RESPONSE TO APPLICANT’S AMENDMENT
1. Applicant's amendment, filed 11/13/2025, is acknowledged.
2. Claims 1-5 and 7-16 are pending.
3. Claims 5, 7-11 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
4. Claims 1-4 and 12-16 are under examination as they read on an oligomerization tag comprising an immunoglobulin Fc region or a fragment thereof and a polyHis domain wherein the polyHis domain has 8-12 histidine residue and the species of SEQ ID NO:18 and the oligomerization tag is configured to form 3 mers to 12 mers or a hexamer of a dimers.
5. In view of the amendment filed on 11/13/2025, only the following rejection are remained.
6. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
7. Claims 1 and 12-15 stand rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kobayashi et al (THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO. 3, pp. 1716–1725, 2010), as is evidenced by the specification at pages 25, lines 5+ and Table 3 for the same reasons set forth in the previous Office Action mailed 08/13/2025.
Applicant’s arguments, filed 10/28/2013, have been fully considered, but have not been found convincing.
Applicant submits that Kobayashi et al discloses Figure 1 consisting of two panels (A) a schematic diagram of protein constructs and (B) a gel image showing protein purity.
Panel A: Schematic of Recombinant BAEBL Fusion Proteins
Panel (A) illustrates the design of a recombinant protein used to study how the malaria parasite Plasmoldium falciparum binds to human red blood cells.
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The native BAEBL protein includes SP (signal Peptide), region II (responsible for binding to red blood cells), 3Cys (cysteine-rich region), TMD (transmembrane Domain), and Tail in the intracellular portion. The recombinant fusion protein (BAEBL/Fc-8His) was engineered to include a secretion signal (FHL-1), the Fc region of mouse IgG2a (to facilitate purification and detection), and an 8xHis tag at the C-terminus.
Panel B: SDS-PAGE Gel of Recombinant Proteins
Applicant submits that Panel (B) shows a silver-stained SDS-PAGE gel used to verified the purity and molecular weight of the recombinant proteins. Two proteins, BAEBL/Fc-8His (the fusion protein) and mIgG2aFc (used as a negative control) are shown in the panel (B). Each protein appears as a single band at the expected molecular weight, confirming successful expression and purification.
Applicant asserts that it would not be inherent that the referenced BAEBL-Fc-His8 polypeptide would express the oligomer recited in claim 1 or any of its dependent claims for the following reasons:
SDS-PAGE Analysis Shows No Evidence of Oligomerization
As shown in Figure 1B, the recombinant BAEBL-Fc-His8 protein appears as a single band
at the expected molecular weight when analyzed by SDS-PAGE under denaturing
conditions. This indicates that no covalent oligomerization (e.g., via disulfide bridges) is present. If oligomers were formed through stable disulfide bonds, they would be expected to be visible as higher molecular weight species. No such higher molecular weight species are observed in the gel.
This is not found persuasive because simply because the BAEBL/Fc-8His was not run under non-reducing SDS-PAGE condition. Kobayashi et al fails to teach that the SDS-PAGE gel was run under non-reducing condition. In the contrary, Kobayashi shows the control mIgG2aFc ( which a dimer linked by disulfide bonds under non-reducing conditions) is monomer on the SDS-PAGE gel indicating that the gel is run under reducing conditions. Further, Under the Pull-down Assay, Kobayashi et al teach that the BAEBL/Fc-8His (the fusion protein) comprising disculfide bridge was incubated with SDS (denaturing detergent) prior and during running on reducing SDS-PAGE gel. Also, prior to running on the gel, the BAEBL/Fc-8His and the beads were boiled (to fully unfold and separate subunits) for 5 min in a buffer containing SDS and 2-mercaptoethanol (reducing agent to break disulfide bonds) and then separated by SDS-PAGE gel. Given that BAEBL-Fc-His8 was treated and run with 2-ME/boiling would break covalent disulfide bonds and ensure complete reduction to monomers. Importantly, the referenced BAEBL-Fc-His8 protein contains both Fc region and 8Xhis tag which would cause protein oligomerization. As is evidenced by the specification that the data shown in Table 3 strongly indicate that the oligomerization is an intrinsic property of Fc-polyHis tags. Applicant cannot represent to the public that their claimed oligomer comprising an Fc region and 8xHix tag would intrinsically oligomerize, while at the same time discounting the relevance of the very same BAEBL-Fc-His8 protein to inherent property of the prior art oligomer. If the instant claims are enabled so is the prior art. However, if the prior art is not enabled neither is the instant claims. Kobayashi et al teachings meet the claimed structure; the claimed oligomerization is considered inherent. There is no structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art.
