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 .
Claims Status
The Election filed 21Jul2025, was previously acknowledged and entered. Applicant elected a species of multispecific antibody comprising a “polypeptide chain of Formula (I): VH-CH1-(CH2)S-(CH3)T-X-(V1 )P; and a polypeptide chain of formula (II): (V3)r-Z-VL-CL-Y-(V2)q; wherein: p =1, q =1, r =0, V1 = dsscFv, V2 = dsscFv, V3 (not present if r=0) but if r were 1, dsscFv”.
The Amendment filed on 25Nov2025 is acknowledged in which (1) claim(s) 24 is/are canceled by Applicant, (2) claim(s) 28 is/are new, and (3) Applicant’s amendments have canceled the species of multispecific antibody which was previously elected in the Response to the Election of Species Requirement mailed 03Jun2025. The antibody corresponding to the species of multispecific antibody comprising polypeptide chain of Formula(I): VH-CH1 and Formula (II): VL-CL-Y-V2 , as recited in instant claim 1 filed on 25Nov2025 are rejoined for prosecution and under consideration herein. Claim(s) 6, 10, and 12-16 is/are withdrawn as being drawn to non-elected species.
Claim(s) 1-5, 7-9, 11, 17-23, and 25-28 is/are pending and presented for examination on the merits.
Response to Amendment and Arguments
The objection(s) to claim(s) 1, 18, and/or the specification have been withdrawn in view of the Amendment filed on 25Nov2025.
The rejection(s) of claim(s) 16 under 35 U.S.C. § 112(a), of claim(s) 1-11, 16-23, 25-57 under 35 U.S.C. § 112(b), of claim(s) 1-3, 8, 10-11, 17, 19-23, 25, 27 under 35 U.S.C. § 102, and of claim(s) 4-7, 18 under 35 U.S.C. § 103 have been withdrawn in view of the recent claim amendment filed on 25Nov205, which canceled the previously elected species and necessitates new rejections and/or objection(s).
As all previously presented rejection(s) and/or objection(s) have been withdrawn, Applicant arguments are not addressed herein.
Rejections/Objections Maintained/New Rejections Necessitated by Claim Amendments
Claim Rejections - 35 USC § 112(b)
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 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.
Claim(s) 26-27 is/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 26, step “c”, recites the limitation "s is 1 and t is 1" in line 9 and “s is 0 and t is 0” in line 11. There is insufficient antecedent basis for this limitation in the claim. For the purposes of compact prosecution, claim 26 step c will be considered to read “obtaining a composition of polypeptide chains of formula (I) and polypeptide chains of formula (II). Applicant can overcome this rejection by amending the claim to remove limitations without antecedent basis.
Claim 27, step “a”, recites the limitation "s is 1 and t is 1" in lines 5-6 and “s is 0 and t is 0” in line 7. There is insufficient antecedent basis for this limitation in the claim. For the purposes of compact prosecution, claim 27 step a will be considered to read “obtaining a composition of polypeptide chains of formula (I) and polypeptide chains of formula (II). Applicant can overcome this rejection by amending the claim to remove limitations without antecedent basis.
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 1-5, 7-8, 11, 17, 19-22, and 26-28 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2018/0100007 A1 (hereinafter “US007”).
Regarding instant claims 1-5, 7-8, 11, US007 teaches a multispecific antigen-binding protein comprising one polypeptide of the formula VH-CH1, and a second polypeptide of the formula VL-CL-Linker-scFv [e.g., ¶ 0030, 0107-0109, 0131; fig. 29]. US007 further teaches that the Fab, the dsscFv, or both comprise a VH3 domain and that protein A binds VH3 [e.g., abstract; ¶ 0003-0005, 0032-0066, 0073, 0095-107, 0134].
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Regarding instant claims 17, US007 further teaches the Fab-dsscFv are joined by a peptide linker [e.g., ¶ 0132].
