DETAILED ACTION
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 the Application
Receipt is acknowledged of Applicants’ Amendment and Remarks, filed on 06/18/2026 in which claims 1-2, 11, 27, 29, and 33 are amended, claims 3-10, 12-24, 26, 28, 30-32, and 34 are canceled, and claims 35-40 are newly added. Claims 1-2, 11, 25, 27, 29, 33 and 35-40 are pending and are examined on the merits herein.
Priority
The instant application is a 371 of PCT/US2020/055053, filed on 10/09/2020, which claims domestic benefit of 62/913,679, filed on 10/10/2019.
Information Disclosure Statement
The two information disclosure statements (IDS) both dated 05/18/2026 comply with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Objections and Rejections Withdrawn
Applicant’s amendment and remarks, filed 06/18/2026, with respect that the specification is objected to because of illegible chemical structures and incomplete sequence disclosures has been fully considered and is persuasive, as a substitute specification containing new structures and completed sequence disclosure has been submitted. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 06/18/2026, with respect that claims 14 and 18 are objected to due to illegible figures has been fully considered and is persuasive, as claims 14 and 18 are canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 06/18/2026, with respect that claims 14-18, and 20-21 are rejected under 35 U.S.C. 112(b) as using the same variable with multiple definitions has been fully considered and is persuasive, as claims 14-18 and 20-21 are canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 06/18/2026, with respect that claims 12-24, 28, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Zamora-Atenza in view of Bertozzi, Rensen, Pickens, and BroadPharm has been fully considered and is persuasive, as claims 12-24, 28, and 34 are canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 06/18/2026, with respect that claims 12-24, and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, 19, 25, 28-29, 31-36, and 38-43 of copending Application No. 17/654,984 has been fully considered and is persuasive, as claims 12-24 and 28 are canceled. This rejection has been withdrawn.
The following are modified grounds of rejection necessitated by Applicant’s amendment in which the scope of formula (I) has been narrowed and claims 12-24, 28, and 34 are canceled.
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.
Claims 1-2, 11, 25, 27, 29, 33, 37, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Zamora-Atenza et. al (Arthritis Research and Therapy, 2014; PTO-892 12/19/2025) in view of Bertozzi et al. (ChemRxiv, 2019; PTO-892 12/19/2025), Rensen et. al (Journal of Biological Chemistry, 2001; PTO-892 12/19/2025), Pickens et. al (Bioconjugate Chemistry, 2018; PTO-892 12/19/2025), and BroadPharm (Safety Data Sheet for Azido-PEG4-hydrazide HCl Salt, 2018; PTO-892 12/19/2025).
Zamora-Atenza teaches methods for treating rheumatoid arthritis (RA) by targeting TNF-α using Adalimumab, which is an anti-TNFα monoclonal antibody that specifically blocks the interaction of TNFα with its receptors and binds both soluble and transmembrane TNFα (abstract). TNFα contributes to joint destruction by attracting leukocytes, inducing inflammatory cytokines, upregulating adhesion molecules on endothelial cells (page 1, paragraph 1).
The teachings of Zamora-Atenza differ from that of the instantly claimed invention in that Zamora-Atenza does not teach a compound of instant claim 1.
Bertozzi teaches that a general strategy for targeting secreted and plasma membrane proteins for degradation is an unmet need that could dramatically impact human health (page 1, paragraph 1). Bertozzi thus discloses lysosome targeting chimeras (LYTACs), which represent a modular strategy for directing secreted and membrane proteins for degradation in the context of both basic research and therapy (abstract). The LYTAC platform enables depletion of both secreted and membrane proteins via a mechanism of action that is orthogonal and complementary to existing technologies (paragraph bridging pages 1-2). LYTACs consist of antibodies fused to ligands targeting the protein for degradation, and Bertozzi discloses a proof-of-principle example in which an antibody fused to agonist glycopeptide ligands for the cation-independent mannose-6-phosphate receptor (abstract). The antibody was conjugated by non-specifically labeling lysines of the antibody with bicyclononyne and subsequently conjugating this modified antibody to azide-terminated glycopolypeptides via Cu-free strain-promoted azide-alkyne cycloaddition (page 3, paragraph 1). Bertozzi concludes that the chemical tunability and modularity of LYTACs will offer new opportunities in targeted protein degradation for both research and translational applications (page 5, paragraph 1).
