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 .
Election/Restrictions
Claims 37, 40 and 44 are amended and claims 38, 39, 41 and 43 are newly canceled. Applicant's election with traverse of Group I in the reply filed on 06/12/2026 is acknowledged. The traversal is on the grounds that (1) claim 37 has been amended to include specific mutations on the engineered CAlpha and/or CBeta, which neither Xu et al. (WO2019057122) nor Jakobsen (US2005/0009025) teach and (2) there is no burden. Applicant’s amendment to claim 37 overcomes the prior art references of Xu et al. and Jakobsen, which were used to break unity. While Xu et al. teach the substitution of A18C on CBeta, they do not teach the substitution of P90C on CAlpha, thus Applicant’s argument that the art no longer anticipates or renders obvious the claims is persuasive and claim 55 will be rejoined. Regarding Applicant’s argument (2), for the record, burden is not a consideration in applications filed under 35 USC 371.
The restriction requirement between Groups I and II as set forth in the Office action mailed on 04/14/2026 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 37, 40, 42 and 44-56 are under examination.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The foreign priority document is in English. The priority date of the instant claims is 01/19/2021.
Drawings
The drawings filed 07/14/2023 are objected to because they are illegible in crucial areas. For instance, see Figures 12 and 13:
PNG
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535
2282
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Greyscale
PNG
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601
2260
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Greyscale
Further, the graphs and tables contain shading and the font sizes in some of the figures are too small to interpret.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities.
(i) The text in the tables is difficult to read, especially Tables 1, 10, 14, 18 and 22-24, where much of the font is too small to read and interpret. The specification must have text written plainly and legibly in portrait orientation and presented in a form having sufficient clarity and contrast between the paper and the writing thereon to permit the direct reproduction of readily legible copies in any number by use of photographic, electrostatic, photo-offset, and microfilming processes and electronic capture by use of digital imaging and optical character recognition; and only a single column of text. Text written in a non-script type font (e.g., Arial, Times Roman, or Courier, preferably a font size of 12) lettering style having capital letters which should be at least 0.3175 cm. (0.125 inch) high, but may be no smaller than 0.21 cm. (0.08 inch) high (e.g., a font size of 6) See 37 CFR 1.52(a) and (b).
(ii) The disclosure is also objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See p. 28, paragraph [00181] and p. 57, paragraph [00321]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Appropriate correction is required.
Claim Objections
Claims 55 is objected to because of the following informalities. Claim 55 recites “administrating to the subject”, which is grammatically awkward, and should be replaced by “administering”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 37, 40, 42 and 44-56 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.
Claim 37 has been amended to add the clause “and compared to a CAlpha comprising the sequence of SEQ ID NO: 10 and a CBeta comprising the sequence of SEQ ID NO: 11, the engineered CAlpha and the engineered CBeta have any of the following groups of mutations:
(i) P8C and D86C on CAlpha
(ii) P90C on CAlpha and A18C on CBeta
(iii) Q34C and I82C on CAlpha;
(iv) P8C and P84C on CAlpha;
(v) A9C and F88C on CAlpha;
(vi) V35C and S81C on CAlpha; or
(vii) S36C and S81C on CAlpha.
According to the instant specification, Table 1 (pages 58-60), the mutations to CAlpha set forth in parts (i)-(vii) of claim 37 correspond to SEQ ID NOs: 79/42, 80/50, 34, 36, 46, 30 and 32, respectively (i.e., SEQ ID NOs: 79 and 42 and 80 and 50 share the same mutations). The phrase, “a CAlpha comprising the sequence of SEQ ID NO: 10” in this context is interpreted as requiring all of SEQ ID NO: 10 without insertions or deletions for the entirety of the sequence, but that may contain additional unrecited residues outside of the sequence, i.e. added prior to the N-terminal or after the C-terminal of the polypeptide. In the instant case, however, SEQ ID NOs: 30, 32, 34, 36, 46 and 50 are all 91mer polypeptides missing the final four residues present on SEQ ID NO: 10, namely, PESS, or Pro-Glu- Ser-Ser. Therefore, SEQ ID NOs: 30, 32, 34, 36, 46 and 50 cannot be reasonably construed as comprising the sequence of SEQ ID NO: 10. The claim amendment is confusing because the claim language does not clearly set forth the actual limitations in the claim.
