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 .
DETAILED ACTION
Status of the Claims
1. Claims 1-50 are the original claims filed 7/21/2022. In the Response of 3/8/2023, claims 3-5, 7, 9, 16, 18, 24, 29, 32, 34, 42, 44, and 46 are amended, and claims 12-15, 17, 19- 23, 26-28, 30-31, 33, 38-41, and 48-50 are canceled. In the Reply of 8/14/2025, claim 29 is amended. In the Response of 12/30/2025, claims 1-3, 6-8, 10, 16, 45, and 47 are amended, claims 4, 11, and 18 are canceled, and new claim 51 is added.
Claims 1-3, 5-10, 16, 24-25, 29, 32, 34-37, 42-47, and 51 are all the claims.
Claims 35-37 are withdrawn.
Claims 1-3, 5-10, 16, 24-25, 29, 32, 34, 42-47, and 51 are the claims under examination.
The amendments to the claims raise new grounds for rejection. This Office Action is final.
Priority
2. USAN 17/759,282, filed 07/21/2022, is a National Stage entry of PCT/CN2021/ 073347, International Filing Date: 01/22/2021, claims foreign priority to PCT/ CN2020/073960, filed 01/23/2020.
Information Disclosure Statement
3. As of 3/10/2026, a total of four (4) IDS are filed: 3/30/2023; 11/22/2024; 8/14/2025; and 12/30/2025. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Objections
Specification
4. The objection to the disclosure because of informalities is withdrawn. Clean substitute and marked-up copies of the specification are filed.
a) The specification is amended to rectify the improper use of the term, i.e., BiaCore, UniProt, GenBank, Alexa, CytoFlex, GraphPad, SAFEbody, MabSelect, TSKGel, HiTrap, BiTE, which is a trade name or a mark used in commerce
b) The comments about the additional amendments to the specification (and outside of the scope of the Examiner’s objections) on p. 15 of the Response of 12/30/2025 are considered and entered.
Claim Objections
5. The objections to Claims 1-11, 16, 18, 24-25, 29, 32(a), 34, and 42-47 because of informalities is moot for the canceled claims and withdrawn for the pending claims.
a) Claims 1-11, 16, 18, 24-25, 29, 32(a), 34, and 42-47 are amended to recite “wherein the amino acid position numbering is based on EU numbering.”
b) Claims 1-11, 16, 18, 24-25, 29, 32(a), 34, and 42-47 are amended in Claim 1 to clarify the CH3 domains are an IgG isotype.
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
6. The rejection of Claims 1, 3-8 and 45 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is moot for the canceled claims and withdrawn for the pending claims.
a) Claims 1 and 3-8 are amended to delete not only the romanette numbering but both the text for each of original romanette (ii) and (iii).
b) Claim 3 from which Claim 6(iii) depends is amended to provide the proper antecedent basis for the limitation in claim 6(iii).
c) Claim 3 from which Claim 8(iii) and (iv) depend is amended to provide the proper antecedent basis for the limitation in Claim 8(iii) and (iv)
d) Claim 45 is amended to delete the limitation "or vector".
Rejections Maintained-in-Part/ Withdrawn-in-part
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
7. The rejection of Claim 47 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in part and maintained-in-part.
Withdrawn in part: claim 47 is amended to replace disease or condition with “cancer.”
Maintained in part: claim 47 does not define the minimum essential residues for an antigen binding aspect of the heterodimeric protein of claim 34. None of claim 34 or the claims from which it depends reference the anti-HER x anti-CD3 constructs with Fc mutations of the invention.
Applicants allege as being fully supportive of the claimed invention the results from Example 8 of the Specification that exemplifies construct TY24051. TY24051 is a bispecific antibody of an IgG (IgG1) isotype comprising a Fab that specifically targets HER2 and an scFv that specifically targets CD3, wherein the Fc heterodimeric motif is TYM13, which includes a cysteine residue at position 400 of the first CH3 domain and a cysteine residue at position 390 of the second CH3 domain. As shown in FIG. 19, TY24051 construct shows dose-dependent killing of HER2- positive tumor cells SKOV3.
