DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application, Amendments and/or Claims
The amendment and Applicant’s arguments, filed 02 March 2026, have been entered in full. The Sugo Declaration under 37 CFR 1.132, filed 02 March 2026, has been entered in full.
Claims 4-14, 16, 17, 19, 21, 22, 24 and 25 are canceled. Claims 15, 18 and 28 are withdrawn from consideration as being drawn to a non-elected invention. Claims 1-3, 20, 23, 26, 27, 29-34 are amended. Claims 1-3, 20, 23, 26, 27, 29-34 are under examination.
Information Disclosure Statement
The information disclosure statement(s) (IDS) (filed 02 March 2026) was received and complies with the provisions of 37 CFR §§1.97, 1.98 and MPEP § 609. It has been placed in the application file and the information referred to therein has been considered as to the merits.
Withdrawn Objections And/Or Rejections
The objection to the amendment that was filed 18 June 2024 under 35 U.S.C. 132(a) because it introduced new matter into the disclosure, as set forth initially at pages 20-22 of Office Action (10 March 2025) and again at page 4 Office Action (01 October 2025), is withdrawn in view of the amendment (02 March 2026).
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 1-3, 20, 29, 31 and 33 remain rejected under 35 U.S.C. 103 as being unpatentable over Zoffmann Jensen et al. (US 2010/0303802; published Dec 2, 2010) in view of by Masuho et al. (US Patent 4,350,626; published 21 September 1982), Geall et al. (US Patent 10,487,149; published 11/26/19, priority date 4/1/16) and Yazdi et al. (Cancer Research 55:3763-3771; September 1, 1995), as evidenced by Crook et al. (Developmental Immunology, Vol 4:235-246; 1996).
The basis for this rejection is set forth at pages 4-12 of previous Office Action (01 October 2025).
APPLICANT’S ARGUMENTS: Applicant discusses a prima facie case of obviousness under 35 U.S.C. 103. Applicant argues that the cited references do not teach or suggest selecting CD71 as a target antigen for antibody-siRNA conjugates.
Applicant argues that the Office Action acknowledges that Zoffmann Jensen does not disclose an anti-CD71 antibody.
Applicant argues that Geall's construct is an antibody-linker-polynucleotide-linker-polymer architecture (A- X-B-Y-C) in which the polymer component is integral to function. Applicant argues that the polymer in Geall is designed to assist in endosomal escape and overall performance. Applicant argues that the present invention, by contrast, is limited to an antibody-linker-siRNA conjugate that does not include such a polymer. Applicant cites the Sugo Declaration.
Applicant argues that Yazdi employs anti-transferrin receptor antibodies in immunotoxin conjugates and that these constructs deliver protein toxins, not nucleic acids. Applicant maintains that there is nothing in Yazdi that suggests CD71 targeting is suitable for siRNA or other nucleic acid delivery, nor is there any teaching that CD71 targeting addresses the endosomal barrier or yields gene silencing. Applicant cites the Sugo Declaration.
Applicant cites the Sugo Declaration and states that Cuellar et al. (Nucleic Acids Research 43:1189-1203, 2015) examined CD71 in the context of antibody-RNA conjugates and reported that targeting CD71 did not affect biodistribution in a way that would support its use as a preferred delivery target and that the reference provides that CD71 is not a promising antigen for nucleic acid delivery.
Applicant maintains that a reference "teaches away" when it would discourage a person of skill in the art (POSITA) from following the path taken by the Applicant. Applicant cites MPEP § 2145. Applicant states that the combination of Geall, Yazdi, and Cuellar does not provide a motivation to select CD71 for siRNA delivery. Applicant argues to the contrary, Cuellar affirmatively signals that CD71 is not a promising antigen for antibody-RNA conjugates. Applicant argues that cited art therefore does not supply a teaching or suggestion to select CD71 as a target antigen for a polymer-free antibody-siRNA conjugate as claimed.