2. No Functionalization of Fc Cysteines to Promote Dimerization
Applicant submits that the experimental procedures do not describe any chemical modification, mutation, or oxidative treatment of the cysteine residues in the Fc domain. Without such
functionalization, disulfide-mediated dimer formation is not expected to occur in a controlled or consistent manner. Therefore, the Fc domain in this construct is not presumed to drive oligomerization under the conditions used.
This is not persuasive because it is merely attorney argument, unsupported by evidence. See Meitznerv. Mindick, 549 F.2d 775, 782 (CCPA 1977) ("Argument of counsel cannot take the place of evidence lacking in the record."). In an SDS-PAGE analysis, the mIgG2aFc protein is a dimer linked by disulfide bonds under non-reducing conditions, appearing as a single band at its approximate full molecular weight (around 50-60 kDa for the dimer). Under tandard reducing conditions, these disulfide bonds are broken, and the protein separates into its constituent monomers, which appear as a single band at a lower molecular weight (around 25-30 kDa for the monomer). It appears that the SDS-PAGE analysis in Fig. 1 done by Kobayashi et al were under reducing condition since the MW of the mIgG2aFc is between 25-30 kDa. Importantly, the present of Fc region or fragment thereof with 8xHis tag would intrinsically lead to oligomerization as is evidenced by the specification. Irrespective of the presence of chemical modification, mutation, or oxidative treatment of the cysteine residues in the Fc domain, linking the Fc region or fragments thereof with 8xHis tag will produce oligomeric protein as is evidence by the specification at pages 25, lines 5+ and Table 3.
8. Claims 1 and 12-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gong et al. (PLoS ONE 7(1): e30169. doi:10.1371/journal.pone.0030169), as is evidenced by the specification at pages 25, lines 5+ and Table 3 for the same reasons set forth in the previous Office Action mailed 08/13/2025.
Applicant’s arguments, filed 11/13/2025, have been fully considered, but have not been found convincing.
Applicant points that page e30169 of Gong States: Recombinant protein synthesis using the sequence obtained from GenBan (CAJ20677), primers wer designed from plasmid construction in pBSV-Fc-8His [25]. The N-terminus of the protein contains four repeats of . . ..
Applicant submits CAJ20677 was prepared as disclosed in reference [25] which is the Kobayashi reference discussed above. Therefore, Gong does not anticipate claim 1 or its dependent claims for the same reasons discussed above in connection with Kobayashi.
This is not found persuasive because Gong et al teachings meet the claim language. Gong et al teach a protein comprising Fc and 8xHis tag. Accordingly, Gong teachings anticipate the claimed invention.
9. Claims 1 and 12-15 stand rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 20140363372, as is evidenced by the specification at pages 25, lines 5+ and Table 3.
for the same reasons set forth in the previous Office Action mailed 08/13/2025.
Applicant’s arguments, filed 11/13/2025, have been fully considered, but have not been found convincing.
Applicant submits that the experimental data provided in the `372 publication provide no evidence that any resulting fusion proteins form oligomers of two or more as recited in claim 1 and its depending claims. Looking at the experimental data provided in the specification, only having ordinary skill in the art would conclude that
1. Binding Kinetics:
Surface plasmon resonance (SPR) and ELISA binding assays (Figures 11-13) show that the interaction between the TMCC3-intercoil-Fc-10His construct and various monoclonal antibodies follows a simple 1:1 binding model. This is an indication that the antigen (i.e., TMCC3-intercoil-Fc-10His) is monomeric in solution.