Regarding CBeta, the instant specification at Table 1 (pages 58-60) discloses that SEQ ID NOs: 31, 33, 35, 43 and 47 all comprise the sequence of SEQ ID NO: 11 and share 100% sequence identity with SEQ ID NO: 11. Instant SEQ ID NO: 51 differs from instant SEQ ID NO: 11 by a substitution of a C for an A at residue 20:
Query Match 99.5%; Score 773; DB 1; Length 141;
Best Local Similarity 99.3%;
Matches 140; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 1 LEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVCTD 60
||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||
Db 1 LEDLKNVFPPEVAVFEPSECEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVCTD 60
Qy 61 PQPLKEQPALQDSRYALSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQ 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PQPLKEQPALQDSRYALSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQ 120
Qy 121 IVSAEAWGRASDKTHTCPPCP 141
|||||||||||||||||||||
Db 121 IVSAEAWGRASDKTHTCPPCP 141
However, the specification and part (ii) of claim 37 state that the CBeta has an A18C substitution, rather than an A20C substitution. The instant specification discloses a paragraph [00149]:
As used herein throughout the application, “XnY” with respect to a TCR constant region is intended to mean that the nth amino acid residue X on the TCR constant region (based on the numbering in Figures 12-13 as provided herein) is replaced by amino acid residue Y, where X and Y are respectively the one-letter abbreviation of a particular amino acid residue.
Figures 12 and 13, however, are completely illegible, thus is not possible to interpret why the numbering differs from that of the sequence alignment. The claim language does not make clear how a substitution at residue 20 of SEQ ID NO: 11 is represented by a substitution at residue 18.
Further, the final three residues of instant SEQ ID NO: 37 are CTP, while the final three residues of SEQ ID NO: 11 are PCP. In other words, SEQ ID NO: 37 possesses an additional Thr residue inserted between the final Cys and Pro: Cys-Thr-Pro instead of Pro-Cys-Pro. Claim 37 recites “CBeta comprising the sequence of SEQ ID NO: 11”, which in this context is interpreted as requiring all of SEQ ID NO: 11 without insertions or deletions for the entirety of the sequence, but that may contain additional unrecited residues outside of the sequence, i.e. added prior to the N-terminal or after the C-terminal of the polypeptide. Again, the claim amendment is confusing because the claim language does not clearly set forth the actual limitations in the claims.
Claims 40, 42 and 44-56 are hereby included in this rejection for depending upon an indefinite claim without resolving the indefiniteness.
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.
Claim 55 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a condition that responds to a bispecific antibody directed to (1) PD-L1 and 4-1BB (2) HER2 D2 and HER2 D4, (3) IL-17 and IL-20 (4) IL-4 and IL-13, does not reasonably provide enablement for eliminating or preventing any condition or disease with any bispecific antibody. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” (See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 Fed. Cir. 1988) These factors include, but are not limited to: (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Claim 55 recites a method of treating a condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the polypeptide complex of claim 37, wherein the condition can be alleviated, eliminated, treated, or prevented when the first antigen and the second antigen are both modulated. The specification teaches that the first antigenic specificity may include (see paragraph [00177]):
CD3, 4-1BB (CD137), OX40 (CD134), CD16, CD47, CD19, CD20, CD22, CD33, CD38, CD123, CD133, CEA, cdH3, EpCAM, epidermal growth factor receptor (EGFR), EGFRvIII (a mutant form of EGFR), HER2, HER3, dLL3, BCMA, Sialyl-Lea, 5T4, ROR1, melanoma-associated chondroitin sulfate proteoglycan, mesothelin, folate receptor 1, VEGF receptor, EpCAM, HER2/neu, HER3/neu, G250, CEA, MAGE, proteoglycans, VEGF, FGFR, alphaVbeta3-integrin, HLA, HLA-DR, ASC, CD1, CD2, CD4, CDS, CD6, CD7, CD8, CD11, CD13, CD14, CD21, CD23, CD24, CD28, CD30, CD37, CD40, CD41, CD44, CD52, CD64, c-erb-2, CALLA, MHCII, CD44v3, CD44v6, p97, ganglioside GM1, GM2, GM3, GD1a, GD1b, GD2, GD3, GT1b, GT3, GQ1, NY-ESO-1, NFX2, SSX2, SSX4 Trp2, gp100, tyrosinase, Muc-1, telomerase, survivin, G250, p53, CA125 MUC, Wue antigen, Lewis Y antigen, HSP-27, HSP-70, HSP-72, HSP-90, Pgp, MCSP, EpHA2, cell surface targets GC182, GT468 or GT512, IL-17, IL-20, IL-13, and IL-4.
The specification also discloses that the first and second antigenic specificity may be the same or different (see paragraph [00224]). Any disease or condition that is treatable with any antibody is encompassed by the claimed method; thus, the claim is broad.
