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 .
Claims 1-2 17-18, 21, 51 and 66 are under consideration
Terminal Disclaimer
The terminal disclaimer filed on 10/31/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US11,510,993-B2 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Rejections/Objections Withdrawn
The 35 USC § 112(b) rejection of claim 21 has been withdrawn in view of claim amendments.
The 35 USC § 112(a) written description rejection of claims 1-2 17-18, 21, 51 has been withdrawn in view of claim amendments.
All 35 USC § 103 rejections have been withdrawn in view of claim amendments.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1-2 17-18, 21, 51 and 66 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1, 17 and 51, the parentheses surrounding the amino acid sequences and SEQ ID NOs following all instances of “CDR1”, “”CDR2” and “CDR3” each independently renders the claim indefinite because it is unclear whether the limitation(s) enclosed by the parentheses are part of the claimed invention. See MPEP § 2173.05(d).
Note: For examination, claims 1, 17 and 51 will be examined as if the sequences/SEQ ID NOs in the parentheses are required by the claims.
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.
Claim(s) 1-2, 17-18, 21, 51 and 66 is/are rejected under 35 U.S.C. 103 as being unpatentable over Graversen (Graversen, et al., Mol. Ther. 2012 20(8):1550, of record) in view of Brixner (Brixner, et al., US 5,094,848; Issue date 03/10/1992, of record), Zimmerman (Zimmerman, et al., Bioconjugate Chem. 2014 29:351, of record), J-Global (J-Global; Entry for (1-cyclooctyne-3-yloxy)acetic acid; URL= https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201107080065961417; Published 07/8/2011; Accessed 07/17/2025, of record) and Smith (Smith, et al., WO 2013/093465-A2; Published 06/27/2013, of record)
Graversen teaches on the subject of an anti-CD163/dexamethasone antibody-drug conjugate targeting CD163 in macrophages (Graversen, Abstract). Graversen teaches that that synthetic glucocorticoids (GCs) such as dexamethasone are used widely in the treatment of a range of inflammatory and autoimmune conditions and that GCs exert their effects via binding to the ubiquitous GC steroid receptor, altering transcription of a large range of genes (Graversen, p 1550, ¶ 1). Graversen teaches that the anti-inflammatory effect of GCs relates to their effects on lymphocytes and macrophages, with their effect on macrophages being due to the GC-induced reduction of expression of the proinflammatory cytokines TNF-a, IL1 and IL5, all of which are validated targets for anti-inflammatory therapy (Graversen, p 1550, ¶ 1). Graversen teaches that the anti-CD163/dexamethasone ADC of Graversen works by targeting macrophages with GC by way of targeting CD163, which is highly expressed on macrophages at atherosclerotic lesions and inflamed joints in rheumatoid arthritis (Graversen, p 1550, ¶ 2). Graversen teaches that the ADC of Graversen comprises the structure (Graversen, p 1551, Fig. 1):
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Graversen teaches that the anti-CD163/dexamethasone ADC of Graversen was tested in vivo in a LPS-induced inflammation rat model using multiple doses: 1 mg/kg and 0.02 mg/kg (for dexamethasone alone) and 0.02 mg/kg and 0.004 mg/kg (for the ADC, with values being with respect to dexamethasone), with the anti-inflammatory response being monitored by measuring TNF-a and IL-1 (Graversen, p 1551, ¶ 6). Graversen teaches that, with respect to TNF-a, the 1 mg/kg dose of free drug and the 0.02 mg/kg ADC produced similar anti-inflammatory effects with similar data being obtained for IL-1 (Graversen, p 1551, ¶ 5- 1552, ¶ 1; Fig. 6).
Graversen does not teach that the anti-CD163 conjugate comprises drug-linker moiety 1-4, wherein the linkage between the linker and the antibody takes place at a p-azidophenylalanine residue on the anti-CD163 antibody and that the resultant ADC is administered in methods of treating rheumatoid arthritis (RA). Graversen does not teach that the antibody component of the ADC of Graversen is an anti-CD163 antibody that comprises a light chain CDR1, CDR2 and CDR3 of SEQ ID NO: 60, YAS and SEQ ID NO: 61, respectively and a heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 62, YSG and SEQ ID NO: 63, respectively.