Response to Arguments
It is noted that the features upon which applicant relies (i.e., the protein structure for the TY24051 clone) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The interpretation encompasses a genus of anti-HER x anti-CD3 constructs with Fc mutations that correspond to the structure of claims 24, 29, 32 and 34 that include masking peptides aside from conventional heavy and light chains
of the invention and beyond those taught in the specification. Because applicant seeks patent protection for all such constructs, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Status of the Art for Antibodies
Methods of preparing antibodies from a variety of species to a protein or peptide of interest were well-established in the art at the time the invention was made. But application of those methods to any given antibody was still a matter of trial-and-error testing, and the skilled person could not automatically predict which residues in the CDRs would be tolerant of mutations, or which amino acid substitutions would maintain antigen binding. Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. For example, it is generally the case that absent the fundamental structure provided for by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, a person of ordinary skill cannot visualize or otherwise predict, what an antibody with a particular set of functional properties would look like structurally.
Has Applicant provided a common structure sufficient to visualize the genus?
Applicant has not provided a common structure sufficient to visualize the genus of all possible functional constructs but for the TY24051 clone. One of ordinary skill in the art would have understood what clones functioned similarly, and would not have known which VH and VL domains could be paired and masked to the extent the construct performed in a predictable manner.
Therapeutic antibodies such as those instantly claimed are still not understood well enough to allow researchers to predict with certainty what modifications can be made to a primary antibody sequence such that binding is maintained. “[T]he major test of understanding is whether the changes associated with antibody maturation can be predicted with any reasonable accuracy, and whether there is sufficient information for developing therapeutic antibodies,” Vajda et al., “Progress toward improved understanding of antibody maturation,” Current Opinion in Structural Biology, 67 pp. 226-231 (2021 (PTO 892)) at p. 226, col. 2, lines 20-24.
As recently as 2020, researches were still speculating as to how to reliably identify further putative binders from antibody sequence data, see, e.g., Marks et al., “How repertoire data are changing antibody science,” J. Biol. Chem. 295(29) 9823-9837 (2020 (PTO 892)), acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” p. 9831, col. 2, para. 2.
Computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” (Akbar et al., Cell Reports 34, 108856, Mar. 16, 2021 at p. 2, col. 2, para. 2 (PTO 892)). The current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics volume 22, Article number: 116 (2021 (PTO 892)) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
It is asserted that neither the specification nor the state of art at the time of filing disclosed structural features common to the members of the genus for reliably assigning different antibody structures based on sequence data for one antibody clone, which would support the premise that the inventors possessed the full scope of the claimed method of treatment invention.
Rejections Maintained
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.
8. The rejection of Claim(s)
A) Applicants allege Table 1 of Kannan merely recites residues involved in the CH3-CH3 domain interaction based on which residues have side chain heavy atoms positioned closer than 4.5A with the heavy atoms of other residues. Kannan only exemplifies an Fc fusion construct lacking the hinge region and comprising a Y349C/S354C substitution, demonstrating that "the pharmacokinetics of Fc fusion proteins lacking a hinge region are significantly improved by the introduction of a disulfide bond into the CH3 interface."
Response to Arguments
Kannan specifically teaches and claims 1. A polypeptide comprising an antibody Fc region, said Fc region comprising a deletion or substitution of one or more cysteines of the hinge region and substitution of one or more CH3 -interface amino acids with a sulfhydryl containing residue. The crux of the Kannan invention is substitution with a sulfhydryl-containing residue of one or more CH3-interface amino acids where Table 1 identifies the candidate residues of the instant broadly claimed Fc region, namely, 390C and 400C in paired CH3 domains.
