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 1-27 are the original claims filed 3/21/2023. In the Preliminary Amendment of 8/7/2023, Claims 4, 6, 9, 11, 12, 15-17, 19, 20, 24, 25, and 27 are amended and claims 7-8, 13-14, 18, 22-23, and 26 are cancelled. In the Response of 5/15/2026, claims 1, 6, 16-17, 19-20, 25, and 27 are amended and new claims 28-30 are added.
Claims 1-6, 9-12, 15-17, 19-21, 24-25, and 27-30 are pending.
Applicants amendment of the claims raises new grounds for rejection. The Office Action is final.
Priority
2. USAN 18/124,096, filed 03/21/2023, is a Continuation of PCT/US2021/051047, filed 09/20/2021, PCT/US2021/051047 Claims Priority from Provisional Application 63/080,950, filed 09/21/2020. The priority date of 09/21/2020 is granted.
Information Disclosure Statement
3. AS of 6/30/2026, a total of two (2) IDS are filed: 0/29/2023; and 9/30/2025. The corresponding initialed and dated 1449 forms are considered and or record.
Withdrawal of Objections
Specification
4. The objections to the disclosure because of informalities is withdrawn. Clean and marked-up copies of the specification are filed.
a) The amended specification rectifies the improper use of the term Capto, Tris, Orion, UNIX, MEGALIGN, DNASTAR, BiTE, which is a trade name or a mark used in commerce.
b) The specification is amended to replace “…a conductivity of about 100 mS/cm.”
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
5. The rejection of Claims 6 and 16 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
a) Claim 6 is amended to delete the trademark/trade names CaptoTM Adhere resin and CaptoTM Adhere ImpRes resin.
b) Claim 16 is amended to depend from claim 11 to rectify the deficiency for insufficient antecedent basis for the limitation in claim 16.
Rejections Maintained
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
6. The rejection of Claims 1-6, 9-12, 15-17, 19-21, 24-25, and 27-30 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 maintained. New claims 28-29 are joined and that depend from the previously rejected claims.
A) Applicants allege claim 1 is amended to clarify that the claimed methods relate to “bispecific IgG CrossMab antibodies.” Applicant submits that claim 1, as amended, clarifies the structure of the antibodies being purified. In addition, the instant specification discloses methods for purifying the CrossMab antibodies from specific mispaired variants, as illustrated, for example, in Figure 2B.
Response to Arguments
It is incorrect that the claims are amended to recite bispecific IgG CrossMab antibodies. The amended claims recite a bispecific IgG CrossMab multispecific antibody. The specification does not differentiate a bispecific antibody from a multispecific antibody at
[0056] A “bispecific antibody” is a multispecific antibody comprising an antigen-binding domain that is capable of specifically binding to two different epitopes on one biological molecule or is capable of specifically binding to epitopes on two different biological molecules. A bispecific antibody may also be referred to herein as having “dual specificity” or as being “dual specific.” Unless otherwise indicated, the order in which the antigens bound by a bispecific antibody are listed in a bispecific antibody name is arbitrary. In some embodiments, a bispecific antibody comprises two half antibodies, wherein each half antibody comprises a single heavy chain variable region and optionally at least a portion of a heavy chain constant region, and a single light chain variable region and optionally at least a portion of a light chain constant region. In certain embodiments, a bispecific antibody comprises two half antibodies, wherein each half antibody comprises a single heavy chain variable region and a single light chain variable region and does not comprise more than one single heavy chain variable region and does not comprise more than one single light chain variable region. In some embodiments, a bispecific antibody comprises two half antibodies, wherein each half antibody comprises a single heavy chain variable region and a single light chain variable region, and wherein the first half antibody binds to a first antigen and not to a second antigen and the second half antibody binds to the second antigen and not to the first antigen.
The POSA cannot reasonably ascertain what additional structure(s) is encompassed within the multispecific aspect of the claimed antibody as a whole.
B) Applicants allege on p. 9, line 1 of the Response of 5/15/2026 “the Examiner recognizes that Figure 3 discloses conditions relevant to the instant claims.”
Response to Arguments
Applicants are requested to identify by exact page and line number in the OA of 2/18/2026, where any explicit or implicit acknowledgment by the Office is made towards Figure 3 disclosing relevant conditions for the method.
C) Applicants allege Figure 3 provides details regarding the multi-mode chromatography and exemplifies the claimed methods and to which claim 1 has been amended to clarify the conditions under which the mispaired variant preferentially binds the multi-mode chromatographic material relative to the bispecific IgG CrossMab antibody.
Response to Arguments
None of the claims recite a concentration range or an amount for the generic bispecific IgG CrossMab multispecific antibody and Figure 3 is silent on (i.e., does not teach or suggest) a concentration range or an amount for the purported universal bispecific IgG CrossMab multispecific antibody. Applicants have not responded to the art references from the OA of 2/18/2026 that identify the challenges of multi-mode chromatography for selection of antibodies. The response is incomplete.