Brixner teaches on the subject of increasing the specificities of pharmaceutical agents for given sites of action by covalently linking the agent via a diphosphate to a targeting moiety that is a polypeptide specific for the given site of action (Brixner, Abstract). Brixner teaches that many therapeutic agents suffer from non-selectivity of effect, with a technique often used to address this problem being covalently linking the therapeutic agent to a targeting protein that is an antibody via a linkage that is cleaved (freeing the therapeutic agent) at the site of action (Brixner, Col 1, lines 5-36). Brixner teaches the innovative concept of Brixner is a cleavable diphosphate linking antibodies to therapeutic agents, with the diphosphate being cleaved by cellular phosphodiesterase and 5’-nucleotidase and acid phosphidase (Brixner, Col 1, line 38-Col 2, line 20). Brixner teaches that the compounds of Brixner comprise the structure:
A-bridge-targeting moiety
… wherein A is the agent, the targeting moiety is the antibody and the bridge comprises the formula:
L1n-DP-L2
… wherein DP is a diphosphate, L1 is an optional bridging spacer, L2 is a linking group connecting DP with the targeting moiety and n is 0 or 1 (Brixner, Col 2, line 52- Col 3, line 14).
Zimmerman teaches that incorporation of nonnatural amino acids (nnAA) comprising bio-orthogonal conjugation chemistries into antibodies offers site-specific solutions to making ADCs and also eliminate the heterogeneity and instability inherent in other methods of ADC manufacture (Zimmerman, page 351, ¶ 1). Zimmerman teaches that an essential component of most nnAA incorporation systems consist of an aminoacyl tRNA synthase that charges a specific tRNA with a nnAA (Zimmerman, p 351, ¶ 2- p 352, ¶ 1). Zimmerman teaches that the work of Zimmerman comprised successful use of an open cell free synthesis (OCFS) as a high throughput screening system to redirect M. jannaschii tyrosyl T RNA synthase (TyrRS) toward the nnAA p-azidophenylalanine (pAMF), thus allowing for the incorporation of pAMF into antibodies (Zimmerman, p 352, ¶ 4). Zimmerman teaches that pAMF comprising trastuzumab variants were conjugated to MMAF by way of strained cyclooctyne-azide, copper-free “click” chemistry via a DBCO-PEG-MMAF drug-linker moiety (Zimmerman, p ¶ 5).
J-Global teaches that the compound 1-(cyclooctyn-3-yloxy)acetic acid (CAA) was a known compound as of July 8th, 2011 (J-Global, p 1).
Smith teaches on the subject of storage-stable compositions comprising polypeptide binding moieties conjugated to therapeutic agents (Smith, Abstract). Smith teaches that one antibody suitable for the conjugates of Smith is the anti-CD163 antibody Mac2-158, which comprises a VH and VL of Smith’s SEQ ID NOs: 1 and 2 respectively, with Smith’s SEQ ID NO: 1 comprising heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 62, YSG and SEQ ID NO: 63 and Smith’s SEQ ID NO:2 comprising light chain CDR1, CDR2 and CDR3 of SEQ ID NO: 60, YAS and SEQ ID NO: 61 (Smith, p 22, lines 10-25).
It would be prima facie obvious to one of ordinary skill in the art to modify the anti-CD163/dexamethasone ADC of Graversen to such that the linker moiety comprises the cleavable diphosphate of Brixner with the CAA of J-Global as the crosslinker and the antibody component comprises the pAMF (same as pAzF) of Zimmerman, where the conjugation between the drug-linker and the anti-CD163 antibody occurs between the pAMF crosslinker and the pAMF in the antibody in view of the teachings of Brixner and Zimmerman and administer the resultant ADC in methods of treating RA. The net result of this combination would be a drug-linker moiety identical to instant 1-4 linked to the anti-CD163 antibody of Graversen via the CAA on 1-4 and a pAMF on the antibody, wherein the resultant ADC is administered in methods of treating RA. One of ordinary skill in the art would be motivated to do this in order to better treat RA. The teachings of Brixner and Zimmerman each provide improvements to the ADC of Graversen that would be obvious to one of ordinary skill in the art. The diphosphate of Brixner provides a means to facilitate the selective release of the dexamethasone of Graversen at the site of action only by way of the enzymatically cleavable phosphate group. The pAMF/cyclooctyne conjugation of Zimmerman provides a site-specific, biorthogonal conjugation scheme to reduce the heterogeneity and instability inherent in other methods of ADC manufacture as taught by Zimmerman. Additionally, Zimmerman provides a known incorporation system capable of incorporating pAMF into the anti-CD163 antibody of Graversen. The CAA of J-Global provides a crosslinker moiety that is art-equivalent to the DBCO of Zimmerman as well as carboxy acid group to facilitate incorporation to the linker in position L2 of Brixner, as carboxy acid/amine conjugation is very well known in the art. One of ordinary skill in the art would have a reasonable expectation of success modifying the anti-CD163/dexamethasone ADC of Graversen to such that the linker moiety comprises the cleavable diphosphate of Brixner with the CAA of J-Global as the crosslinker and the antibody component comprises the pAMF (same as pAzF) of Zimmerman, where the conjugation between the drug-linker and the anti-CD163 antibody occurs between the pAMF crosslinker and the pAMF in the antibody in view of the teachings of Brixner and Zimmerman because: 1) Graversen teaches an anti-CD163/dexamethasone ADC, 2) the diphosphate linker of Brixner provides a means to facilitate release of the dexamethasone of Graversen, 3) the pAMF/cyclooctyne conjugation of Zimmerman provides a site-specific, biorthogonal conjugation scheme to reduce the heterogeneity and instability inherent in other methods of ADC manufacture, 4) Zimmerman also provides a means to incorporate pAMF into the anti-CD163 antibody of Graversen and 5) the CAA of J-Global provides a strained cycloalkyne moiety that is art-equivalent to the DBCO of Zimmerman and a free carboxy acid group, allowing incorporation into position L2 of the linker of Brixner using routine chemistry. One of ordinary skill in the art would have a reasonable expectation of success administering the resultant ADC to treat RA because Graversen teaches that CD163 is highly expressed on macrophages in joints affected by RA and Graversen teaches that the anti-CD163/dexamethasone ADC of Graversen was highly effective at reducing pro-inflammatory cytokine expression.