Applicant argues that the Proposed Combination of References Relies on Hindsight and Lacks a Unified Technical Rationale. Applicant argues that the law of obviousness requires more than the mere possibility that prior art references could be combined. There must be some teaching, suggestion, or motivation that would have led the POSITA to make the specific combination with a reasonable expectation of success. Hindsight reasoning has been consistently rejected by the courts. Applicant cites In re Oetiker, 977 F.2d 1443, 1447 (Fed. Cir. 1992); W.L. Gore & Assocs., Inc. v. Garlock, Inc., 721 F.2d 1540, 1553 (Fed. Cir. 1983).
Applicant maintains that the Office Action's theory of obviousness requires assembling elements from several technically distinct references. Applicant cites the Declaration. Applicant argues that the Office Action’s combination-borrowing an antibody from one context, a polymer-dependent architecture from another, and a general linkage from a third-only appears straightforward when reconstructed with knowledge of Applicant's successful results.
Applicant argues that the Inherency Finding on Long-Term Gene Knockdown Is Unsupported and Reflects Hindsight. Applicant argues that the Office Action asserts that an anti-CD71-linker-siRNA conjugate would "inherently" inhibit target gene expression in a muscle cell of a subject for 14 days (or 28 days) after a single intravenous injection, and thereby treats the long-term knockdown limitations as inherent properties of the prior art combinations. Applicant argues that this inherency finding lacks factual support and is inconsistent with the technical record. Applicant argues that as summarized in the Sugo Declaration, the actual record shows that prior antibody-nucleic acid conjugates repeatedly failed to achieve any knockdown or required high doses, multiple administrations, or additional components to obtain modest effects. Applicant cites the Declaration.
The Sugo Declaration under 37 CFR 1.132: The Declaration states that the cited references do not teach or suggest selecting CD71 as a target antigen for antibody-siRNA Conjugates. The Declaration states that the Office Action notes that Zoffmann Jensen does not teach that the antibody or antigen-binding fragment thereof in the antibody-linker-siRNA conjugate is an anti-CD71 monoclonal antibody, but relies on Geall's disclosure of anti-transferrin receptor antibodies and Yazdi's disclosure of specific anti-TfR monoclonal antibodies (such as SE9 and OKT9) as a basis for substituting the antibody in Zoffmann Jensen. The Declaration states that, technically, this overlooks key differences in construct design and function.
The Declaration maintains that Geall's construct is fundamentally different from what is claimed. Geall uses an antibody-linker-polynucleotide-linker-polymer architecture (A-X-B-Y-C). The Declaration states that the polymer component is not incidental and that it plays an important role in enabling endosomal escape and overall function of the conjugate. The Declaration states that the present invention, by contrast, is limited to an antibody-linker-siRNA conjugate that explicitly excludes additional components such as Geall's polymer. The Declaration maintains that if one simply removes the polymer from Geall's design, the mechanism that Geall relies on changes dramatically. Applicant argues that a person skilled in the art would not assume that a polymer-free construct would behave in the same way or maintain the same ability to escape endosomes.
The Declaration argues that Yazdi's work is in another context and that Yazdi uses anti-transferrin receptor antibodies in immunotoxin conjugates (for example, antibodies conjugated to gelonin). The Declaration states that these are protein toxins, not nucleic acids. The Declaration states that there is no demonstration in Yazdi that CD71 targeting, by itself, is suitable for siRNA or other nucleic acid delivery, nor is there any teaching that CD71 targeting overcomes the endosomal barrier for nucleic acids or results in gene silencing.
The Declaration discusses the Cuellar reference (Nucleic Acids Research, 43, 1189-1203; 2015). The Declaration states that Cuellar examined CD71 in the context of antibody-RNA conjugates and reported that CD71 targeting does not change biodistribution in a way that would support its use as a preferred delivery target. The Declaration argues that this provides that CD71 is not a promising antigen for nucleic acid delivery and maintains that one would have taken Cuellar's conclusions as a warning against using CD71 for siRNA delivery, not as a motivation to design an anti-CD71-siRNA conjugate without a polymer. The Declaration maintains that based on this body of work, there was no clear reason, before the instant invention, to expect that substituting in an anti-CD71 antibody and simultaneously removing the polymer (as in our claims) would produce a functional, endosomally escaping siRNA delivery system.
