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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 22Jun2026 has been entered.
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 22Jun2026 is acknowledged in which (1) claim(s) 24 is/are canceled by Applicant, and (2) 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 22Jun2026 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 Claim(s) 6, 10, and 12-16 is/are withdrawn as being drawn to non-elected species.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
All previous rejections have been withdrawn in view of the recent claim amendment filed on 22Jun2026, which added new limitations to the claims, requiring new rejections. Only arguments pertinent to the new rejections are addressed herein. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
NEW REJECTIONS/OBJECTIONS AS NECESSITATED BY AMENDMENT
Claim Objections
Claim(s) 2-5, 7-9, 11, 17-19, 22-23, 25-26 is/are objected to because of the following informalities: “A multi-specific antibody…” (e.g., line 1 of claims 2-5, 7-9, 11, 17-19; lines 2-3 of claims 22, 25; or lines 1-2 of claims 23, 26) should be “The multi-specific antibody…”. Appropriate correction is required.
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) 1-5, 7-8, 11, 17, 19-22, 26-28 is/are rejected under 35 U.S.C. 103 as obvious over US 2018/0100007 A1 (hereinafter “US007”), as evidenced by Graille et al. (PNAS, May 9, 2000, vol. 97, no. 10, 5399–5404; hereinafter “Graille”).
Note for clarity of the record:
The rejections below are drawn to the multi-specific antibody, comprising:
a first polypeptide (formula I) of VH-CH1-X-(v1)p, wherein X is absent, and p = 0; and
a second polypeptide (formula II) of (V3)r-Z-VL-CL-Y-(V2)q, wherein r = 0, Z is absent, and q = 1.
Given the above, the instant rejection is of a multispecific antibody comprising:
formula I of “VH-CH1”, wherein VH is a variable heavy chain domain, and CH1 is a heavy chain constant region domain 1; and
formula II of “VL-CL-Y-V2”, wherein VL is a variable light chain domain, CL is a constant light chain domain, Y is a linker, and V2 is a dsscFv.
Rejection(s):
Regarding instant claims 1-5, 7-8, 11, US007 teaches a Fab-dsscFv antibody (e.g., a multispecific antigen-binding protein) comprising one polypeptide of the formula VH-CH1 (e.g., instant Formula I), wherein VH is a variable heavy chain domain and CH1 is a heavy chain constant region domain 1, and a second polypeptide of the formula VL-CL-Linker-dsscFv (e.g., instant Formula II), wherein VL is a variable light chain and CL is a light chain constant domain [e.g., ¶ 0030, 0095-0109, 0131; fig. 29]. US007 teaches that the antibody (e.g., Fab-dsscFv) comprises a human VH3 domain [e.g., abstract; ¶ 0032-0073]. US007 further teaches there are multiple human immunoglobulin heavy chain variable domain framework subgroups, that “VH3” refers to subgroup 3 thereof [e.g., ¶ 0134], and that VH3 domains are known to bind to protein A [e.g., ¶ 0005]. Protein A (e.g., also known as ‘SpA’) binding is restricted to the human VH3 subgroup with no evidence of protein A binding by any of the other human VH subgroups, as evidenced by Graille [e.g., abstract; pg. 5403, col. 1, “VH Specificity of the SpA Binding Interaction”].
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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(s) 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].
US007 does not expressly teach a Fab-dsscFv antibody wherein only the Fab comprises a protein A binding domain.