“Prior art status of multi-mode chromatography for antibodies
Further in view of the insufficient information for the single aAgA/aAgB prototype described in the specification are the caveats of using multi-mode (mixed-mode) chromatography on just any antibody. The challenges for different antibody isotypes in multimode chromatography include the need for tailored purification strategies to address the unique properties and characterisics of each isotype. For instance, the structural similarities between monoclonal antibodies and bispecific antibodies require careful selection of chromatographic interactions and resins to ensure effective separation and purification. Additionally, the need for high selectivity and versatility in chromatography tools is crucial to overcome the challenges posed by the diverse structures of bsAbs. (Yoshikawa, iptonline.com/collections/ipt-spring-2025/overcoming-challenges-in-bispecific-antibody-production-with-mixed-mode-chromatography-and-scalable-purification-solutions-spring-2025).
Multimodal chromatography has emerged as a powerful method for the purification of therapeutic antibodies. However, process development of this separation technique remains challenging because of an intricate and molecule-specific interaction towards multimodal ligands, leading to time-consuming and costly experimental optimization. (Hess et al., J. Chromatography A, Volume 1718, 15 March 2024, 464706).
The POSA is not reasonably apprised of the full breadth and scope of the claimed method envisaged by Applicants where description of the actual multispecific antibody is not divulged nor are the detailed steps used in the practice of the purification for the single limited prototype of Example 1 much less the criticality of the order in which they are performed.”
Applicants admission of record on pp.10-11 of the Response of 5/15/2026 substantiates the unpredictability of the species of CrossMab much less the single method step invention. Applicants aver that the “bispecific CrossMab multispecific antibody variant species comprising the co-localized, negatively charged residues [are what] gives rise to its distinctive surface properties” and that “Given the complex and unpredictable nature of mispaired CrossMab antibodies, a person of ordinary skill in the art would have had no reasonable expectation that this specific CrossMAb species could be selectively removed using the claimed [single-step selective clearance] methods.” Herein again, none of the claims define by sequence the antibody species of CrossMab much less the variant thereof in order to appreciate the single-step selection method associated with cluster patterns of residues. Notably, if the co-localized, negatively charged residues (“mutations”, p. 10, line 13 of the Response) are what constitute the symbols shown in Figure 2A:
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, the POSA cannot even reasonably ascertain what those residues comprise.
D) Applicants further state the co-location of three negatively charged mutations on the heavy and light chains produces a distinct, negatively charged surface patch on the mispaired Fab arm (see Figure 2B); this selective interaction likely arises from the combined effects of (i) an anion-exchange component interacting with the negatively charged patch in the constant domain, and (ii) a hydrophobic interaction component engaging exposed hydrophobic residues revealed by denaturation of the variable domain.
Response to Arguments
In response to applicant's arguments, it is noted that the features upon which applicant relies (i.e., 3 negatively charged mutations; negatively charged patch; and hydrophobic residues) 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).
None of the claims are drawn to the co-localization of negatively charged residues that give[s] rise to its distinctive surface properties of the claimed CrossMAb variant species or its selective purification.
MPEP (II)(A)(3)(a)
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that inventor was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that “if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function”.). “Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function.” Id.
Because Applicants admission on the record is that the invention is unpredictable, then by logic, there is NOT a well-established correlation between structure and function.
The rejection is 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.
7. The rejection of Claim(s) 1-2, 6, 9, 11-12, 15-17, 19-21, 24-25 and 27 under 35 U.S.C. 103 as being unpatentable over von Hirschheydt et al (US 11945839; 2018-12-20) is maintained.
Applicants allege the claims are directed to a particular CrossMab variant characterized by light chain mispairing (Fig 2B), the particular variant is not taught by the reference, and the mismatched species can be removed by a single chromatographic step.
Response to Arguments
von Hirschheydt teaches a multispecific CrossMab antibody and a LC mispaired variant thereof (i.e., one or more light chains are paired with a non-complementary heavy chain) are separately eluted from a mutli-mode medium, thereby separating the multispecific CrossMab antibody from the LC mispaired variant.
von Hirschheydt teaches a single step multi-mode approach combining hydrophobic functional groups (HIC) with anion exchange
(98) Examples of chromatographic unit operations with which the HIC can be combined according to the methods of the invention include, but are not limited to, chromatographic unit operations comprising the use of solid phases (e.g., resins) that selectively bind to one or more components of a load fluid via cation exchange, anion exchange, hydrophobic interaction, hydrophilic interaction, hydrogen bonding, pi-pi bonding, metal affinity and/or specific binding via biomolecules (e.g., affinity resins comprising immunoglobulins, immunoglobulin fragments, and enzymes).