The Declaration argues that the proposed combination of references relies on hindsight and lacks a unified technical rationale. The Declaration states that the rejection requires assembling elements from four different references: Zoffmann Jensen: a general antibody-siRNA A-X-Y framework, Masuho: general SH-maleimide linking chemistry on antibodies, Geall: anti-TfR antibodies in a construct that relies on a polymer for function, and Yazdi: anti-TfR antibodies used in protein toxin immunoconjugates. The Declaration states that these references come from different technical contexts: generic siRNA-antibody conjugates, general bioconjugation chemistry, polymer-containing nucleic acid constructs, and immunotoxins. The Declaration states that scientists do not simply mix and match isolated features from such distinct systems without a concrete rationale tied to the specific technical problem they are trying to solve-in this case, efficient, polymer-free, endosomal escape of siRNA with sustained knockdown.
The Declaration states that before their work, there was no coherent teaching that: (1) CD71 would be a suitable antigen for siRNA delivery, (2) a polymer was not needed for endosomal escape in this context, and (3) the particular combination of anti-CD71 antibody, maleimide linkage to antibody cysteines, and siRNA would yield durable knockdown in muscle after intravenous administration. The Declaration states that the way the references are combined in the Office Action -taking an antibody from one context, a polymer-dependent architecture from another, and a general linking reaction from a third-is only straightforward when looking backward from the knowledge of our successful results. The Declaration maintains that a person of ordinary skill would not have predicted the claimed configuration from this mixture of references.
The Declaration states that the Office Action further asserts that an anti-CD71-linker-siRNA conjugate would inherently inhibit target gene expression in muscle cells of a subject for 14 or 28 days after a single intravenous injection. The Declaration maintains that this is not consistent with the technical record in this field. The Declaration states that before the instant invention, many antibody-nucleic acid conjugates, including those targeting internalizing receptors, failed to produce any gene knockdown because they remained trapped in endosomes. When activity was seen in other systems, it typically required high doses, multiple administrations, or additional components such as polymers or cationic carriers to assist endosomal escape. The Declaration maintains that in contrast, the instant anti-CD71 conjugate, using the specific linker and structural features described in the application and without a polymer, produced sustained suppression of target gene expression in muscle for 14 or more days after a single intravenous injection. The Declaration states that based on experience and the prior art, it would not have been expected that a generic anti-CD71-siRNA conjugate, constructed without a polymer, to show this magnitude and duration of in vivo silencing.
The Declaration asserts that the prior art does not show that simply combining an anti-CD71 antibody, a maleimide-based linker, and siRNA inherently yields long-term knockdown. The properties we observed arise from the specific combination and design described in the application, and they were not predictable from earlier work.
Applicant’s arguments have been fully considered but are not found persuasive. The Sugo Declaration under 37 CFR 1.132 filed 02 March 2026 is insufficient to overcome the rejection of claims 1-3, 20, 29, 31 and 33 based upon 35 U.S.C. 103 as being unpatentable over Zoffmann Jensen et al. (US 2010/0303802; published Dec 2, 2010) in view of by Masuho et al. (US Patent 4,350,626; published 21 September 1982), Geall et al. (US Patent 10,487,149; published 11/26/19, priority date 4/1/16) and Yazdi et al. (Cancer Research 55:3763-3771; September 1, 1995) as evidenced and Crook et al. (Developmental Immunology, Vol 4:235-246; 1996), as set forth in the last Office Action, for the following reasons.
