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 .
Response to Amendment
The response filed 13 August 2026 is acknowledged. No claims are amended.
Claim Status
Claims 1, 4, 5, 7, 14-18, 20-26, and 28-32 are pending. Claims 16-18, 20-22, 24, and 26 are withdrawn as drawn to an unelected invention or species as previously described. Claims 1, 4, 5, 7, 14-15, 23, 25, and 28-32 are under consideration in the instant office action.
Claim Interpretation- Of Record
Claim 23 is directed to a trivalent multimer produced by a method as described below. The MPEP states "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process” See MPEP 2113(I). The method of claim 23 comprises: immunizing a transgenic animal comprising a nucleic acid encoding a common light chain variable region and an unrearranged heavy chain variable region with two or more antigens; obtaining a panel of antibodies comprising said common light chain variable region and rearranged heavy chain antibody chains that specifically bind said two or more antigens; integrating into a host cell, a nucleic acid encoding the common light chain variable region and two or more rearranged heavy chains, which specifically bind said two or more antigens, wherein two of said rearranged heavy chains comprise a constant region comprising CH1, CH2 and/or CH3 domain capable of pairing via the formation of a disulfide bridge; cultivating the host cell under conditions to provide for expression of an intact trivalent multimer comprising the common light chain and two or more rearranged heavy chains, wherein two of said rearranged heavy chains are paired via a disulfide bridge between the CH1 and CH2 domain of each of said two rearranged heavy chains; and treating the intact multivalent multimer with an enzyme that cleaves the CH2 and/or CH3 region from each of the two said rearranged heavy chains, maintaining the pairing of the two said rearranged heavy chains via a disulfide bridge to form the multivalent multimer.” The method of claim 23 provides the following structure to the product of claim 23: a trivalent multimer with a common light chain and three rearranged heavy chains wherein two of the heavy chains are paired at the end of their respective CH1 domains by a disulfide bridge; and that the trivalent multimer does not have a complete CH2/CH3 region.
Claim Rejections - 35 USC § 103- Maintained
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.
Claims 1, 4-5, 14-15, 23, 25, 30, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over WO2016079076 to Bacac et. al. published 26 May 2016 (Of Record, PTO-892 dated 6/26/2025) in view of WO2016160976 to Ghayur et. al. and Holliger, P., Hudson, P. Engineered antibody fragments and the rise of single domains. Nat Biotechnol 23, 1126–1136 (2005). https://doi.org/10.1038/nbt1142.
Regarding claim 1, Bacac et. al. teaches a bispecific antigen binding molecule for T cell activation and re-direction to target cells comprising 3 Fab regions (Abstract, Fig. 1A). As shown in Fig. 1A and the examiner’s notes below, antigen binding molecule comprises 2 three chain binding regions and three light chain binding regions, each comprising a heavy chain variable domain with a VH and CH1 and a paired VL and CL, respectively; two of the Fabs are connected via a linker at the heavy chain variable region of Fab2 and the CH1 region of Fab3 (see also p. 3 lines 24-26; p. 37 lines 1-3); Fab1 and Fab2 are paired via a hinge comprising at least 2 disulfide bonds at the C-terminus of the heavy chain region of Fab1 and Fab2. The bispecific antigen binding molecule of Bacac et. al. further comprises an Fc domain region, where the Fc domain lacks the particular amino acids L234, L235, and P239 (equivalent to a portion) in order to reduced binding of the Fc domain to activating Fc receptor (p. 5 lines 30-p. 6 line 3). Bacac et. al. teaches that the heavy chains of immunoglobulins such as the instant binding molecule are disulfide bonded (p. 23 lines 14-16) and depicts the two disulfide bonds at the C-terminal end of the heavy chain region comprising the VH domain and the CH1 domain (See Examiner’s Fig. 1 below).
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Examiner’s Figure 1. Depicts an annotated version of Fig. 1A of Bacac et. al. Examiner’s notes marking the relevant parts of the structure that are equivalent to the instant claims are in red and blue.
Bacac et. al. teaches the trivalent multimer with a peptide linker comprising typically about 2-20 amino acids, and suitable embodiments including “non-immunogenic peptide linkers include, for example, (G.sub.4S).sub.n (SEQ ID NO: 300), (SG.sub.4), (SEQ I D NO: 301), (G.sub.4S).sub.n ( SEQ I D NO: 300) or G.sub.4(SG.sub.4)„ (SEQ I D NO: 302) peptide linkers, "n" is generally a number between 1 and 10, typically between 2 and 4. A particularly suitable peptide linker for fusing the Fab light chains of the first and the second antigen binding moiety to each other is (G.sub.4S)2 (SEQ I D NO: 303). An exemplary peptide linker suitable for connecting the Fab heavy chains of the first and the second antigen binding moiety is EPKSC(D)-(G.sub.4S).sub.2 (SEQ ID NOs 304 and 305). Additionally, linkers may comprise (a portion of) an immunoglobulin hinge region. Particularly where an antigen binding moiety is fused to the N-terminus an Fc domain subunit, it may be fused via an immunoglobulin hinge region or a portion thereof, with or without an additional peptide linker” (p. 51 lines 6-18). SEQ ID NO: 303 is identical to instant SEQ ID NO: 4; SEQ ID NO: 305 is identical to instant SEQ ID NO: 13 (reads on the linker connecting Fab2 and Fab3).