In Table 1, Kannan specifically teaches substitution for each of ASN (N)390 and Ser(s)400 with cysteine as contacting residues in chain A and B for each of the CH3 domains.
“at least a portion of an immunoglobulin hinge region”: the plain meaning of newly amended Claim 1 can be reasonably construed as a partial structure or a portion of a hinge. Kannan’s disclosure is dispositive to the removal of the hinge specifically where Kannan teaches the combination of partial hinges with disulfide bonded CH3 domains
“Described herein are methods of improving stability of antibody Fc scaffolds, particularly Fc scaffolds lacking the hinge region, lacking a portion of the hinge region that forms disulfide bonds, or wherein the hinge region contains substitution of one or more cysteine residues. Such methods involve introducing one or more engineered disulfide bonds at the CH3 domain interface.”
“In other embodiments, only a portion of the hinge region is deleted, preferably a portion comprising the cysteine residues.”
B) Applicants allege the 390C+400C substitution pair has been consistently shown to demonstrate heterodimer-driving contribution.
Response to Arguments
Kannan’s disclosure is dispositive to Applicants assertion that heterodimers are not resultant from the CH3-interface comprising C-C bonds. Kannan specifically teaches the cysteine substitutions serve as a “cysteine clamp” in the formation of heterodimeric CH3-interface:
“Positions Y349 and S354 are juxtaposed in the WT Fc CH3 interface. In a Fc heterodimer, one CH3 region may contain a Y349C substitution and the other CH3 region may contain a S354C substitution. The stability of charged pair heterodimers comprising the (Y349C/S354C) cysteine clamp mutations was found to be superior to heterodimers that did not comprise the cysteine clamp. In particular, the monomers of a charged pair heterodimers without a cysteine clamp were observed in separate bands on SDS-PAGE, while the charged pair heterodimers with the cysteine clamp mutation were observed in a single band. The same was true of charged pair heterodimers comprising a (L351C/L351C) cysteine clamp mutation.”
Because the disulfide bond involves the same residue in both chains, both the T394 and L351 sites are applicable to WT Fc homodimers as well as engineered Fc heterodimers, such as Fc chains with knobs-into-holes, or charged pair mutations.
Applicants have not provided sufficient rebuttal evidence much less in view of the currently amended claims to establish by a preponderance of the evidence that the claims are nonobvious over Kannan. Applicants have not shown with intrinsic or extrinsic evidence of a heterodimeric protein comprising a portion of an Ig hinge and CH3-interface cysteine substitutions at positions 390 and 400 yields unexpected or surprising results over the generic teachings of Kannan.
The rejection is maintained.
9. The rejection of Claim(s) 32(a) and 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kannan et al (WO 2015/017548; 2/5/2015; Amgen) as applied to claims 1, 16, 24 and 29 above, and further in view of Davis et al. (WO 2007/110205; 10/4/2007; MERCK PATENT GMBH) is maintained.
Applicants allege the teachings of Kannan are stated above. Davis does not cure the deficiencies of Kannan. The only reference to positions 390 and 400 in Davis is used in a structural alignment to align human IgG and human IgA sequences (see Table 2 of Davis).
Response to Arguments
Applicants have not provided sufficient rebuttal evidence much less in view of the currently amended claims to establish by a preponderance of the evidence that the claims are nonobvious over Kannan. Applicants have not shown with intrinsic or extrinsic evidence of a heterodimeric protein comprising a portion of an Ig hinge and CH3-interface cysteine substitutions at positions 390 and 400 yields unexpected or surprising results over the generic teachings of Kannan.