1. Regarding Applicant and the Declaration’s arguments of Geall’s teaching of an antibody-linker-polynucleotide-linker-polymer (A-X-B-Y-C); that the polymer component is not incidental as it plays an important role in enabling endosomal escape and that a person skilled in the art would not assume that a polymer-free construct would behave in the same way or maintain the same ability to escape endosomes:
Geall teaches in certain embodiments, Formula (I): A-X-B-Y-C. Formula I is wherein A is a binding moiety; B is a polynucleotide; C is a polymer; X is a bond or first linker; and Y is a bond or second linker.
Geall teaches in some embodiments, D is conjugated to the molecule of Formula (I) according to Formula (II): (A-X-B-Y-C.sub.n)-L-D; Formula II wherein A is a binding moiety; B is a polynucleotide; C is a polymer; X is a bond or first linker; Y is a bond or second linker; L is a bond or third linker; D is an endosomolytic moiety.
Contrary to the presented arguments, Geall teaches a construct that does not rely on a polymer with endosomolytic activity.
In addition, Zoffmann-Jensen et al. teach an antibody-siRNA conjugate in the form of A-X-Y, wherein A is an antibody, X is a linker and Y is an siRNA molecule. Zoffmann Jensen et al. teach a pharmaceutical composition comprising the conjugate and a pharmaceutically acceptable carrier. Zoffmann-Jensen et al. clearly teach an antibody-linker-siRNA conjugate that does not include a polymer (wherein the polymer has the function of escaping the endosome). Therefore, the antibody-linker-siRNA construct of Zoffmann Jensen would have the function of endosomal escape.
2. Regarding Applicant and the Declaration’s arguments that Yazdi employs anti-transferrin receptor antibodies in immunotoxin conjugates, that these constructs deliver protein toxins, not nucleic acids, that there is nothing in Yazdi that suggests CD71 targeting is suitable for siRNA or other nucleic acid delivery, nor is there any teaching that CD71 targeting addresses the endosomal barrier or yields gene silencing and that the proposed combination of references relies on hindsight, lacks a unified technical rationale and requires assembling elements from four different references:
One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The Yazdi reference was used because it teaches anti-CD71 monoclonal antibodies 5E9 and OKT9. In addition to the teachings of Zoffmann Jensen, Geall; all of the Zoffmann Jensen, Geall and Masuho references teach antibody-conjugates using linkers with maleimide groups. Masuho teach that antibodies have sulfhydryl (SH) groups and that the SH on the antibody can directly link with the maleimide group.
The Examiner notes that the instant claims fail to recite a specific siRNA sequence. The claimed medicament conjugate, as taught by the combination of cited references, would inherently inhibit target gene expression in muscle cells of a subject for 14 or 28 days after a single intravenous injection. .
3. Regarding Applicant and the Declaration’s arguments about the Cuellar reference (Nucleic Acids Research, 43, 1189-1203; 2015); that the Cuellar reference provides that CD71 is not a promising antigen for nucleic acid delivery and that one would have taken Cuellar's conclusions as a warning against using CD71 for siRNA delivery. That a reference "teaches away" when it would discourage a person of skill in the art (POSITA) from following the path taken by the Applicant (MPEP § 2145(X)(D)(1)); that Cuellar examined CD71 in the context of antibody-RNA conjugates and reported that CD71 targeting does not change biodistribution in a way that would support its use as a preferred delivery target and that the combination of Geall, Yazdi, and Cuellar does not provide a motivation to select CD71 for siRNA delivery:
The Examiner notes that the Cuellar reference was never employed in any of the pending rejections. In addition, the reference was not submitted with the instant arguments and Declaration. The Examiner has located the Cuellar reference, which was submitted with a previous IDS (dated 19 December 2018).
Contrary to the presented arguments, Cueller never examined CD71 in the context of antibody-RNA conjugates and reported that CD71 targeting does not change biodistribution in a way that would support its use as a preferred delivery target.
