may occur on every nucleotide on the sense strand and/or antisense strand) [0288] (claims 19 and 27). Maier et al. teaches dsRNA agents conjugated to at least one ligand (e.g., ASGPR ligand) is advantageous for inhibition of target gene expression [0010] and [0110]. Specifically, a ligand provides an enhanced affinity for a selected target, e.g., molecule, cell or cell type, compartment, or receptor [0460].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the dsRNA of Rader et al. with the dsRNA agent of Maier et al. because Rader et al. teaches immunoconjugates for treatment of cancer and other diseases wherein the immunoglobulin molecules are conjugated to one or more drug moieties such as siRNA for modifying expression and Maier et al. teaches a double-stranded RNA (dsRNA) agent for inhibiting the expression of a target gene to treat various disease conditions. One skilled in the art would have made such a substitution in order to achieve the predictable result of inhibiting expression of a target gene capable of disease treatment.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the conjugate of Rader et al. with the ligand of Maier et al. because both Rader et al. and Maier et al. teach dsRNA for delivery to a subject for cancer treatment. One would have combined the elements according to the teachings of Maier et al. in order to achieve the predictable result of adding a ligand for targeting a particular target as taught by Maier et al. One skilled in the art would have been motivated to do so to provide enhanced affinity of the complex for a selected target.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Rader et al. (WO 2017/049139; reference cited by Applicant) in view of Maier et al. (US 2017/0275626; reference cited by Applicant) as applied to claims 1, 4-8, 10, 15, 19, 23, 27, 30, 33, 34, 39, 40, 43, 46, 48, 54, 57, 58, 62, and 66 above, and further in view of Safari et al. (Advanced Pharmaceutical Bulletin 2017).
Regarding claim 2, the teachings of Rader et al. and Maier et al. are discussed above.
However, Rader et al. and Maier et al. do not teach the melting temperature of the dsRNA.
Safari et al. teaches that the propensity of a duplex to form internal hairpins and the relative stability are two significant factors of siRNA efficiency which can be estimated by prediction of melting temperatures (Tm). Sequences with the Tm of 20°C -60°C is recommended because the siRNAs with this range of Tm are better silencer [page 604, left column, second full paragraph].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the melting temperature of the dsRNA agent of Maier et al. as taught by Safari et al. One would have been motivated to do so because Safari et al. taught that siRNAs with melting temperatures within the range of 20°C-60°C are better silencers.
Response to Arguments
Applicant's arguments filed October 15, 2025 have been fully considered but they are not persuasive.
Applicant asserts the following:
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This argument is not found persuasive. Independent claim 1 as currently written recites the combination of light and heavy chains in the alternative. Therefore, the prior art only needs to teach one of the recited combinations of antibody light and heavy chains, not all of the recited combinations. As discussed in the 35 U.S.C. 103 rejection above, Rader et al. teaches SEQ ID NO: 5 (light chain variable region of an HER2-h38C2-DVDl immunoglobulin) which has a match to instant SEQ ID NO: 26 and Rader et al. teaches SEQ ID NO: 6 (heavy chain variable region of an HER2-h38C2-DVDl immunoglobulin) which has a match to instant SEQ ID NO: 27. Therefore, the Examiner is maintaining the 35 U.S.C. 103 rejection for the reasons discussed above.
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.
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Claims 1, 2, 4-8, 10, 15, 19, 23, 27, 30, 33, 34, 39, 40, 43, 46, 48, 54, 57, 58, 62, and 66 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12, 15, and 16 of U.S. Patent No. 11,197,934 in view of Maier et al. (US 2017/0275626; reference cited by Applicant) and Safari et al. (Advanced Pharmaceutical Bulletin 2017).
Claim 12 of the ‘934 patent is drawn to “An immunoconjugate having the formula Ig-(L-D)n, wherein: (a) Ig is a dual variable domain immunoglobulin molecule, or an antigen-binding fragment thereof, wherein the dual variable domain immunoglobulin molecule comprises: (i) a first variable domain that binds to a binding target; and (ii) a second variable domain that comprises the variable domain of a humanized catalytic antibody 38C2 (h38C2); wherein the first variable domain of Ig is positioned closer to an N-terminus than the second variable domain; (b) L is a linker that is covalently conjugated to the reactive lysine residue of h38C2; (c) D is a drug moiety; and (d) n is selected from an integer from 1 to 12,” wherein D is an siRNA. Claim 16 of the ‘934 patent depends from claim 12 and specifies that the Ig comprises the amino acid sequences of SEQ ID NOS: 5 and 6. SEQ ID NO: 5 of the ‘934 patent (designated as Db below) has a match to instant SEQ ID NO: 26 (designated as Qy below) as shown in the alignment below.