It would have been obvious to a PHOSITA to modify the Fab-dsscFv antibody as taught by US007 to include the that Fab comprises a VH3 domain and the dsscFv does not comprise a VH3 domain (e.g., is VH1, VH2, VH4, etc.), because US007 teaches both the antibody structure and that the antibody (e.g., Fab-dsscFv) comprises “a human VH3 domain” (e.g., ‘a’ is singular and is considered to mean “one”) [e.g., abstract; ¶ 0032-0073]. This conclusion of obviousness is based on the 'obvious to try rationale'. Briefly, the Fab-dsscFv antibody taught by US007 comprises only two total VH domains (e.g., see annotated US007 figure 29 above for details); therefore in order for the Fab-dsscFv to comprise only one single VH3 domain as taught by US007 (see above), there are only two possible embodiments: (1) formula I comprises VH-CH1, wherein the VH domain is a VH3 (e.g., binds protein A), and formula II comprises VL-CL-Linker-dsscFv, wherein the dsscFv VH domain comprises a VH domain that is not VH3 (e.g., VH1, VH2, VH4, etc.) and therefore does not bind protein A (e.g., the instant-claimed invention); or (2) formula I comprises VH-CH1, wherein the VH domain is not a VH3 (e.g., VH1, VH2, VH4, etc.) and therefore does not bind protein A, and formula II comprises a VL-CL-Linker-dsscFv, wherein the dsscFv comprises a VH3 domain that binds protein A. Given the above, it would have been obvious for a skilled artisan to try both configurations of single VH3 domain Fab-dsscFv antibodies that were not expressly disclosed by US007 to determine which configuration is optimal, which is well within the purview of one skilled in the art. Therefore, it would have been obvious to a PHOSITA to arrive at the Fab-dsscFv of the instant invention because as discussed above there are only two possible alternate embodiments thereof to try, wherein embodiment “(1)” above is the same as the instant invention. There is an expectation of success for a PHOPSITA to modify the Fab-dsscFv antibody structure taught by US007 to include that the Fab comprises a VH3 domain and the dsscFv does not comprise a VH3 domain (e.g., is a VH1, VH2, VH4, etc.), because engineering of Fab-dsscFv antibodies and methods thereof are known in the art (e.g., as taught by US007). This rationale aligns with choosing from a finite number of identified, predictable solutions with a reasonable expectation of success; see MPEP 2143(I)(E).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues, in summary, that Heywood (hereinafter “US007”) does not expressly teach that the antibody chain comprising a formula of VL-CL-Linker-scFv is engineered to NOT bind protein A; that the Office is relying upon inherency; and that the inclusion or the word “or” does not establish that a particular species is necessarily disclosed, but rather that it merely indicates that multiple options exist within a broad genus.
In response, “inherency” was not relied upon in the previous rejections as asserted by Applicant. Briefly, US007 expressly teaches the Fab-dsscFv antibody structure and expressly teaches “a human VH3 domain” containing antibody (e.g., “a” is singular) [e.g., abstract; ¶ 0032-0073], as well as “In a further embodiment of the method according to the invention, the VH3 domain-containing antibody comprises at least 2 human VH3 domains” [e.g., ¶ 0074]. A skilled artisan would understand the aforementioned disclosure to mean that US007 also teaches embodiments wherein antibodies comprise only one single VH3 domain because otherwise US007 wouldn’t need to expressly teach a “further embodiment” that comprises “at least 2 VH3 domains”. As discussed in detail in the rejection above, a skilled artisan would understand that this for embodiments taught in US007 wherein only one peptide chain (e.g., of formula I) comprises a VH3 domain, that the complementary peptide chain (e.g., of formula II) wouldn't bind peptide A (see above for details).
Applicant arguments have been thoroughly reviewed but are not persuasive. The new rejection(s) of claim(s) 1-5, 7-8, 11, 17, 19-22, and 26-28 are maintained.
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0100007 A1 (hereinafter “US007”) as evidenced by Graille et al. (PNAS, May 9, 2000, vol. 97, no. 10, 5399–5404; hereinafter “Graille”), 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”), and Ransdell et al. (Journal of Chromatography Open 8 (2025) 100263; hereinafter “Ransdell”).
The teachings of US007 as recited above are applied.
Regarding instant claim(s) 9, US007 further teaches that the antibody (e.g., the Fab-dsscFv) comprises two VH3 domains [e.g., ¶ 0074]. As discussed in the rejections above, the Fab-dsscFv only comprises two VH domain (e.g., one in the Fab and one in the dsscFv), and therefore both the Fab and the dsscFv comprise VH3 domains in the aforementioned embodiment.
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”].
Regarding instant claim 9, Ransdell teaches that the inclusion of additional protein A binding domains can increase impurities (e.g., undesired) during antibody production and purification [e.g., abstract, introduction; pg. 2, col. 1, ¶ 2-3], because protein A non-selectively captures undesired impurities such as half-bodies (e.g., one chain only), homodimers, etcetera [e.g., pg. 2, col. 1, ¶ 2-3].