At page 13, first column, 2nd paragraph, Cuellar's states; “RNAi targeting in vivo has been previously reported using transferrin to deliver nanoparticles carrying siRNA cargo”. “In this case, targeting refers to enhanced cellular uptake and silencing, rather than selective accumulation in the targeted tissue. Indeed, transferrin targeting did not affect biodistribution, as both targeted and non-targeted particles accumulated to a similar extent in the tumor microenvironment (due to the enhanced permeability and retention effect) as well as in the liver and kidneys” (see page 13, first column, 2nd full paragraph).
The Examiner notes that Cuellar is referring to reference number 6, which is Bartlett et al. (Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc. Natl. Acad. Sci. U.S.A., 104, 15549–15554; 2007).
The Examiner has provided the Barlett reference. Barlett et al. teach the use of transferrin NOT an anti-transferrin receptor antibody. The instant invention is drawn to a construct comprising an anti-CD71 antibody (also known as an anti-transferrin receptor antibody). Barlett et al. employ nanoparticle-based technology. Nanoparticle-based technology is NOT recited in the claims.
Therefore, Applicant and the Declaration’s arguments are not commensurate in scope with claimed invention.
Lastly, Barlett et al. state, “Although both nontargeted and transferrin-targeted siRNA nano-particles exhibit similar biodistribution and tumor localization by positron emission tomography (PET), transferrin-targeted siRNA nanoparticles reduced tumor luciferase activity by 50% relative to nontargeted siRNA nanoparticles 1 day after injection.
4. Regarding the Declaration’s arguments that before the instant invention, many antibody-nucleic acid conjugates, including those targeting internalizing receptors, failed to produce any gene knockdown because they remained trapped in endosomes:
The Examiner notes that the instant claims are drawn to a medicament product comprising a monoclonal anti-CD71 antibody, a non-cleavable linker comprising a maleimide group at the end of the linker (or a valine-citrulline linker comprising a maleimide group) and an siRNA molecule.
The instant claims are not drawn to a method comprising intravenously administering a particular amount of the claimed product which inhibits target gene expression in a muscle cell of a subject after 14 days.
The Examiner maintains that the combination of cited prior art references teach the claimed product.
5. Regarding the Declaration’s argument that before their work, there was no coherent teaching that: (1) CD71 would be a suitable antigen for siRNA delivery, (2) a polymer was not needed for endosomal escape in this context, and (3) the particular combination of anti-CD71 antibody, maleimide linkage to antibody cysteines, and siRNA would yield durable knockdown in muscle after intravenous administration:
The Examiner notes that Geall teaches the use of an anti-transferrin receptor antibody (i.e. anti-CD71) in the (A- X-B-Y-C) construct, wherein B is siRNA, X and Y are linkers and C is a polymer. As was stated above, Geall employs polymers that do not have endosomolytic activity. Geall teaches valine-citrulline linker comprising a maleimide group.
6. Regarding Applicant and the Declaration’s arguments about inherency:
The Examiner notes that where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established and the burden of proof rests upon the Applicant to demonstrate that the prior art does not necessarily or inherently possess the characteristics of Applicant's claimed product. In re Fitzgerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977)). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
The Examples of the instant application employ a construct comprising a specific siRNA sequence and a specific linker, which functionally targets/inhibits gene expression in muscle cells of a subject for 14 or 28 days after a single intravenous injection. However, the instant claims do not recite any such limitations. Applicant and the Declaration have not demonstrated that the prior art does not necessarily or inherently possess the characteristics of the product, as currently claimed.
Claim 23 and 26 remain rejected under 35 U.S.C. 103 as being unpatentable over Zoffmann Jensen et al. in view of Masuho et al., Geall et al. and Yazdi et al. as evidenced by Crook et al., as applied to claim 1 above, and further in view of Raouane et al. (Journal of Medical Chemistry. Volume 54:4067-4076; May 11, 2011).
The basis for this rejection is set forth at pages 12-13 of previous Office Action (01 October 2025). Applicant has combined the arguments to address this rejection. The rejection is maintained for reasons discussed above and reasons of record.