Query Match 84.3%; Score 1593; DB 1; Length 332;
Best Local Similarity 93.4%;
Matches 310; Conservative 6; Mismatches 16; Indels 0; Gaps 0;
Qy 21 DQQLTQSPSSLSASVGDRVTITCRASQSIGSWLSWYQQKPGKAPKLLIYGASNLASGVPS 80
| |:||||||||||||||||||||||| : : ::||||||||||||||| || | |||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPS 60
Qy 81 RFSGSRSGTDYTLTISSLQPEDFATYYCLGASPNGWAFGQGTKVEIKASTKGPELQMTQS 140
||||||||||:||||||||||||||||| |||||||||||||||||||||||
Db 61 RFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKASTKGPELQMTQS 120
Qy 141 PSSLSASVGDRVTITCRSSQSLLHTYGSPYLNWYLQKPGQSPKLLIYKVSNRFSGVPSRF 200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PSSLSASVGDRVTITCRSSQSLLHTYGSPYLNWYLQKPGQSPKLLIYKVSNRFSGVPSRF 180
Qy 201 SGSGSGTDFTLTISSLQPEDFAVYFCSQGTHLPYTFGGGTKVEIKRTVAAPSVFIFPPSD 260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SGSGSGTDFTLTISSLQPEDFAVYFCSQGTHLPYTFGGGTKVEIKRTVAAPSVFIFPPSD 240
Qy 261 EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS 320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS 300
Qy 321 KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 352
||||||||||||||||||||||||||||||||
Db 301 KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 332
SEQ ID NO: 6 of the ‘934 patent (designated as Db below) has a match to instant SEQ ID NO: 27 (designated as Qy below) as shown in the alignment below.
Query Match 90.7%; Score 2837.5; Length 574;
Best Local Similarity 94.1%;
Matches 540; Conservative 11; Mismatches 18; Indels 5; Gaps 3;
Qy 21 EQQVVESGGGLVQPGGSLRLSCAVSGFSLNSYGVIWVRQAPGKGLEYVS-IIGSSGNTYY 79
| |:||||||||||||||||||| |||:: : |||||||||||:|: | ::| | |
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRY 60
Qy 80 ASSVKGRFTISRDTRLNTVYLQMNSLRAEDTAVYFCARYYGDSGF---DSWGQGTLVTVS 136
| ||||||||| || || |||||||||||||||:|:|: || || | ||||||||||
Db 61 ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGD-GFYAMDYWGQGTLVTVS 119
Qy 137 SASTKGPEVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMSWVRQSPEKGLEWVSEIRL 196
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 120 SASTKGPEVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMSWVRQSPEKGLEWVSEIRL 179
Qy 197 RSDNYATHYAESVKGRFTISRDNSKNTLYLQMNSLRAEDTGIYYCKTYFYSFSYWGQGTL 256
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 180 RSDNYATHYAESVKGRFTISRDNSKNTLYLQMNSLRAEDTGIYYCKTYFYSFSYWGQGTL 239
Qy 257 VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA 316
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 240 VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA 299
Qy 317 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAP 376
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 300 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAP 359
Qy 377 ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 436
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 360 ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 419
Qy 437 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP 496
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 420 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP 479
Qy 497 PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 556
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 480 PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 539
Qy 557 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 590
||||||||||||||||||||||||||||||||||
Db 540 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 573
Maier et al. teaches a double-stranded RNA (dsRNA) agent for inhibiting the expression of a target gene wherein the dsRNA agent comprises a sense strand and an antisense strand, each strand having 14 to 40 nucleotides [0011]. Maier et al. teaches that the dsRNA agent may comprise only a single overhang, which can strengthen the interference activity of the dsRNA, without affecting its overall stability wherein the overhang is located at the 3′-terminal end of the antisense strand (claim 8). Further, the dsRNA may also have a blunt end at the 5’-end of the antisense strand (claim 7). The asymmetric blunt end at the 5′-end of the antisense strand and 3′-end overhang of the antisense strand favor the guide strand loading into RISC process [0268]. Maier et al. teaches that the dsRNA agents further comprise a thermally destabilizing modification at position 7 counting from the 5′-end of the antisense strand [0222] (claim 30). Maier et al. teaches that the sense strand and antisense strand typically form a duplex dsRNA wherein the duplex region may be 12-40 nucleotide pairs in length [0264] (claims 5-6). In addition, each residue of the sense strand and antisense strand is independently modified with 2′-O-methyl or 2′-fluoro [0281] (claims 4, 15, 23, and 34). Maier et al. teaches that the dsRNA agent can comprise a 5’-end vinylphosphonate (5’-VP) at the 5’-end of the antisense strand [0052] (claim 33). Maier et al. teaches that the dsRNA may comprise at least one phosphorothioate internucleotide linkage on the sense strand or antisense strand or both (e.g., the internucleotide linkage modification may occur on every nucleotide on the sense strand and/or antisense strand) [0288] (claims 19 and 27). Maier et al. teaches dsRNA agents conjugated to at least one ligand (e.g., ASGPR ligand) is advantageous for inhibition of target gene expression [0010] and [0110]. Specifically, a ligand provides an enhanced affinity for a selected target, e.g., molecule, cell or cell type, compartment, or receptor [0460].