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 VH domain of the dsscFv of the Fab-dsscFv antibody as taught by US007, to include substitution(s) (e.g., residue 57) to VH3 domains to prevent protein A binding as taught by Bach, to arrive at the instant invention of an antibody comprising (I) a VH-CH1 chain (e.g., formula I), wherein the VH domain is a VH3 domain; and (II) a VL-CL-Linker-scFv (e.g., formula II), wherein the scFv domain is a VH3 domain that does not bind protein A. A PHOSITA would have been motivated to include substitutions to the VH3 domain to create a variant that does not bind protein A in the dsscFv of the Fab-dsscFv as taught by US007, because US007 teaches the base Fab-dsscFv comprising a VH3 domain for both the Fab and the dsscFv VH domain, that VH3 binds protein A, and that protein A binding is commonly used in antibody purification methods [e.g., ¶ 0032-0069, see rejections above for details]; Bach teaches nearly half of all human-derived VH are of the VH3 subfamily (e.g., more likely than not that a human VH domain would be VH3 and naturally bind protein A). The inclusion of additional protein A binding domains can increase impurities (e.g., undesired) during antibody production and purification due to non-selective protein A binding, as taught by Ransdell (see above for details). Given the above, a PHOSITA would understand that engineering the dsscFv VH3 domain of the Fab-dsscFv comprising two VH3 domains (see rejection above for details) as taught by US007 to not bind protein A would avoid unnecessary Formula II chain only fragments (e.g., undesired impurities) 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 modify the VH domain of the dsscFv of the Fab-dsscFv antibody as taught by US007, to include substitution(s) (e.g., residue 57) to VH3 domains to prevent protein A binding as taught by Bach, because US007 teaches the base Fab-dsscFv antibody structure wherein the dsscFv VH domain in a VH3, and Bach teaches the substitution(s) to create a VH3 variant that does not bind to protein A. 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.
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0100007 A1 (hereinafter “US007”) as evidenced by Graille et al. (PNAS, May 9, 2000, vol. 97, no. 10, 5399–5404; hereinafter “Graille”), 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 are applied.
Regarding instant claim(s) 18, 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 instant 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 Fab-dsscFv 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, 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 i, and Brinkmann teaches the specific VH and VL residue modifications in an scFv to make a dsscFv. 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.
Claim(s) 23, 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0100007 A1 (hereinafter “US007”) as evidenced by Graille et al. (PNAS, May 9, 2000, vol. 97, no. 10, 5399–5404; hereinafter “Graille”), as applied to claim 1 above, and further in view US 2018/0237521 A1 (hereinafter “US521”).
The teachings of US007 as recited above are applied.
Regarding instant claim(s) 23, 25, 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 instant 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 instant 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 thereof 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 teaches 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.
Response to Arguments
Applicant argues, in summary, (1) repeats that Heywood (hereinafter “US007”) does not expressly teach that the antibody chain comprising a formula of VL-CL-Linker-scFv is engineered to NOT bind protein A; (2) the modification of the dsscFv to comprise a VH3 that doesn’t bind protein A is contrary to US007 because US007 separates antibodies based on protein A affinity; and (3) that Brinkmann and Finney do not remedy the deficiencies of US007.
In response to (1), see the response to arguments for the 35 USC 102 rejections above.
Briefly, argument (2) is not commensurate with the scope of the claims, as the instant claims are drawn to an antibody (e.g., a composition) and not a method (e.g., Applicant argues the instant claimed composition would be contrary to a single method of antibody purification embodiment of US007). Briefly in response to (2)-(3), for clarity of the record, Brinkmann and Finney were not relied upon to teach that the dsscFv doesn’t bind protein A, rather US007 was relied upon the teach the base Fab-dsscFv antibody composition, wherein the VH domain of fab comprises a VH3 domain that binds protein A; Bach was relied upon to teach that more than half of human VH domains are VH3 domains (e.g., more likely than not that a human scFv would comprise a VH3 that binds protein A), as well as VH3 domains variants that do not bind protein A, and Ransdell was relied upon to teach protein A binding properties and binding of antibody manufacturing impurities (see above for details); and a skilled artisan would understand that engineering an scFv domain attached to an LC chain of a multichain antibody to not bind protein A would reduce undesired antibody manufacturing impurities (see rejection above for details).
Applicant arguments have been thoroughly reviewed but are not persuasive. The new rejection(s) of claim(s) 9, 18, 23, and 25 are maintained.
Conclusion
No claims are currently allowed.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