Claims 27, 30, 32 and 34 remain rejected under 35 U.S.C. 103 as being unpatentable over Liu (WO 2016/007741. THE REGENTS OF THE UNIVERISTY OF CALIFORNIA published 14 January 2016) in view of Masuho et al. (US Patent 4,350,626; published 21 September 1982), Geall et al. (US Patent 10,487,149; published 11/26/19, priority date 4/1/16) and Yazdi et al. (Cancer Research 55:3763-3771; September 1, 1995) as evidenced by Crook et al. (Developmental Immunology, Vol 4:235-246; 1996).
The basis for this rejection is set forth at pages 13-18 of previous Office Action (01 October 2025).
APPLICANT’S ARGUMENTS: Applicant argues that the Liu reference Does Not Remedy the Deficiencies of Other References in Rejecting Claim 27. Applicant argues that for the reasons set forth above with respect to CD71 selection, polymer dependence, and inherency, a POSITA would not reasonably have expected a polymer-free anti-CD71-siRNA conjugate to perform as claimed. Applicant argues that Liu's disclosure does not change this conclusion. Applicant cites the Declaration.
Applicant argues that the Claimed Invention Addresses a Long-Standing Unmet Need in Antibody-Mediated Nucleic Acid Delivery. Applicant cites the Declaration.
Applicant argues that Prior Work Teaches Away from the Claimed CD71-Targeted Configuration. Applicant argues that key prior art references actively discouraged the specific configuration that the inventors ultimately adopted. This is important under the case law, which holds that teachings that lead away from the claimed invention weigh strongly against a finding of obviousness (In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994)). Applicant cites the Declaration and Cuellar et al.
The Sugo Declaration under 37 CFR 1.132: The Declaration states that for the reasons explained above in connection with the rejections based on Zoffmann Jensen, Geall, and Yazdi, a person of ordinary skill would not have been led to the claimed anti-CD71-siRNA conjugates, nor would they have expected them to provide the observed long-term gene knockdown without a polymer.
The Declaration states that in the Liu reference, valine-citrulline-type linkers such as MC-vcPAB are used to attach antibodies to small-molecule cytotoxins or cytostatic agents and that Liu does not disclose using these linkers to attach siRNA, and does not address the specific problems associated with nucleic acid delivery, such as endosomal escape and cytoplasmic release. The Declaration states that there is no indication in Liu that a linker system developed for small-molecule toxins could simply be repurposed for siRNA while still achieving efficient, long-lasting silencing. The Declaration states that even when combined with Masuho, Geall, and Yazdi, Liu does not provide the missing teaching that a polymer-free anti-CD71-Val-Cit-siRNA conjugate would overcome endosomal entrapment and confer the sustained in vivo knockdown recited in claim 27.
The Declaration states that the claimed invention addresses a long-standing unmet need in antibody-mediated nucleic acid delivery. The Declaration states that there has been a long-standing need for an antibody-mediated nucleic acid delivery system that can reliably overcome endosomal entrapment and achieve potent, durable gene knockdown in vivo and that multiple approaches did not solve this problem.
The Declaration states that early covalent approaches conjugated nucleic acids to lysine residues on antibodies. For example, N. Normand-Sdiqui and S. Akhtar (International Journal of Pharmaceutics, 163: 63-71 (1998)) conjugated oligodeoxynucleotides to lysine residues of anti-CD71 antibodies. The constructs bound CD71 and were internalized, but they showed no knockdown activity. The Declaration states that similar results were reported by Walker et al. (Pharmaceutical Research, 12, 1548-1553 (1995)) and Hudson et al. (International Journal of Pharmaceutics, 182(1), 49-58 (1999)), again with no gene silencing despite cellular uptake.