However, it is not clear how Applicant arrived to the conclusion that the antigen (i.e., TMCC3-intercoil-Fc-10His) is monomeric in solution since monoclonal anti-TMCC3 antibodies can bind a dimeric TMCC3 in 1:1 binding model due to steric hindrance.
2. Absence of Cooperative or Multivalent Binding Effects:
If the Fc domain were inducing dimerization or higher-order oligomerization, one having ordinary skill in the art would expect to observe:
- Non-linear binding curves,
- Enhanced apparent affinity due to avidity effects,
- Multiple binding phases in kinetic assays.
None of these phenomena are observed. The dissociation constants (Kd) are in the low nanomolar to sub-nanomolar range, consistent with high-affinity monovalent interactions, not multivalent binding.
Taken together, the binding kinetics and the absence of multivalent effects observed in the experimental data disclosed in U.S. 2014/0363372 do not provide robust support for the Examiner’s interpretation. Accordingly, U.S. 2014/0363372 does not disclose the oligomer recited in claim 1 or any of its dependent claims.
This is not found persuasive because the `372 publication meet the limitation and the structure of the instant claims. It appears that Applicant argues that the full scope of their claims is not enabled since there are proteins comprising Fc and 8x HIS tags are not oligomer. The instant specification is enabled so is the prior art. However, if the prior art is not enabled neither is the instant claims.
10. 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.
11. Claim 16 rejected under 35 U.S.C. 103 as being unpatentable over Kobayashi et al (THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO. 3, pp. 1716–1725, 2010), Gong et al. (PLoS ONE 7(1): e30169. doi:10.1371/journal.pone.0030169), US 20140363372, as is evidenced by the specification at pages 25, lines 5+ and Table 3, each in view of WO2010128193 for the same reasons set forth in the previous Office Action mailed 08/13/2025.
Applicant’s arguments, filed 11/13/2025, have been fully considered, but have not been found convincing.
Applicant submits that none of the primary references discloses the subject matter of claim 1, the combination of these references with the teachings of WO2010/128193 is insufficient to produce
It remains the Examiner’s position that it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the region II of BAEBL, sequence, CD46 or TMCC taught by Kobayashi et al, Gong et al., and US 20140363372 with the ECD CD38 taught by the `193 publication in the method of expressing CD38-Fc-8/10his.
12. Claims 2- 4 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
13. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US 20170058015 A1 (filing date 6/18/2014).
The `015 publication teaches [0352] a design for two base synTac molecules is presented in FIG. 3A-3B. Briefly, this construct utilizes a native human B2M leader sequence to allow for efficient secretion and ER processing immediately followed by a candidate epitope (labeled as peptide). Once in the ER the leader sequence is fully removed and allows for the presentation of the peptide in the MHC binding pocket. For a “light chain” linkage (LC, FIG. 3A), this is coupled to the native B2M molecule through linker L1 and the MOD through linker L2. This entire cassette is linked to another B2M leader sequence, the MHC heavy chain (e.g. human HLA-A02:01 or murine H-2Kd in the examples), and an Fc domain (either human IgG1 or murine IgG2a) by a viral porcine teschovirus-1 (P2A) “self-cleaving” peptide to allow for stoichiometric expression of each chain. The P2A peptide was chosen as this has the highest reported “cleavage” efficiency of all viral 2A peptides expressed in mammalian cells [29]. The “heavy chain” (HC, FIG. 3B) linkage is similar however the viral P2A peptide now follows the B2M and the MOD follows the second leader peptide, leading to the protein construct shown in FIG. 2C. Both constructs can terminate in an 8×His tag for ease of purification. SEQ ID NO:70 which is synTac 40 polypeptide comprising murien IgG2a Fc followed by 8x HIS tag (see Fig. 8B). SynTac 69 (SEQ ID NO: 71) disulfide bridge formed between residues Q94C and P245C comprising murein IgG2a Fc, followed by 8x HIS tag (see Fig. 9C). SynTac 70-Disulfide bridge formed between residues Q94C and P242C (SEQ ID NO: 73) comprising murein IgG2a Fc, followed by 8x HIS tag (Fig. 9D).
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14. 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 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 mailing date of this final action.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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December 11, 2025
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644