Rensen teaches that the hepatic asialoglycoprotein receptor (ASGPr) is expressed on the surface of hepatocytes and plays a role in the clearance (endocytosis and lysosomal degradation) of proteins from the serum (page 37577, paragraph 1). Because of its unique localization, abundance, and high internalization capacity, the ASGPr is widely used as a target for the specific delivery of genes and therapeutic agents to hepatocytes (page 37583, paragraph 4). Rensen further discloses ligands that have the structural requirements for proper recognition by the ASGPr and are useful for the design of systems for ASGPr mediated targeting of drugs to hepatocytes (page 37578, paragraph 3). Rensen describes a novel triantennary N-acetylgalactosamine-terminated cluster (Z-Tris(GalNAc)3) that was synthesized and conjugated to a steroid structure via a tyrosine residue (page 37578, paragraph 6). The triantennary ligand is shown below.
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Rensen shows that the Tris(GalNAc)3 ligand successfully targeted liposomes to hepatocytes in vivo through recognition by ASGPr.
Pickens reviews the state of the art in bioconjugation via azide−alkyne cycloaddition. Pickens teaches that the emergence of “click chemistry” has revolutionized bioconjugate chemistry by providing facile reaction conditions amenable to both biologic molecules and small molecule probes such as fluorophores, toxins, or therapeutics (abstract). Of all the bioorthogonal click reactions that have been developed, the most widely applied is the copper-catalyzed azide−alkyne cycloaddition reaction (CuAAC). In order to improve upon the CuAAC reaction, the strain promoted azide−alkyne cycloaddition reaction (SPAAC) was introduced, which mitigated several disadvantages of the CuAAC (page 686, paragraph 2). Pickens provides the following general formula for the outcomes of SPAAC reactions (Table 1).
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In the biopharmaceutical field, click chemistry is an attractive option for antibody-drug conjugates in which click chemistry is being explored for the conjugation of payloads to antibodies, and heterobifunctional linkers have been used to functionalize the payload molecule (page 693, paragraph 1). A large variety of heterobifunctional linkers are commercially available with different of solubilizing moieties like PEG and sulfate groups. PEGylated forms of the heterobifunctional linkers are available in various lengths, which permits precise spacing of the reactive handle. Pickens teaches that including PEG in the linker can improve water solubility and alleviate steric effects between the two molecules (page 692, paragraph 4). Pickens further teaches that NHS esters are among the most popular compounds used to functionalize biomolecules due to their aqueous compatibility, commercial availability, and ability to selectively target primary amines present on lysine residues or the N-terminus (page 688, paragraph 2). As shown below, a primary amine on the biomolecule reacts with the NHS ester to form an azide functionalized protein (Figure 2A).
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Pickens further teaches that linkers employed for installation of a reactive handle include DBCO-COOH, shown below (Figure 3D).
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BroadPharm discloses the compound DBCO-PEG4-acid, which is shown below (section I).
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One of ordinary skill in the art would have been motivated to apply the LYTAC strategy of Bertozzi to the Adalimumab of Zamora-Atenza in order to provide targeted degradation of TNF-α in the treatment of RA because Bertozzi teaches that LYTAC platform enables depletion of both secreted and membrane proteins and Zamora-Atenza teaches that TNFα, which occurs in both soluble and transmembrane forms, contributes to joint destruction in RA.
In order to achieve a LYTAC of Adalimumab, it would have been prima facie obvious to combine the teachings of Zamora-Atenza with that of Bertozzi, Rensen, Pickens, and BroadPharm before the effective filing date of the claimed invention by derivatizing the Adalimumab of Zamora-Atenza using a linker composed of the DBCO-PEG4-acid of BroadPharm joined by SPAAC to an azide modified lysine residue as taught by Pickens in order to provide a linker which can conjugate to the Adalimumab of Zamora-Atenza because Pickens teaches that DBCO-COOH is employed in the installation of a reactive handle and that NHS esters react with a primary amine on a biomolecule to provide an azide functional handle. One of ordinary skill in the art would have been motivated to derivatize Adalimumab using the commercially available DBCO-PEG4-acid heterobifunctional linker of BroadPharm because Pickens teaches that a large variety of heterobifunctional linkers are commercially available and that including PEG in the heterobifunctional linker can improve water solubility and alleviate steric effects between the two molecules. It would have further been prima facie obvious to append the DBCO functionalized linker to the triantennary Tris(GalNAc)3 ligand of Rensen, because Rensen teaches that ASGPr is expressed on the surface of hepatocytes and plays a role in the clearance of proteins from the serum and discloses triantennary ligands for recognition by the ASGPr that are useful for ASGPr mediated targeting of drugs to hepatocytes. One of ordinary skill in the art would have had a reasonable expectation of success because Bertozzi teaches that antibody conjugates, in which the antibody is linked to a targeting ligand via Cu-free strain-promoted azide-alkyne cycloaddition, are useful for targeting secreted and membrane proteins for degradation, and Rensen provides ligands targeting drugs to ASGPr expressed on the surface of hepatocytes, which plays a role in the endocytosis and lysosomal degradation of proteins from the serum.