The Declaration states that subsequent work shifted to electrostatic complexes. Song et al. (Nature Biotechnology, 23(6), 709-717 (2005)) used a fusion protein (F105-P, an anti-HIV-I gp160 Fab fused to protamine) to bind siRNA electrostatically. In vitro, they observed suppression of HIV-1 replication in infected CD4-positive T cells. In vivo, they reported tumor growth inhibition using siRNAs against c-myc, MDM2, and VEGF in B16 melanoma models, but only at a total siRNA dose of about 80 μg (approximately 3.2-4.0 mg/kg) and only when given as three separate injections (days 0, 1, and 3). The activity was obtained, but it required relatively high doses and multiple administrations. The Declaration states that Ma et al. (ACS Chemical Biology, 6(9), 962-970 (2011)) directly compared two anti-Lewis-Y antibody-siRNA formats targeting STAT3: a covalent conjugate (using a HyNic/SS-FB bisarylhydrazone linkage containing a disulfide) and an electrostatic complex (using polyarginine peptides). The electrostatic complexes showed dose-dependent knockdown, whereas the covalent conjugate showed no knockdown at all, despite confirmed cellular uptake. Knockdown could only be rescued by co-treatment with chloroquine, an endosome-destabilizing agent, demonstrating that the covalent conjugates were trapped in endosomes and could not escape into the cytoplasm. The Declaration states that cysteine-based covalent conjugation with "THIOMAB" technology was reported by Cuellar. They generated seven different antibody-RNA conjugates (ARCs) targeting various internalizing receptors by attaching SMCC-maleimide-modified siRNAs to engineered cysteine residues in the antibody heavy chain. The Declaration states that only two ARCs (targeting TENB2 and NaPi2b) showed any silencing, at concentrations of 50-250 nM (TENB2) or 250 nM (NaPi2b), and five ARCs-including those targeting known internalizing antigens-showed no knockdown. In vivo, an anti-TENB2 ARC targeting PPIB required 24 mg/kg administered three times to achieve only about 33% knockdown in tumor tissue. The Declaration discusses the instant Examples.
The Declaration states that the prior work teaches away the claimed CD71-Targeted Configuration. The Declaration states that Cuellar is particularly instructive. The Declaration states that Cuellar prepared seven different ARCs targeting various internalizing receptors using engineered cysteine residues and maleimide chemistry and only the ARCs targeting TENB2 and NaPi2b showed any silencing, and even then only at 50-250 nM (TENB2) or 250 nM (NaPi2b). The Declaration states that ARCs targeting other well-known internalizing antigens, including Her2, showed no silencing despite confirmed internalization and preserved antibody and siRNA activity. The Declaration states that Cuellar concluded that there was no clear predictive relationship between intracellular trafficking pathways and knockdown, and could only state that "components of the endosomal and lysosomal pathways" were important, without identifying which antigens would work. The Declaration maintains that Cuellar specifically discussed CD71 and reported that targeting CD71 does not affect biodistribution (third paragraph, left column, p. 1201). The Declaration argues that this would signal to a person of ordinary skill that CD71 is not a promising target for improving delivery or distribution of an antibody-RNA conjugate.
Applicant’s arguments have been fully considered but are not found persuasive. The Sugo Declaration under 37 CFR 1.132 filed 02 March 2026 is insufficient to overcome the rejection of claims 27, 30, 32 and 34 under 35 U.S.C. 103 as being unpatentable over Liu (WO 2016/007741. THE REGENTS OF THE UNIVERISTY OF CALIFORNIA published 14 January 2016) in view of Masuho et al. (US Patent 4,350,626; published 21 September 1982), Geall et al. (US Patent 10,487,149; published 11/26/19, priority date 4/1/16) and Yazdi et al. (Cancer Research 55:3763-3771; September 1, 1995) as evidenced by Crook et al. (Developmental Immunology, Vol 4:235-246; 1996), as set forth in the last Office Action, for the following reasons.
1. Regarding Applicant and the Declaration’s arguments of the Liu reference: That in the Liu reference, valine-citrulline-type linkers such as MC-vcPAB are used to attach antibodies to small-molecule cytotoxins or cytostatic agents and that Liu does not disclose using these linkers to attach siRNA, and does not address the specific problems associated with nucleic acid delivery, such as endosomal escape and cytoplasmic release.