It would be prima facie obvious to use Mac2-158 anti-CD163 antibody of Smith as the antibody component in the ADC collectively taught by Graversen, Brixner, Zimmerman and J-Global discussed in the preceding paragraph. One of ordinary skill in the art would be motivated to do this in order to use an anti-CD163 antibody that is art equivalent anti-CD163 antibody of Graversen in the ADC collectively taught by Graversen, Brixner, Zimmerman and J-Global discussed in the preceding paragraph. One of ordinary skill in the art would have a reasonable expectation of success using the Mac2-158 anti-CD163 antibody of Smith as the antibody component in the ADC collectively taught by Graversen, Brixner, Zimmerman and J-Global discussed in the preceding paragraph because Smith teaches that Mac2-158 is an anti-CD163 antibody suitable for use in immunoconjugates.
Response to Arguments
Applicant's arguments filed 10/31/2025 have been fully considered but they are not persuasive.
Applicant argues that the combined cited art does not provide sufficient teaching to motivate a person having ordinary skill in the art to construct anti CD163 ADCs comprising antibodies with the instant HC and LC sequences for use in treating inflammatory disorders. This is not persuasive because, as detailed above: 1) Graversen teaches anti-CD163 ADCs with a different anti-CD163 antibody for use treating inflammatory conditions, 2) Smith teaches an anti-CD163 antibody with the instant claimed HC and LC sequences and 3) it is obvious to substitute known, equivalent art elements (in this case the antibody of Smith in place of the antibody of Graversen). Applicant argues that all of claims 1-2, 17-18, 21, 51 and 62 have been amended to incorporate all limitations of canceled claim 62, including the anti-CD163 antibody comprising the HC and LC CDR sequences recited in now cancelled claim 62 linked to linker-drug moiety 1-4 via a pAzF nnAA. Applicant attempts to differentiate the instant claimed immunoconjugate from the anti-CD163 immunoconjugate collectively taught by Graversen, Brixner, Zimmerman, J-Global and Smith by pointing to Example 19 of the instant Specification, which demonstrates the instant claimed anti-CD163 immunoconjugate comprising drug-linker 1-4 conjugated via a pAzF nnAA remained stable in serum, but was rapidly released in lysosomal extracts (Remarks of 10/31/2025, p 4, ¶ 1-2; Specification, p 75, line 1- p 77, line 27). Applicant then argues that the citations of the prior art do not teach ADCs having this particular property. Additionally, Applicant argues that Applicant teaches linkers in which the stability of the ADC in the lysosome is tunably degradable based on the linker. Demonstration of unexpected results can rebut a prima facie case of obviousness (See MPEP § 716.02(a)). Regarding Applicant’s demonstration that the instant claimed ADC linker-drug moiety exhibits differential stability in plasma vs under lysosomal conditions is not an unexpected result for a modern ADC linker-drug moiety. It is highly desirable in the field of ADC linker design to produce drug-linker moieties that remain stable in plasma but are labile (and therefore release free drug) under conditions the conjugate encounters post-internalization by the target cell (typically lysosomal conditions). As such, demonstrating that an immunoconjugate comprising modern ADC drug-linker design elements possesses a differential linker stability property that is highly desired in the field of ADC drug-linker design is not a demonstration of unexpected results.
Additionally, evidence offered to rebut a prima facie case of obviousness must be commensurate with the scope of the claims the evidence is offered to support (See MPEP §716.02(d). None of the instant claims as amended recite any limitation even mentioning or describing the differential and/or tunable stability Applicant argues to be allegedly unexpected properties.
Conclusion
Claims 1-2 17-18, 51 and 66 are rejected.
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.
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/SYDNEY VAN DRUFF/ Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643