Davis teaches heterodimeric IgG- and IgA-containing CH3 domains in an engineered structure where a cysteine forms a disulfide bond between each of the CH3 domains:
The multidomain protein comprises a first subunit comprising the first engineered domain and a second subunit comprising the second engineered domain. The naturally occurring homologous parent domains are immunoglobulin superfamily domains, which are antibody CH3 domains. Preferably, the CH3 domains comprise IgG and IgA CH3 domains. The first and second engineered domains are part of polypeptide chains that are associated by a disulfide bond. One of the first and second engineered domains comprises at least two non-adjacent sequence segments derived from the same parent domain. Each of the amino acid sequence segments comprises two or more amino acids. The protein-protein interaction interface of the first engineered domain comprises at least two amino acids from each parent domain. The multidomain protein also comprises a first bioactive domain, where the first bioactive domain occupies a position N-terminal of the first engineered domain. The first bioactive domain comprises an antibody variable domain. The multidomain protein further comprises a second bioactive domain, where the second bioactive domain occupies a position C-terminal of the first engineered domain. The second bioactive domain also comprises a second antibody variable domain with distinct specificity. Alternatively, the multidomain protein comprises at least first and second non-identical engineered domains that meet at an interface, the interface of each of the first and second engineered domains comprising at least two amino acid sequence segments, each derived from a different naturally-occurring homologous parent domain, thus conferring a assembly specificity distinct from the assembly specificity of the parent domains, where the first and second engineered domains form heterodimers with one another preferentially over forming homodimers. Alternatively, the multidomain protein comprising at least first and second non-identical engineered domains that meet at an interface, where (a) the first and second engineered domains are derived from two or more naturally-occurring homologous parent domains, (b) the interface from the first engineered domain comprises at least one amino acid sequence segment interacting with an amino acid sequence segment on the interface of the second engineered domain derived from the same parent domain, and (c) the first and second engineered domains form heterodimers with one another preferentially over forming homodimers. In the multimeric protein, the domain is part of a polypeptide chain that comprising a cysteine that forms a disulfide bond that enhances multimerization. Preferred Molecule: The bioactive domain is an antibody CH3 domain, a CH2-CH3 domain, or a CH1-CH2-CH3 domain.
Davis claims 1. A multidomain protein comprising at least a first and a second nonidentical engineered domain, each of the first and the second engineered domain containing a protein-protein interaction interface comprising amino acid sequence segments derived from two or more naturally occurring homologous parent domains, thereby conferring on said first and second engineered domains assembly specificities distinct from assembly specificities of the parent domains, wherein the first and second engineered domains form heterodimers with one another preferentially over forming homodimers.
Davis claims 5. The multidomain protein of claim 4, wherein the CH3 domains comprise IgG and IgA CH3 domains.
6. The multidomain protein of any of the claims 1 - 5, wherein the first and second engineered domains are part of polypeptide chains that are associated by a disulfide bond.
Davis teaches “The CH3 homodimer forms a dimerization interface between D sheets. It is important to find two CH3 domains that have significant differences in this interface, in order to make an effective pair of SEEDs that will preferentially heterodimerize.” Of note is that the interface shown in Table 2 of Davis for the 390/400 are identified as interface residues that effect the formation of heterodimers.
Applicants have not identified with sufficient technical distinction that the reference art teaches structures that are so distinct from the instant claimed.
The rejection is maintained.
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.
10. The provisional rejection of Claims 1-11, 16, 18, 24-25, 29, 32(a), 34, and 42-47 on the ground of nonstatutory double patenting as being unpatentable over claim 56 of copending Application No. 18/855,066 (reference application US 20250257133) is moot for the canceled claims and maintained for the pending claims.
Applicants request that the provisional rejection is held in abeyance is granted. The response is incomplete.
New Grounds for Rejection
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.
11. Claims 1-3, 5-10, 16, 24-25, 29, 32, 34, 42-47, and 51 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.
Claims 1-3, 5-10, 16, 24-25, 29, 32, 34, 42-47, and 51 are indefinite for the phrase “a least a portion of an immunoglobulin hinge region.” The specification provides literal support for the phrase but does not define what portion is retained or removed from a hinge as a whole. The POSA cannot reasonably ascertain the metes and bounds of the invention.
Conclusion
12. No claims are allowed.
13. 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.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643