Liu teaches immunoconjugates comprising an antibody attached to an effector, wherein said effector is selected from the group consisting of a second antibody, a detectable label, a cytotoxin or cytostatic agent, a liposome containing a drug, a radionuclide, a drug, a prodrug, a viral particle, a cytokine, a chelate and an siRNA (abstract and paras 0003, 0091 and 0092). Liu teaches the antibody can be covalently attached to the effector through linkers (paras 0260-0267). Therefore, this antibody-linker-siRNA construct would have the function of endosomal escape.
In addition, Liu teaches valine-citrulline linkers comprising a valine-citrulline peptide moiety and a maleimide group such as the maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (MC-vcPAB) linker.
Liu teaches an embodiment wherein the Mc-vcPAB linker is used to attach the antibody to a cytotoxin or cytostatic agent. However, MPEP 2123 teaches: disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or non-preferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Liu et al. do not teach against using linkers comprising a valine-citrulline peptide moiety and a maleimide group when attaching an antibody to siRNA.
Geall et al. also teach valine-citrulline peptide moiety linkers. Geall et al. teach that linker can be a valine-citrulline linker comprising a valine-citrulline peptide moiety and a maleimide group.
Contrary to the presented arguments, there are teachings of antibodies linked to siRNA via linkers comprising a valine-citrulline peptide moiety and a maleimide group.
2. Regarding Applicant and the Declaration’s arguments that there has been a long-standing need for an antibody-mediated nucleic acid delivery system that can reliably overcome endosomal entrapment and achieve potent, durable gene knockdown in vivo and that multiple approaches did not solve this problem:
The Examiner reminds Applicant that the instant claims are drawn to a medicament product comprising a monoclonal anti-CD71 antibody-a non-cleavable linker comprising a maleimide group at the end of the linker (or a valine-citrulline linker comprising a maleimide group) and an siRNA molecule.
The Examiner maintains that anti-antibody-linker-siRNA constructs were known in the art before the date of the instant application (i.e. June 20, 2016).
Zoffmann-Jensen et al. (US 2010/0303802; published Dec 2, 2010). Geall et al. (US Patent 10,487,149; published 11/26/19, priority date 4/1/16). References submitted by Applicant (Cuellar et al. Nucleic Acids Research 43:1189-1203, published 2015 and Walker et al. Pharmaceutical Research, Vol. 12/No. 10:1548, published 1995). Walker et al. teach a construct comprising an anti-transferrin receptor antibody (i.e. anti-CD71 antibody), a linker and siRNA.
3. Regarding Applicant and the Declaration’s arguments that the prior work teaches away the claimed CD71-targeted configuration:
The Examiner has already discussed this in the arguments above. Cuellar cites Bartlett et al. (Proc. Natl. Acad. Sci. U.S.A., 104, 15549–15554; 2007). As was stated above, Barlett et al. teach the use of transferrin, not an anti-transferrin receptor antibody (i.e. anti-CD71 antibody). Barlett et al. also employ nanoparticle-based technology. The arguments that the prior work teaches away from the claimed medicament conjugate comprising anti-CD71 monoclonal antibody-linker-siRNA are not applicable.
Regarding the actual Cuellar reference; the Examiner notes that none of the employed antibodies was an anti-CD71 antibody.
Cuellar et al. employ antibodies against seven different cell surface receptors. Cuellar et al. teach antibody-linker-siRNA constructs wherein the linker comprises a maleimide group, which links to an SH group on the antibody. Cuellar teaches that covalently attaching using both non-reducible and reducible linkers supported silencing and therefore linker reduction is not needed to liberate the siRNA for silencing.
It is noted that the argument that only two constructs in the Cuellar reference showed silencing, is not found pervasive. The reference evidences a teaching of antibody-linker-siRNA constructs before June 20, 2016.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/R.M.D/Examiner, Art Unit 1647 5/21/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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