Regarding instant claim 25, it would have been prima facie obvious to combine the Tris(GalNAc)3 conjugated Adalimumab suggested by the combined teachings of Zamora-Atenza, Bertozzi, Rensen, Pickens, and BroadPharm with an excipient because Zamora-Atenza teaches that Adalimumab is administered as an injection, which indicates that the antibody is administered as a solution and suggests a composition comprising the excipient water.
Regarding instant claim 33, it would have been prima facie obvious to treat RA in a human subject using the Tris(GalNAc)3 conjugated Adalimumab suggested by the combined teachings of Zamora-Atenza, Bertozzi, Rensen, Pickens, and BroadPharm because Zamora-Atenza teaches that Adalimumab is used in the treatment of RA patients, who would be understood by one of ordinary skill in the art to be human subjects.
Claims 35-36, 38, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Zamora-Atenza et. al (Arthritis Research and Therapy, 2014; PTO-892 12/19/2025) in view of Bertozzi et al. (ChemRxiv, 2019; PTO-892 12/19/2025), Rensen et. al (Journal of Biological Chemistry, 2001; PTO-892 12/19/2025), Pickens et. al (Bioconjugate Chemistry, 2018; PTO-892 12/19/2025), and BroadPharm (Safety Data Sheet for Azido-PEG4-hydrazide HCl Salt, 2018; PTO-892 12/19/2025), as applied to claims 1 and 27, further in view of Burke et al. (Mol Cancer Ther, 2017; PTO-892).
The combined teachings of Zamora-Atenza, Bertozzi, Rensen, Pickens, and BroadPharm are discussed in detail above.
The combined teachings of Zamora-Atenza, Bertozzi, Rensen, Pickens, and BroadPharm differ from that of the instantly claimed invention in that they do not expressly teach a linker which comprises either three or five ethylene glycol repeating units.
Burke discusses optimization of a PEGylated linker for antibody drug conjugates. Burke teaches that emergence of antibody–drug conjugates (ADC) has led to increased efforts to identify new payloads and develop improved drug-linker technologies (abstract). There are many design factors crucial to the development of effective ADCs and plasma pharmacokinetics has emerged as an important parameter in ADC pharmacology (page 116, paragraph 1). Burke investigates the effects of PEG length on the pharmacological properties of an ADC (page 117, paragraph 3). Burke discloses that increasing PEG length in the drug-linker results in an increase in apparent ADC size as measured by SEC chromatograms (paragraph bridging page 117-118). Burke provides a comparison of the therapeutic window of an ACD comprising a glucuronide-MMAE linker system with either PEG4, PEG8, PEG12, or PEG24 (page 123, paragraph 1). Specifically, a clear relationship was observed in vivo between PEG size and plasma pharmacokinetics, ultimately resulting in a relationship between PEG size and the therapeutic window. ADC clearance in rats decreased as PEG unit length increased. An in vivo xenograft model indicated greater activity was obtained with ADCs bearing PEG units sufficient in length to maximize plasma exposure (paragraph bridging page 119-120 and Fig. 5A).
It would have been prima facie obvious for one of ordinary skill in the art to optimize the PEG length in the linker of the compound suggested by the combined teachings of Zamora-Atenza, Bertozzi, Rensen, Pickens, and BroadPharm because Burke teaches that PEG length is a result effective variable such that one of ordinary skill in the art would have been motivated to optimize the number of ethylene glycol repeating units in a PEGylated linker and thereby optimize the plasma pharmacokinetics of the antibody conjugate. One of ordinary skill in the art would have a reasonable expectation of success because the combined teachings of Zamora-Atenza, Bertozzi, Rensen, Pickens, and BroadPharm suggest an antibody conjugate comprising a PEGylated linker and Burke teaches the optimization of PEG unit length in PEGylated linkers in order to optimize the plasma pharmacokinetics of antibody conjugates.