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the dsRNA of patent ‘934 with the dsRNA agent of Maier et al. because patent ‘934 teaches immunoconjugates for treatment of cancer (e.g., claim 15) and other diseases wherein the immunoglobulin molecules are conjugated to one or more drug moieties such as siRNA for modifying expression and Maier et al. teaches a double-stranded RNA (dsRNA) agent for inhibiting the expression of a target gene to treat various disease conditions. One skilled in the art would have made such a substitution in order to achieve the predictable result of inhibiting expression of a target gene capable of disease treatment.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the conjugate of patent ‘934 with the ligand of Maier et al. because both Rader et al. and Maier et al. teach dsRNA for delivery to a subject for cancer treatment. One would have combined the elements according to the teachings of Maier et al. in order to achieve the predictable result of adding a ligand for targeting a particular target as taught by Maier et al. One skilled in the art would have been motivated to do so to provide enhanced affinity of the complex for a selected target.
Safari et al. teaches that the propensity of a duplex to form internal hairpins and the relative stability are two significant factors of siRNA efficiency which can be estimated by prediction of melting temperatures (Tm). Sequences with the Tm of 20°C -60°C is recommended because the siRNAs with this range of Tm are better silencer [page 604, left column, second full paragraph].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the melting temperature of the dsRNA agent of Maier et al. as taught by Safari et al. One would have been motivated to do so because Safari et al. taught that siRNAs with melting temperatures within the range of 20°C-60°C are better silencers.
Claims 1, 2, 4-8, 10, 15, 19, 23, 27, 30, 33, 34, 39, 40, 43, 46, 48, 54, 57, 58, 62, and 66 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14, 20, and 29 of U.S. Patent No. 12,286,487 in view of Rader et al. (WO 2017/049139; reference cited by Applicant), Maier et al. (US 2017/0275626; reference cited by Applicant), and Safari et al. (Advanced Pharmaceutical Bulletin 2017).
Claim 14 of patent ‘487 is drawn to an antibody drug conjugate comprising at least one drug moiety that is conjugated to an antibody compound via a reactive arginine residue in the antibody compound wherein the antibody compound comprises a variant of catalytic antibody 38C2 or antigen binding fragment thereof that contains a substitution of arginine for the reactive lysine residue in the hydrophobic cleft. Claim 29 of patent ‘487 is drawn to the antibody drug conjugate of claim 14 wherein the drug moiety is a siRNA.
Rader et al. teaches an immunoconjugate having the formula Ig-(L-D)n, where: Ig is a dual variable domain immunoglobulin molecule, or an immunoglobulin-fragment (antigen-binding fragment) thereof, where the dual variable domain immunoglobulin molecule comprises a first variable domain that binds to a binding target, and a second variable domain that comprises a reactive residue; L is a linker that is covalently conjugated to the reactive residue of the second variable domain of Ig; and D is a drug moiety [0010]. Rader et al. teaches that the drug moiety is an expression modifying moiety such as a siRNA of about 20 to about 25 base pairs, or hairpin double strand RNA (hairpin dsRNA) [00177] and [00186]. Rader et al. teaches that the first variable domain of Ig is positioned closer to an N-terminus than a second variable domain [00209]. Rader et al. teaches that the Ig can be a bispecific immunoglobulin molecule [00209]. Rader et al. teaches that the amino acid sequences of a first variable domain region, which provides antigen binding functionality, can include humanized sequences [00142]. Rader et al. teaches that a binding target is a tumor cell surface antigen [00210]. Rader et al. teaches that L is a reversible linker, an irreversible linker, a cleavable linker, a non-cleavable linker, a branched linker, or a linear linker [00212]. Rader et al. teaches SEQ ID NO: 4 which is an amino acid sequence of a heavy chain variable region of a humanized 38C2 (h38C2) antibody [0014]. Rader et al. also teaches that the second variable domain of Ig comprises the amino acid sequence of SEQ ID NO: 4 [00209]. SEQ ID NO: 4 has a 100% match to instant SEQ ID NO: 10. Rader et al. teaches that the first and second variable domain are linked along their light chain or heavy chain by a peptide linker sequence [00138].
