DETAILED ACTIONS
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, 4-5, 22-23, 28, 34, 48-49 and 94-100 are under consideration.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/23/2025 has been entered.
Rejections/Objections Withdrawn
The 35 USC 112(b) rejections of claims 28 and 30 have been withdrawn in view of claim amendments
The 35 USC 112(d) rejection of claim 93 is moot in view of claim cancellation
All 35 USC 102 and 35 USC 103 rejections articulated in the previous Office Action have been withdrawn in view of claim amendments.
New Rejections/New Rejections Necessitated by Amendment
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, 4-5, 22-23, 28, 48-49, 94-95 and 97-100 and is/are rejected under 35 U.S.C. 103 as being unpatentable over Hobbes (Hobbes, et al., US 2013/0184442 A1; Published 07/18/2013, of record) in view of Xuan (Xuan, et al., Agnew. Chem. Int. Ed. 2017 56:5096, of record)) and Ciu (Ciu, et al., US 2020/0062827 A1; Published 2/27/2020; Priority to 3/30/2017 via US 62/47886)
Hobbes teaches that BPA is a synthetic, photo-reactive amino acid that can be incorporated into a peptide during synthesis and forms covalent bonds with other amino acids under UV light (Hobbes, ¶ 0005). Regarding claim 1, Hobbes teaches a method of specific covalent labeling to immunoglobins by using a synthetic Z domain (which has affinity for the antibody’s Fc fragment) comprising BPA, with the method comprising a) providing the IgG binding protein with the photoreactive motif, b) forming a mixture of the IgG binding protein and antibodies and c) UV illuminating the mixture for site-specific labeling of said antibodies (this also satisfies claims 48 and 49, as no treatments using any additional agents (Hobbes, ¶ 0006-0007). Regarding claims 22-23 and 100, Hobbes teaches that affinity compound of Hobbes is situated between CH2 and CH3 of the antibody involved 11 residues from helix 1 and helix 2 of the B domain of Protein A (Hobbes, ¶ 0004). Regarding claims 4 and 5, Hobbes discloses that labeled affinity peptide were produced by Fmoc-based solid phased synthesis (Hobbes, ¶ 0040-0045). Hobbes also teaches methods of labeling antibodies to fluorescent compounds and radioisotopes using the antibody-binding platform of Hobbes. (Hobbes, ¶ 0012). Regarding claims 94-95 and 97-100, Hobbes teaches antibody labeling platforms that attach an agent that is a radionuclide residue, wherein the antibody being labeled is human IgG1. Regarding claim 100, Hobbes teaches that the covalent bond between the affinity compound and the antibody to be labeled is located within the antibody CH2-CH3 hinge region (Hobbes ¶ 0004)
Hobbes does not teach embodiments of the antibody labeling platform of Hobbes wherein the affinity compound is a S. aureus B domain sequence comprising SEQ ID NO: 2, or a fragment thereof that is also less than 35 AA in length. Hobbes does not teach the antibody labeling platform of Hobbes wherein antibody-reactive crosslinker is FPheK that is inserted at position 25 of a S. aureus protein A.
Xuan teaches on the use of noncanonical amino acids (ncAAs) PheK and FPheK, which comprise aryl carbamate side chains, to form crosslinks with adjacent Lys, Cys and Tyr residues (Xuan, Abstract). Xuan teaches that aryl carbamates are moderate electrophiles that have been used as cleavable linkers in ADCs that undergo proximity-assisted nucleophilic attack to release drugs (Xuan, p 5096, ¶ 2). Xuan teaches that the distance between the Lys8 of an anti-thioredoxin affimer (a peptide mimetic that is structurally similar to an antibody’s Fc domain) (Xuen, p 5097, ¶ 2) is only 7.1 angstroms when the Z-protein/affimer complex is formed (Xuan, p 5097, ¶ 2-3; Fig 3A.; Fig 3 A-B)
PNG
media_image1.png
184
197
media_image1.png
Greyscale
Fig 4A of Xuan reference.