Response to Arguments
Applicant's arguments filed 06/18/2026 have been fully considered but they are not persuasive.
Applicant argues that the claimed ASGPR binding moiety is wholly different than the M6Pn oligomers taught by Bertozzi (Remarks, paragraph bridging page 13-14), and thus there is therefore nothing in Bertozzi that is combinable with any of the cited art to suggest the presently claimed compounds (Remarks, page 14, paragraph 1). This is not persuasive.
The teachings of Bertozzi are not relied upon to teach the structure of the ASGPR binding moiety of the instant claims. Rather, Bertozzi is relied upon to teach a general strategy for targeting proteins for degradation in which antibodies are fused to ligands targeting the protein for degradation. It is the teachings of Rensen which provide an ASGPR binding moiety which would have been prima facie obvious to employ according to the general strategy of Bertozzi.
Applicant further states that Rensen merely describes a theory whereby ASGPR might be used in drug targeting without any evidentiary support and thus cannot be used in an "obvious to try" basis for a case of obviousness of using GalNAc-based fragments in the claimed compounds (Remarks, paragraph bridging page 13-14). Applicant further argues that the LCO ligands of Rensen are wholly different from the instantly claimed compounds because they are not covalently bonded to a liposome (Remarks, page 15, paragraph 2). This is not persuasive.
The current obviousness rationale is based on KSR rationale (G) from MPEP 2141(III). According to the current obviousness rationale, one of ordinary skill in the art would have been motivated to append the suggested DBCO functionalized linker to the triantennary Tris(GalNAc)3 ligand of Rensen in order to achieve a LYTAC of Adalimumab in order to provide targeted degradation of TNF-α in the treatment of rheumatoid arthritis. One of ordinary skill in the art would have been motivated to do so because Rensen teaches that ASGPr is expressed on the surface of hepatocytes and plays a role in the clearance of proteins from the serum and further teaches triantennary ligands useful for ASGPr mediated targeting of drugs to hepatocytes. Furthermore, the teachings of Rensen are not limited to a proposal of theory. Rather, Rensen discloses that the disclosed ligands have the structural requirements for proper recognition by the ASGPr and thus demonstrates that the ligands are useful for the design of systems for ASGPr mediated targeting of drugs to hepatocytes.
Applicant further argues that the grounds of rejection does not cite any evidence that tagging an antibody with cyclooctyne-based ligands such as those in BroadPharm is known to be equivalent to using the bicyclononyne ligands used in Bertozzi (Remarks, page 16, paragraph 3). This is not persuasive.
In the instant grounds of rejection, the DBCO-PEG4-acid disclosed by BroadPharm is not relied upon as an equivalent of the BCN-NHS of Bertozzi. Rather, Pickens teaches that DBCO-COOH linkers are known in the art for installation of a reactive handle in the field of click chemistry, and that click chemistry is an attractive option for bioconjucation of antibody-drug conjugates. Thus, the teachings of the prior art suggest modification of an antibody with the DBCO-PEG4-acid disclosed by BroadPharm.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 11, 25, 27, 29, 33, and 35-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, 19, 25, 28-29, 31-36, and 38-43 of copending Application No. 17/654,984 (reference application). The claims at issue are not identical because ‘984 recites compounds with a narrower scope of structures. However, they are not patentably distinct from each other because ‘984 is directed to a compound of the below formula (I)
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in which Ab is selected from, among others adalimumab, CRBM has the below structure wherein ZB- may be absent,
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each CON is independently selected from the group consisting of, among others,
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and
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.
Claim 19 further limits that the Linker is a polyethylene glycol linker having 2-12 ethylene glycol residues.
Claim 25 of ‘984 recites pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and at least one compound of claim 1. Claim 29 of ‘984 recites a method of threating an autoimmune disease, cancer, or inflammation in a subject comprising administering a compound of claim 1, which may be formulated as a pharmaceutical composition. Claim 31 of ‘984 recites the method of claim 29 wherein the diseases is, among others, rheumatoid arthritis. Claim 36 of ‘984 recites the method of claim 29 wherein the subject is human.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's remarks filed 06/18/2026 request that the double patenting rejections be held in abeyance until a decision of allowable subject matter is reached. Therefore the rejections have been maintained.
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 extension fee 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 date of this final action.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/
Supervisory Patent Examiner, Art Unit 1693
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