Rader et al. teaches SEQ ID NO: 5 (designated as Db below) which has a match to instant SEQ ID NO: 26 (designated as Qy below) as shown in the alignment below.
Query Match 84.3%; Score 1593; DB 1; Length 332;
Best Local Similarity 93.4%;
Matches 310; Conservative 6; Mismatches 16; Indels 0; Gaps 0;
Qy 21 DQQLTQSPSSLSASVGDRVTITCRASQSIGSWLSWYQQKPGKAPKLLIYGASNLASGVPS 80
| |:||||||||||||||||||||||| : : ::||||||||||||||| || | |||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPS 60
Qy 81 RFSGSRSGTDYTLTISSLQPEDFATYYCLGASPNGWAFGQGTKVEIKASTKGPELQMTQS 140
||||||||||:||||||||||||||||| |||||||||||||||||||||||
Db 61 RFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKASTKGPELQMTQS 120
Qy 141 PSSLSASVGDRVTITCRSSQSLLHTYGSPYLNWYLQKPGQSPKLLIYKVSNRFSGVPSRF 200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PSSLSASVGDRVTITCRSSQSLLHTYGSPYLNWYLQKPGQSPKLLIYKVSNRFSGVPSRF 180
Qy 201 SGSGSGTDFTLTISSLQPEDFAVYFCSQGTHLPYTFGGGTKVEIKRTVAAPSVFIFPPSD 260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SGSGSGTDFTLTISSLQPEDFAVYFCSQGTHLPYTFGGGTKVEIKRTVAAPSVFIFPPSD 240
Qy 261 EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS 320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS 300
Qy 321 KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 352
||||||||||||||||||||||||||||||||
Db 301 KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 332
Rader et al. also teaches SEQ ID NO: 6 (designated as Db below) which has a match to instant SEQ ID NO: 27 (designated as Qy below) as shown in the alignment below.
Query Match 90.7%; Score 2837.5; Length 574;
Best Local Similarity 94.1%;
Matches 540; Conservative 11; Mismatches 18; Indels 5; Gaps 3;
Qy 21 EQQVVESGGGLVQPGGSLRLSCAVSGFSLNSYGVIWVRQAPGKGLEYVS-IIGSSGNTYY 79
| |:||||||||||||||||||| |||:: : |||||||||||:|: | ::| | |
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRY 60
Qy 80 ASSVKGRFTISRDTRLNTVYLQMNSLRAEDTAVYFCARYYGDSGF---DSWGQGTLVTVS 136
| ||||||||| || || |||||||||||||||:|:|: || || | ||||||||||
Db 61 ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGD-GFYAMDYWGQGTLVTVS 119
Qy 137 SASTKGPEVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMSWVRQSPEKGLEWVSEIRL 196
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 120 SASTKGPEVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMSWVRQSPEKGLEWVSEIRL 179
Qy 197 RSDNYATHYAESVKGRFTISRDNSKNTLYLQMNSLRAEDTGIYYCKTYFYSFSYWGQGTL 256
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 180 RSDNYATHYAESVKGRFTISRDNSKNTLYLQMNSLRAEDTGIYYCKTYFYSFSYWGQGTL 239
Qy 257 VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA 316
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 240 VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA 299
Qy 317 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAP 376
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 300 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAP 359
Qy 377 ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 436
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 360 ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 419
Qy 437 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP 496
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 420 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP 479
Qy 497 PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 556
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 480 PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 539
Qy 557 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 590
||||||||||||||||||||||||||||||||||
Db 540 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 573
Rader et al. teaches that immunoconjugates can be formulated into pharmaceutical compositions for therapeutic uses. The compound can be administered to a subject in an appropriate carrier [00205].