Regarding claims 4-5, Bacac et. al. teaches the antigen binding molecule comprises a common light chain capable of pairing with a CD3 and a FOLR heavy chain to prevent mispairing and reduce side products (p. 37 lines 7-20; p. 41 lines 28-p. 42 line 2; Example 2 p. 97 lines 5-p. 98 line 7).
Regarding claims 14-15 and 30, Bacac et. al. teaches the trivalent multimer comprising an anti-CD3 and an anti-FOLR Fab, which bind to two different antigens (CD3 and FOLR). This reads on two different epitopes because there are no epitopes in common between CD3 and FOLR, which are different proteins with different structures. Bacac further et. al. teaches an embodiment where the two anti-FOLR Fab are the same (p. 36 lines 23-24; p. 40 lines 17-20; p. 41 lines 15-32).
Regarding claim 25, Bacac et. al. recites pharmaceutical compositions of the antigen binding fragment and methods of treatment comprising administering the multivalent multimer (p. 31 lines 10-30).
Bacac et. al. teaches that “The term ‘antibody’ herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, and antibody fragments so long as they exhibit the desired antigen-binding activity” (p. 23 lines 27-29, emphasis is the examiner’s). Examples of antigen binding molecules are immunoglobulins and derivatives, e.g. fragments, thereof” (p. 21 lines 18-21); “An "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F(ab')2, diabodies, linear antibodies, single-chain antibody molecules (e.g. scFv), and single-domain antibodies. For a review of certain antibody fragments, see Hudson et al., Nat Med 9, 129- 134 (2003) […] For discussion of Fab and F(ab')2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No. 5,869,046 […] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g. E. coli or phage), as described herein” (p. 23 line 30-p. 24 line 16).
Bacac et. al. does not explicitly teach the trivalent multimer wherein the trivalent multimer lacks a CH2 and/or CH3 region. This is resolved by Ghayur et. al. and Bates et. al.
Ghayur et. al. teaches trivalent molecules with anti-TNF binding properties for enhanced pharmacokinetic characteristics (p. 6 lines 10-19). Ghayur et. al. teaches the proteins in exemplary formats comprising a monovalent arm and a bivalent arm. Ghayur et. al. teaches that the invention includes the antigen-binding portion of the antibodies of the invention and that “Examples of binding fragments encompassed within the term ‘antigen-binding portion’ of an antibody with regard to the trivalent molecules of the present disclosure include fragments that comprise (i) a trivalent fragment consisting of one VH-VH-CH1, one VL-VL-CL, one VH-CH1, and one VL-CL where the anti TNF binder is on the monovalent arm; (ii) a trivalent fragment consisting of one VH-VH-CH1, one VL-VL-CL, one VH-CH1, and one VL-CL, where the anti TNF binder is on the bivalent arm” (p. 9 line 28- p. 10 line 2).
Holliger et. al. teaches “There is a range of applications, however, in which the Fc-mediated effects are not required and are even undesirable. For example, a long serum half-life results in poor contrast in imaging applications, and inappropriate activation of Fc receptor–expressing cells can lead to massive cytokine release and associated toxic effects. To remove the Fc domain (and associated effects), IgGs have been dissected into constituent domains, initially through proteolysis (with such enzymes as papain and pepsin) and later genetically engineered into either monovalent (Fab, scFv, single variable VH and VL domains) or bivalent fragments (Fab′2, diabodies, minibodies, etc.)(Figs. 1 and 2)” (p. 1127, left column ¶1).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to make a fragment of the trivalent multispecific of Bacac et. al., wherein the trivalent fragment consists of only the VH and VL and CH1 and CL domains of the trivalent antibody as taught by Ghayur et. al., which would result in a multispecific antibody fragment consisting of, for example, one VH-CH1-VH-CH1, one VH-CH1, and three VL-CLs and lacking the Fc CH2/CH3 portion as generated by a proteolytic enzyme as taught by Bacac et. al. and Holliger et. al. A person of ordinary skill in the art would understand that such a fragment benefit from reduced immunogenicity and shorter half-life as taught by Holliger. This would have a reasonable expectation of success because both Bacac et. al. and Ghayur et. al. teach that a person of ordinary skill in the art would recognize “antibody” to include fragments of the described antibody structures and Ghayur et. al. explicitly discloses trivalent antibody fragments for a similar trivalent antibody; and further, a person of ordinary skill in the art would recognize as taught by Bacac et. al. and Holliger et. al. that the Fc domain of an antibody may be removed using a proteolytic enzyme such a pepsin, and that this would result in a trivalent fragment similar to that described by Ghayur et. al. when proteolysis was applied to the antibody of Bacac et. al.