Regarding instant claims 19-22, US007 further teaches the antibody is expressed in CHO host cells via one or more vectors encoding the recombinant antibody (e.g., comprising polynucleotide encoding the antibody) [e.g., ¶ 0110, 0157, 167, 0174; claim 13].
Regarding instant claim 26, US007 further teaches a method of producing the multispecific antibody comprise expressing the polypeptide(s) in a host cell, recovering the mixture (e.g., comprising monomers and dimers), and applying the mixture to a protein a affinity chromatography column for purification [e.g., ¶ 0006, 0020; examples 1, 3-6; claim 13].
Regarding instant claim 27, US007 further teaches methods of purifying the multispecific antibody [e.g., ¶ 0008, 0125]. US007 teaches the method of multispecific antibody purification comprises obtaining a mixture of formula (I) and (II) polypeptide chains (see claim 26 rejection above), loading the composition on a protein a column, , washing the protein a column, eluting the multispecific antibody, and recovering the multi-specific antibody [e.g., examples 1, 3-6].
Regarding instant claim 28, US007 further teaches the CL is C Kappa [e.g., ¶ 0104].
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.
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0100007 A1 (hereinafter “US007”) as applied to claim 1 above, and further in view of Bach et al. (J. Chromatogr. A 1409 (2015) 60–69; hereinafter “Bach”), as evidenced by Brinkmann and Kontermann (mAbs. 2017, VOL. 9, NO. 2, 182–212; hereinafter “Brinkmann”).
The teachings of US007 as recited above apply for claim 1.
US007 does expressly not teach a VH3 domain variant that does not bind protein A.
Regarding instant claim 9, Bach teaches that nearly half of all human VH genes belong to the VH3 subfamily [e.g., introduction]. Bach teaches VH3 variants (e.g., a residue 57 substitution) that do not bind protein A [e.g., pg. 61, col 1, para 2; pg. 64, col 2, para 2; pg. 67, “discussion”].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute a VH3 variant that does not bind protein A in place of the VH of the dsscFv fused to the light chain (e.g., instant “V2”) of the multispecific antibody as taught by US007, in the context of designing and developing a multispecific antibody. A PHOSITA would have been motivated to substitute a VH3 variant that does not bind protein A in place of the VH of the dsscFv fused to the light chain (e.g., instant “V2”) of the multispecific antibody as taught by US007, because Bach teaches nearly half of all human-derived VH are of the VH3 subfamily, and a PHOSITA would understand that VH3 is bound by protein A, which is commonly used to purify engineered antibodies (see 102 rejection above). Further, a PHOSITA would understand that LC domains (e.g., VL, CL) don’t bind with protein A, as evidenced by Brinkmann (see pg. 192 “post-assembly approaches…”), and therefore a PHOSITA would also understand the benefit to engineering the dsscFv attached to the LC domain such that it doesn’t bind protein A either in order to avoid unnecessary LC only (e.g., undesired) fragments binding the protein A column along with the desired multispecific antibody (e.g., reduces possible LC contaminants from binding the purification column). There would have been a reasonable expectation of success for a PHOSITA to substitute a VH3 variant that does not bind protein A in place of the VH of the dsscFv fused to the light chain (e.g., instant “V2”) of the multispecific antibody as taught by US007, because Bach teaches the VH3 variant does not bind protein A. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0100007 A1 (hereinafter “US007”) as applied to claim 1 above, and further in view of Brinkmann and Kontermann (mAbs. 2017, VOL. 9, NO. 2, 182–212; hereinafter “Brinkmann”).
The teachings of US007 as recited above apply for claim 1.
US007 further teaches protein A purification of antibody proteins [e.g., para 0433].
US007 does expressly not teach the scFv disulfide stabilization comprises VH44 and VL100 cysteine substitutions.