Maier et al. teaches a double-stranded RNA (dsRNA) agent for inhibiting the expression of a target gene wherein the dsRNA agent comprises a sense strand and an antisense strand, each strand having 14 to 40 nucleotides [0011]. Maier et al. teaches that the dsRNA agent may comprise only a single overhang, which can strengthen the interference activity of the dsRNA, without affecting its overall stability wherein the overhang is located at the 3′-terminal end of the antisense strand (claim 8). Further, the dsRNA may also have a blunt end at the 5’-end of the antisense strand (claim 7). The asymmetric blunt end at the 5′-end of the antisense strand and 3′-end overhang of the antisense strand favor the guide strand loading into RISC process [0268]. Maier et al. teaches that the dsRNA agents further comprise a thermally destabilizing modification at position 7 counting from the 5′-end of the antisense strand [0222] (claim 30). Maier et al. teaches that the sense strand and antisense strand typically form a duplex dsRNA wherein the duplex region may be 12-40 nucleotide pairs in length [0264] (claims 5-6). In addition, each residue of the sense strand and antisense strand is independently modified with 2′-O-methyl or 2′-fluoro [0281] (claims 4, 15, 23, and 34). Maier et al. teaches that the dsRNA agent can comprise a 5’-end vinylphosphonate (5’-VP) at the 5’-end of the antisense strand [0052] (claim 33). Maier et al. teaches that the dsRNA may comprise at least one phosphorothioate internucleotide linkage on the sense strand or antisense strand or both (e.g., the internucleotide linkage modification may occur on every nucleotide on the sense strand and/or antisense strand) [0288] (claims 19 and 27). Maier et al. teaches dsRNA agents conjugated to at least one ligand (e.g., ASGPR ligand) is advantageous for inhibition of target gene expression [0010] and [0110]. Specifically, a ligand provides an enhanced affinity for a selected target, e.g., molecule, cell or cell type, compartment, or receptor [0460].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the antibody of patent ‘487 with the dual variable domain antibody of Rader et al. because Rader et al. teaches that dual variable domains comprise a first variable domain that binds to a target antigen and a second variable domain that includes uniquely reactive residues that provide a site for covalent attachment of a linker molecule [00130]. One would have combined the elements according to the teachings of Rader et al. in order to achieve the predictable result of binding to a target antigen as taught by Rader et al.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the dsRNA of patent ‘487 with the dsRNA agent of Maier et al. because patent ‘487 teaches immunoconjugates for treatment of cancer (e.g., claim 20) and other diseases wherein the immunoglobulin molecules are conjugated to one or more drug moieties such as siRNA for modifying expression and Maier et al. teaches a double-stranded RNA (dsRNA) agent for inhibiting the expression of a target gene to treat various disease conditions. One skilled in the art would have made such a substitution in order to achieve the predictable result of inhibiting expression of a target gene capable of disease treatment.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the conjugate of patent ‘487 with the ligand of Maier et al. because both Rader et al. and Maier et al. teach dsRNA for delivery to a subject for cancer treatment. One would have combined the elements according to the teachings of Maier et al. in order to achieve the predictable result of adding a ligand for targeting a particular target as taught by Maier et al. One skilled in the art would have been motivated to do so to provide enhanced affinity of the complex for a selected target.
Safari et al. teaches that the propensity of a duplex to form internal hairpins and the relative stability are two significant factors of siRNA efficiency which can be estimated by prediction of melting temperatures (Tm). Sequences with the Tm of 20°C -60°C is recommended because the siRNAs with this range of Tm are better silencer [page 604, left column, second full paragraph].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the melting temperature of the dsRNA agent of Maier et al. as taught by Safari et al. One would have been motivated to do so because Safari et al. taught that siRNAs with melting temperatures within the range of 20°C-60°C are better silencers.
Response to Arguments
Applicant's arguments filed October 15, 2025 have been fully considered but they are not persuasive.
Applicant asserts the following:
PNG
media_image5.png
222
810
media_image5.png
Greyscale
This argument is not found persuasive. ‘934 patent teaches SEQ ID NO: 5 and 6 which has a match to instant SEQ ID NO: 26 and 27, respectively as shown in the alignment above. SEQ ID NO: 5 is a light chain variable region of an HER2-h38C2-DVDl immunoglobulin and SEQ ID NO: 6 is a heavy chain variable region of an HER2-h38C2-DVDl immunoglobulin.
Applicant also asserts the following:
PNG
media_image6.png
256
800
media_image6.png
Greyscale
This argument is not found persuasive. Rader et al. (WO 2017/049139) teaches SEQ ID NO: 5 and 6 which has a match to instant SEQ ID NO: 26 and 27, respectively as shown in the alignment above. SEQ ID NO: 5 is a light chain variable region of an HER2-h38C2-DVDl immunoglobulin and SEQ ID NO: 6 is a heavy chain variable region of an HER2-h38C2-DVDl immunoglobulin.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637