Examiner’s comment: what Applicants allege to be a distinguishable feature between the reference and the instant claims is NOT even recited in the claims, namely, “the co-localization of negatively charged residues that gives rise to its distinctive surface properties” Accordingly, Applicants comments are irrelevant to this end.
Examiner’s comment: at least Figure 1F in von Hirschheydt teaches a CrossMab with a mispaired LC.
The rejection is maintained.
8. The rejection of Claim(s) 3-5 under 35 U.S.C. 103 as being unpatentable over von Hirschheydt et al (US 11945839; 2018-12-20) as applied to claim 1 above, and further in view of Yun et al (J Chromatogr A 2015 Feb 13:1381:173-83. doi:10.1016 /j.chroma. 2014.11.081. Epub 2014 Dec 4) is maintained.
Applicants make the general allegation that “none of the cited references teach or suggest the claimed CrossMab variant species or its selective purification” without specific mention of Yun.
The rejection is maintained for the reasons cited under section 7 and the original grounds.
9. The rejection of Claim(s) 10 under 35 U.S.C. 103 as being unpatentable over von Hirschheydt et al (US 11945839; 2018-12-20) as applied to claim 1 above, and further in view of Lee et al ((J Sep Sci. 2017;40:3632–3645) is maintained.
Applicants make the general allegation that “none of the cited references teach or suggest the claimed CrossMab variant species or its selective purification” without specific mention of Lee.
The rejection is maintained for the reasons cited under section 7 and the original grounds.
Withdrawn-in-part/ Maintained-in-part
Claim Objections
10. The objection to Claims 1-6, 9-12, 15-17, 19-21, 24-25, and 27 because of informalities is withdrawn-in-part for claims 1, 6, 9-12, 15-17, 19-21, 24-25, and 27 and maintained-in-part for claims 2-5.
Amended Claims 1, 6, 9-12, 15-17, 19-21, 24-25, and 27 delete “capable of” in Claim 1.
Claims 2-5 are NOT amended to delete the phrase “capable of.”
The objection is maintained.
New Grounds for Objections
Specification
11. The disclosure is objected to because of the following informalities:
a) The figure legend to Figure 2B is objected to for failing to explain the details depicted in the Figure, i.e., the encircled “+” and encircled “–“ that otherwise correspond to Claim 1, element i) 1) and 2), and element ii) 1) and 2).
Appropriate correction is required.
Claim Objections
12. Claims 1-3 are objected to because of the following informalities:
a) Amend claim 1 to recite “a hydrophobic
b) Amend claims 2-3 to recite “wherein the hydrophobic functional group
Appropriate correction is required.
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.
13. Claims 1-6, 9-12, 15-17, 19-21, 24-25, and 27-30 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.
A) Claims 1-6, 9-12, 15-17, 19-21, 24-25, and 27-30 are indefinite for the phrase “a bispecific IgG CrossMab multispecific antibody” in the amended claims throughout. The specification does not differentiate a bispecific antibody from a multispecific antibody at
[0056] A “bispecific antibody” is a multispecific antibody comprising an antigen-binding domain that is capable of specifically binding to two different epitopes on one biological molecule or is capable of specifically binding to epitopes on two different biological molecules. A bispecific antibody may also be referred to herein as having “dual specificity” or as being “dual specific.” Unless otherwise indicated, the order in which the antigens bound by a bispecific antibody are listed in a bispecific antibody name is arbitrary. In some embodiments, a bispecific antibody comprises two half antibodies, wherein each half antibody comprises a single heavy chain variable region and optionally at least a portion of a heavy chain constant region, and a single light chain variable region and optionally at least a portion of a light chain constant region. In certain embodiments, a bispecific antibody comprises two half antibodies, wherein each half antibody comprises a single heavy chain variable region and a single light chain variable region and does not comprise more than one single heavy chain variable region and does not comprise more than one single light chain variable region. In some embodiments, a bispecific antibody comprises two half antibodies, wherein each half antibody comprises a single heavy chain variable region and a single light chain variable region, and wherein the first half antibody binds to a first antigen and not to a second antigen and the second half antibody binds to the second antigen and not to the first antigen.
The POSA cannot reasonably ascertain what additional structure(s) is encompassed within the multispecific aspect of the claimed antibody as a whole.
B) Claims 1-6, 9-12, 15-17, 19-21, 24-25, and 27-30 recite the limitation "the bispecific IgG CrossMab antibody" in claim 1, element iv). There is insufficient antecedent basis for this limitation in the claim because claim 1 is also amended to recite a bispecific IgG CrossMab multispecific antibody.
Conclusion
14. No claims are allowed.
15. 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.
16. 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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu Julie can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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