Xuan also teaches that mutation position amino acid was Glu 98 to non-nucleophilic Asn resulted in a crosslinker that was not able to form stable, covalent crosslinks with Lys8 upon formation of the ProteinZ/ Affimer complex. Both of the nucleophilic side chains of Cys and Tyr were also able form stable crosslinks and that His and Ser were also able to form crosslinks but had low efficiency due to competitive hydrolysis because Xuan teaches p 5097, ¶ 4 – p 5098, ¶ 2); Xuan teaches that prior work within the Xuan group showed that FPheK (para-isothiocyanate phenylalanine; a previously characterize proximity-inducible moiety at position 25 of a Z protein was able to form a stable thiourea linkage with Lys8 of a Afb-Trx fusion protein (an antibody mimetic that also binds to protein A, leading Xuan to hypothesize that FPheK integrated at position 25, leading Xuan to hypothesize that a Z protein with PFeK integrated at position 25 would form a covalent bond to Lys8 (Xuan, p 5098, ¶ 2) and that this was confirmed by generating a Z protein with FPheK at position 25 of a Z protein, incubating it with Afb-Trx and then analyzing it via ESI-QTOF mass spectrometry with Afb-Trx Lys8Asn as a negative control (Xuan, p 5098, ¶ 3).
Ciu teaches on the subject of the protein-A derived linear separation molecule Z33 (Ciu, Abstract). Ciu teaches that Z33 comprises the 33 amino acid sequence FNMQQQRRFYEALHDPNLNEEQRNAKIKSIRDD and maintains its ability to bind antibody Fcs (Ciu, ¶ 4-9).
It would be prima facie obvious to one of ordinary skill in the art to modify the antibody labeling technology of Hobbes to contain the FPheK of Xuan as a conjugating agent instead of the BPA of Hobbes. The net result of this modification would be the antibody labeling system of Hobbes with FPheK incorporated in the Z protein instead of BPA, wherein the FPheK is incorporated at position 25 of the Z protein. One of ordinary skill in the art would be motivated to make this modification in order to link the Z protein to the antibody without requiring the use of UV light to activate the BPA of Hobbes. One of ordinary skill in the art would have a reasonable expectation of success modifying the antibody labeling technology of Hobbes to contain the FPheK of Xuan at position 25 of a Z protein because Xuan demonstrates that Z proteins containing FPheK form covalent bonds with Afb-Trx in the same manner that a previously studied proximity inducible compound and one of ordinary skill in the art would reasonably expect future compounds to behave as previously studied compounds.
It would be prima facie obvious to one of ordinary skill in the art to modify the modified antibody labeling technology collectively taught by Hobbes and Xuan and described above, said antibody labeling technology comprising the Z protein of Hobbes with the FPheK of Xuan inserted at position 25 and substitute the Z protein Fc binding moiety of Xuan with the Z33 Fc Binding moiety taught by Ciu. The net result of this substitution would be an antibody labeling platform comprising a Z33 Fc binding moiety of Ciu comprising the FPheK of Xuan inserted at position 25. One of ordinary skill in the art would be motivated to do this in order to generate a Fc-binding moiety art equivalent to the Z protein of Xuan. One of ordinary skill in the art would have a reasonable expectation of success substituting the Z protein Fc binding moiety of Xuan with the Z33 Fc binding moiety taught by Ciu because Ciu teaches that Z33 possesses the required function of binding antibody Fc regions.
It would be prima facie obvious to one of ordinary skill in the art to substitute the sequence Z33 Fc binding moiety of Ciu component of the modified antibody labeling technology collectively taught by Hobbes, Xuan and Ciu and discussed in the preceding paragraph with the corresponding native S. aureus sequence. The net result of this substitution would be a 33 AA S. aureus B-domain comprising the native S. aureus sequence identical to instant SEQ ID NO: 2. One of ordinary skill in the art would be motivated to do this in order to use the natural Fc binding domain as opposed to the synthetic protein Z. One of ordinary skill in the art would have a reasonable expectation of success because both Protein A B-domains and Z-domains both possess the required function of binding antibody Fcs.
Response to Arguments
Applicant's arguments filed 12/23/2025 have been fully considered but they are not persuasive.
Applicant begins noting the claims have been amended to require: A) a reactive motif that is FPheK, 2) an affinity compound that is a B domain of Protein A or a FcIII peptide. These amendments have been noted and are accounted for in the current Office Action.