The specification teaches the inventive concept is to replace the antibody constant-region interface with modified TCR alpha/beta constant domains that are predisposed to form a stable heterodimer; thus, the antigen-binding moieties are conceptually interchangeable. The engineered CAlpha and CBeta include selected mutations, especially at the C-terminus or nearby contact regions, so the chains pair more tightly and can form non-native interchain bonds [0006]-[0008], [00139]-[00147]. In bispecific formats, this improved first binding arm is paired with a second antigen-binding moiety so the overall molecule assembles with fewer mis-paired species and better drug-like properties [00184]-[00190].
The MPEP 2164.02(I) instructs that the absence of working examples will not by itself render the invention non-enabled if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. Nevertheless, the claims encompass eliminating and/or preventing any disease. The term “preventing” is generally understood in the art to encompass a total protection from disease or injury. The term “eliminating” in this context encompasses curing. Thus, given the high level of required effect, a high level of evidence showing prevention or elimination is also required. The specification contemplates that the conditions or disorders may be “cancer or a cancerous condition, autoimmune diseases, infectious and parasitic diseases, cardiovascular diseases, neuropathies, neuropsychiatric conditions, injuries, inflammations, or coagulation disorder”. The specification does not provide evidence of prevention or elimination of any of these conditions or disorders.
Regarding cancer, according to the website, downloaded 08/17/2026 from the Cleveland Clinic (https://health.clevelandclinic.org/how-to-prevent-cancer) one can reduce one’s risk of cancer, but it is not completely preventable (see 1st paragraph). There are a number of dietary and lifestyle changes to reduce one’s risk of cancer (see Cleveland Clinic website), however, cancer risk is multifactorial; aging, random genetic mutations and hidden environmental exposures increase risk, thereby making total prevention impossible. Likewise autoimmune diseases are not preventable. For instance, Denk et al. (Arthritis Research & Therapy 2010, 12:R45) teach “[t]he chronic autoimmune disease RA is of unknown origin but finally leads to joint destruction” (p. 1, left column). In other words, it is not known who will develop rheumatoid arthritis; thus, it cannot be prevented with the claimed methods and products.
The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without such guidance, the changes which can be made and still maintain activity/utility are unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly extensive and undue. See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Int. 1986). The test of enablement is not whether any experimentation is necessary, but whether, if necessary, it is undue. Due to the large quantity of experimentation necessary to establish the encompassed conditions capable of being prevented or eliminated by the encompassed bispecific antibodies, the lack of direction/guidance presented in the specification regarding and the absence of working examples directed to the same, the complex nature of the invention, and the breadth of the claims which fail to recite limitations on the diseases treated and the bispecific antibodies with which they are treated, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
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 37, 40, 42, 44-54 and 56 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-5, 7-10, 12-14, 16, 20-26 of copending Application No. 19/607,777 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the method of detecting biproducts in a sample of a target asymmetric bispecific antibody recited in the claims of the reference application nevertheless encompasses the TCRs that share 100% sequence identity with instant SEQ ID NOs: 79 and 42 as well as all of the CBetas encompassed by the instant claims with the exception of SEQ ID NO: 51. For example, see the alignment between SEQ ID NO: 9 of the reference application and instant SEQ ID NO: 42:
US-19-607-777-9
Sequence 9, US/19607777
GENERAL INFORMATION
APPLICANT: WUXI BIOLOGICS (SHANGHAI) CO., LTD. (en)
TITLE OF INVENTION: IMAGED CAPILLARY ISOELECTRIC FOCUSING FOR DETECTING MISPAIRING BYPRODUCT IN ASYMMETRIC BISPECIFIC ANTIBODIES (en)
FILE REFERENCE: IEC240517PCT
CURRENT APPLICATION NUMBER: US/19/607,777
CURRENT FILING DATE: 2026-07-20
NUMBER OF SEQ ID NOS: 11
SEQ ID NO 9
LENGTH: 91
TYPE: PRT
FEATURE:
NAME/KEY: source
LOCATION: 1..91
QUALIFIERS: mol_type = protein
organism = synthetic construct
Query Match 100.0%; Score 482; Length 91;
Best Local Similarity 100.0%;
Matches 91; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 PDIQNPDCAVYQLRDSKSSDKSVCLFTDFDSQTQVSQSKDSDVYITDKCVLDMRSMDFKS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 PDIQNPDCAVYQLRDSKSSDKSVCLFTDFDSQTQVSQSKDSDVYITDKCVLDMRSMDFKS 60
Qy 61 NSAVAWSQKSDFACANAFQNSIIPECTFFPS 91
|||||||||||||||||||||||||||||||
Db 61 NSAVAWSQKSDFACANAFQNSIIPECTFFPS 91
The method recited in the claims of the reference application anticipate the instant claims because they encompass the same polypeptide complexes.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA M BORGEEST whose telephone number is (571)272-4482. The examiner can normally be reached M-F 9-5:30 EDT.
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, Jeffrey Stucker can be reached at 5712720911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675
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