Regarding claim 18, Brinkmann teaches the making of bispecific (e.g., multispecific) antibodies, and an engineered VH3 derived VH domain (e.g., in a dsscFv) for the separation of heterodimeric (e.g., multispecific) antibodies by protein A [e.g., title; abstract; pg. 192, “post-assembly approaches…”]. Brinkmann further teaches changing residues VH44 and VL100 to cysteine to generate a disulfide stabilized scFv (e.g., a dsscFv) [e.g., pg. 185, col 1, para 1].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to modify the dsscFv(s) of the multispecific antibody taught by US007, to include the VH44 and VL100 cysteine substitutions to generate dsscFv(s) as taught by Brinkmann, to generate a multispecific antibody with disulfide stabilized scFv domain(s). A PHOSITA would have been motivated to substitute the VH44 and VL100 cysteine substitutions to generate a dsscFv as taught by Brinkmann in place of the dsscFv domain(s) of the multispecific antibody taught by US007, because while US007 teaches a multispecific antibody comprising a dsscFv, it does not teach the specific mutations to make a dsscFv, and Brinkmann teaches specific VH and VL cysteine substitutions to make a dsscFv. There would have been a reasonable expectation of success for a PHOSITA to substitute the VH44 and VL100 residues for cysteines in the dsscFv domain(s) of the multispecific antibody taught by US007 to generate a dsscFv as taught by Brinkmann, because while US007 teaches a multispecific antibody comprising a dsscFv it doesn’t teach the scFv substitutions to make a dsscFv, and Brinkmann teaches the specific VH and VL residue modifications in an scFv to make a dsscFv. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 23, 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0100007 A1 (hereinafter “US007”) as applied to claim 1 above, and further in view US 2018/0237521 A1 (hereinafter “US521”).
The teachings of US007 as recited above apply for claim 1.
US007 further teaches protein A purification of antibody proteins [e.g., para 0433].
US007 does expressly not teach (1) a pharmaceutical composition comprising the multispecific antibody and at least one excipient, or (2) a method of treating a patient in need therefor comprising administering a therapeutically effective amount of the multispecific antibody.
Regarding claim 23, US521 teaches a pharmaceutical composition comprising a multispecific antibody and a pharmaceutically acceptable excipient [e.g., ¶ 0648-0649, 0655-0658, 0679, 0707, 0716], and further teaches the multispecific antibody is a fab-dsscFv [e.g., ¶ 0755-0761]. Regarding claim 25, US521 further teaches a method of treating a patient comprising administering a therapeutically effective amount of antibody molecule or pharmaceutical composition comprising the antibody.
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to combine the Fab-dsscFv antibody as taught by US007, with the (1) a pharmaceutical composition comprising the multispecific antibody and at least one excipient, and/or (2) a method of treating a patient in need therefor comprising administering a therapeutically effective amount of the multispecific antibody as taught by US521, in the context of designing and developing a Fab-dsscFv antibody therapeutic. A PHOSITA would have been motivated to combine the Fab-dsscFv antibody as taught by US007, with the 1) a pharmaceutical composition comprising the multispecific antibody and at least one excipient, and/or (2) a method of treating a patient in need therefor comprising administering a therapeutically effective amount of the multispecific antibody as taught by US521, because both US007 and US521 teach Fab-dsscFv multispecific antibodies, US007 focuses on the expression and purification of the multispecific antibodies but does not teach uses thereof, and US521 teaches therapeutic uses for multispecific antibodies. There would have been a reasonable expectation of success for a PHOSITA to combine the Fab-dsscFv multispecific antibody as taught by US007 with (1) the pharmaceutical composition comprising a Fab-dsscFv, and/or (2) methods of treating comprising Fab-dsscFv administration as taught by US521 because both US007 and US521 teach Fab-dsscFv multispecific antibodies, and US521 teaches therapeutic compositions and uses thereof. This rationale aligns with the principle of applying a known technique to a known method to yield predictable results, supporting a conclusion of obviousness (see MPEP § 2143).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are currently allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu 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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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643