The remainder of Applicant’s arguments stress high the efficiencies (up to 99%) of conjugation observed, over a wide range of numerous antibodies tested, when the instant claimed FPheK-comprising proximity-based conjugation method is used, compared to Hobbes 80% efficiency. A prima facie case of obviousness may be successfully rebutted via demonstration of superior results that would be unexpected to one of ordinary kill in the art (See MPEP § 716.02(a)). While the 99% conjugation efficiency reported by Applicant is certainly impressive, it is not unexpected in view of the teachings of Xuan. Figures 2A, 3A-B, and 5C all show that the proximity-dependent FPheK conjugation of Xuan routinely produces conjugation reactions with efficiencies that are nearly 100%. As such, one of ordinary skill in the art would expect the proximity-dependent FPheK conjugation of Xuan to produce conjugation with efficiency of nearly 100% because the conjugation data of Xuan demonstrates that the proximity-dependent FPheK conjugation of Xuan is a highly efficient reactions and one of ordinary skill in the art would reasonably expect such high efficiencies for Xuan’s conjugation method.
The comparison of Xuan’s conjugation method to Hobbes BPA-based conjugation with 80% conjugation that also requires UV activation is not relevant as this and the prior Office Actions both articulate why one of ordinary skill in the art would be motivated to use the FPheK of Xuan in place of the BPA of Hobbes and why one of ordinary skill in the art would have a reasonable expectation of success doing so. That is to say, the BPA of Hobbes is not present in the modified method of Hobbes and Xuan.
Claim(s) 1, 4-5, 22-23, 28, 34, 48-49, 94-95 and 97-98 and 97-100 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hobbes (Hobbes, et al., US 2013/0184442 A1; Published 07/18/2013, of record) and Xuan (Xuan, et al., Agnew. Chem. Int. Ed. 2017 56:5096, of record)) and Ciu (Ciu, et al., US 2020/0062827 A1; Published 2/27/2020; Priority to 3/30/2017 via US 62/47886) as applied to claims 1, 4-5, 22-23, 28, 48-49, 94-95 and 97-100 above and in further view of Sampath (Sampath, et al., J Nucl Med 2007 48:1501, of record).
The combined teachings of Hobbes, Xuan and Ciu are discussed above.
The combined teachings of Hobbes, Xuan and Ciu do teach that the antibody being linked to the target agent in the method collectively taught by Hobbes, Xuan and Ciu is trastuzumab.
Sampath teaches of trastuzumab that has been labeled with 111In and a near infrared dye (IRDye800) is useful for detecting HER2 overexpression in breast cancers (Sampath, Abstract). Sampath teaches that the labeled trastuzumab was made by first adding DTPA groups at available amines on the antibody (Sampath, p 1502, ¶ 4), then allowing amine reactive, commercially available IRDye 800 to react with the antibody (Sampath, p 1502, ¶ 5) and finally complexing 111In with the DTPA groups on the antibody by adding 111InCl3 (Sampath, p 1502, ¶ 6).
It would be prima facie obvious to one of ordinary skill in the art to combine the conjugation method collectively taught by Hobbes, Xuan and Cau to make the dual labeled trastuzumab of Sampath. One of ordinary skill in the art would be motivated to make the dual labeled trastuzumab of Sampath using the method of Hobbes, Xuan and Ciu in order to make the radiolabeled/fluorescent labeled antibody in order to generate a dual labeled antibody for detecting HER2 overexpression in breast cancers without affecting the antigen binding domain of the trastuzumab. One of ordinary skill in the art would have a reasonable expectation of success using conjugation method collectively taught by Hobbes, Xuan and Ciu to make the dual labeled trastuzumab of Sampath because: 1) Sampath teaches that 111In/IRDye800 antibodies are useful for measuring HER2 overexpression in breast cancer and 2) The combined method of Hobbes, Xuan and Ciu teaches a method capable of adding both fluorescent and radioisotope labels to antibodies without affecting the antibody’s antigen binding domain.
Response to Arguments
Applicant provides no specific arguments to this rejection other than stating Sampath does not remedy the “deficiencies” of Hobbes and Xuan.
Claim(s) 1, 4-5, 22-23, 28, 34, 48-49, 94-100 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hobbes (Hobbes, et al., US 2013/0184442 A1; Published 07/18/2013, of record), Xuan (Xuan, et al., Agnew. Chem. Int. Ed. 2017 56:5096), Ciu (Ciu, et al., US 2020/0062827 A1; Published 2/27/2020; Priority to 3/30/2017 via US 62/47886) and Sampath (Sampath, et al., J Nucl Med 2007 48:1501, of record) as applied to claims 1, 4-5, 22-23, 28, 34, 48-49, 94-95 and 97-98 and 97-100 and in further view of Kim (Kim, et al., Biomol Ther (2015) 23(6):493)
The combined teachings of Hobbes, Xuan, Ciu and Sampath are discussed above. In addition, Hobbes teaches that labeling moieties are coupled to IgG proteins via linkers (Hobbes, ¶ 0012).
The combined teachings of Hobbes, Xuan, Ciu and Sampath do not teach that the moiety attached to the antibody is a toxin or chemotherapeutic.
Kim teaches on the subject of ADCs (Kim, Abstract). Kim teaches that ADCs were derived to minimize off-target systemic toxicity of chemotherapy by conjugating a mAb to a cytotoxin via a linker, with the mAb acting to minimize off-target systemic toxicity by localizing the cytotoxins around the mAb’s target antigen (typically on a tumor cell). (Kim, p 495, ¶ 4-5).
It would be prima facie obvious to one of ordinary skill in the art to combine the trastuzumab of Sampath with the antibody-bound-linker-cytotoxin of Kim and conjugation method collectively taught by Hobbes. The net result of this combination is a trastuzumab ADC, wherein a cytotoxin is conjugated to the trastuzumab via a linker, where conjugation between the linker and antibody takes place using the method collectively taught by Hobbes and Kim. One of ordinary skill in the art would be motivated to do this in order to better treat form an ADC capable of targeting HER2+ breast cancer found when the method of Sampath is performed. One of ordinary skill in the art has a reasonable expectation of success conjugating a cytotoxin to a trastuzumab via a linker to form a HER2 targeting ADC because: both Hobbes and Kim teach conjugation to antibodies via linkers and Kim specifically teaching conjugation of cytotoxins to antibodies via linkers, Kim teaches that cytotoxins linked to antibodies are common in the art and the combined method of Hobbes and Xuan provides a highly efficient, site specific means to conjugate numerous moieties to antibodies via linkers.
Claim(s) 1, 4-5, 22-23, 28-30, 48-49, 94-95 and 97-100 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hobbes (Hobbes, et al., US 2013/0184442 A1; Published 07/18/2013, of record) and Xuan (Xuan, et al., Agnew. Chem. Int. Ed. 2017 56:5096) and Ciu (Ciu, et al., US 2020/0062827 A1; Published 2/27/2020; Priority to 3/30/2017 via US 62/47886) as applied to claims 1, 4-5, 22-23, 28, 48-49, 94-95 and 97-100 above and in further view of Strambio de Castilla (Strambio de Castilla, et al., J Proteome Research 2005 4:2250, of record).
The teachings of Hobbes, Xuan and Cui are discussed above.
Hobbes, Xuan and Ciu do not teach the method of Hobbes, Xuan and Ciu wherein the protein A fragment of Hobbes is replaced by a FcIII fragment.
Strambio de Castilla teaches the peptide FcIII mimics the portion the protein A protein that binds the hinge region of the Fc fragment of an antibody (Strambio de Castilla, p 1, ¶ 3).
It would be prima facie obvious to one of ordinary skill in the art to modify the method of Hobbes, Xuan and Ciu to include the FcIII peptide of Strambio de Castilla instead of the 33 AA B protein fragment of Hobbes, Xuan and Ciu. One of ordinary skill in the art would be motivated to make such a substitution in order to arrive at an art equivalent Fc hinge binding protein suitable for the conjugation of method of Hobbes, Xuan and Ciu . One of ordinary skill in the art would have a reasonable expectation of success substituting the FcIII peptide of Strambio de Castilla for the 33 AA B protein fragment of Hobbes, Xuan and Ciu because both the Z protein of Hobbes and Xuan and the FcIII peptide of Strambio de Castilla possess the shared function of binding the hinge region of the Fc fragment of an antibody.
Response to Arguments
Applicant's arguments filed 12/23/2025 have been fully considered but they are not persuasive.
Applicant argues that Strambio de Castilla offers no teaching or suggestion as to why using FcRIII comprising FPheK could be expected to produce efficient, site-specific crosslinking. First Strambio de Castilla teaches that FcRIII mimics the portion of Protein A that binds the hinge region of an antibody. As such, both FcRIIII and a 33 AA S. aureus B fragment possess the shared property of binding the hinge region similar to Protein A. This shared property means that both affinity compounds are capable of bringing the reactive FPheK to close proximity to an antibody’s hinge region and thus engage in proximity-mediated conjugation.
Conclusion
Claims 1, 4-5, 22-23, 28, 34, 48-49 and 94-100 are rejected.
No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sydney Van Druff whose telephone number is (571)272-2085. The examiner can normally be reached 10 am - 6 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643