Regarding claim 23, as described in the claim interpretation section above, the claim requires the only the product that would be generated by the process as described. Modified Bacac et. al. in view of Ghayur et. al. and Holliger et. al. would result in the fragment of the invention as taught by Bacac et. al. in view of Ghayur et. al. generated by pepsin as taught by Holliger et. al., and linked by the disulfide bonds as taught by Bacac et. al. (protease digestion of the antibody of Bacac et. al. would result in the fragment still comprising the disulfide bonds), and therefore reads on claim 23.
Claims 7, 28, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over WO2016079076 to Bacac et. al. published 26 May 2016 (Of Record, PTO-892 dated 6/26/2025) in view of WO2016160976 to Ghayur et. al. and Holliger, P., Hudson, P. Engineered antibody fragments and the rise of single domains. Nat Biotechnol 23, 1126–1136 (2005). https://doi.org/10.1038/nbt1142 as applied to claims 1 and 5 above, and further in view of U.S. 20170058035 to Logtenberg et. al published 2 March 2017 (Of Record, IDS dated 9/2/2021).
The teachings of Bacac et. al. in view of Ghayur and Holliger in regards to claims 1 and 5 are in the 103 rejection above. Bacac et. al. also teaches a method of generating a common light chain against CD3 via humanization followed by selection via phage-displayed antibody libraries for novel specificities for a bispecific antibody with a second specificity sharing the same light chain (p. 99 line 20-p. 100 line 4). Bacac et. al. teaches that the common light chain “enables successful selection for novel specificities which greatly facilitates the generation and production of bispecific molecules binding to CD3ɛ and e.g. a tumor target sharing the same ‘common’ light chain (p. 100 lines 1-4).
Bacac et. al. in view of Ghayur et. al. and Holliger et. al. does not a common light chain of SEQ ID NO: 1.
This deficiency is resolved by Logtenberg et. al.
Logtenberg et. al. teaches a common light chain sequence of SEQ ID NO: 153 which is 100% identical to instant SEQ ID NO: 1. Logtenberg et. al. teaches bispecific antibodies comprising anti-EGFR and anti-ErbB3 binding domains comprising the common light chain of SEQ ID NO: 153 (claim 1). Logtenberg et. al. teaches that “The heavy chain variable regions of the bispecific antibody of the invention are different from each other, whereas the light chain variable regions are preferably the same in the bispecific antibodies of the invention, i.e. the bispecific antibodies of the invention are preferably composed of two parental antibodies that have the same light chain (i.e. common light chain antibodies). A bispecific antibody wherein the different heavy chain variable regions are associated with the same, or a common, light chain is also referred to as a bispecific antibody with a common light chain. Further provided is therefore a bispecific antibody according to the invention, wherein both arms comprise a common light chain” ([0023]) and “The term ‘common light chain’ according to the invention refers to light chains which may be identical or have some amino acid sequence differences while the binding specificity of the full-length antibody is not affected. It is for instance possible within the scope of the definition of common light chains as used herein, to prepare or find light chains that are not identical but still functionally equivalent, e.g., by introducing and testing conservative amino acid changes, changes of amino acids in regions that do not or only partly contribute to binding specificity when paired with the heavy chain, and the like. The terms ‘common light chain’, ‘common VL’, ‘single light chain’, ‘single VL’, with or without the addition of the term ‘rearranged’ are all used herein interchangeably. It is an aspect of the present invention to use as common light chain a human light chain that can combine with different heavy chains to form antibodies with functional antigen binding domains (WO2004/009618, WO02009/157771, Merchant et al. 1998, Nissim et al. 1994). Preferably, the common light chain has a germline sequence. A preferred germline sequence is a light chain variable region that is frequently used in the human repertoire and has good thermodynamic stability, yield and solubility. A preferred germline light chain is based on O12, preferably it is the rearranged germline human kappa light chain IgVk1-39*01/IGJk1*01 or a fragment or a functional equivalent (i.e. same IgVk1-39 gene segment but different IGJk gene segment) thereof (nomenclature according to the IMGT database worldwide web at imgt.org). Further provided is therefore a bispecific antibody according to the invention, wherein said common light chain is a germline light chain, preferably a rearranged germline human kappa light chain comprising the IgVK1-39 gene segment, most preferably the rearranged germline human kappa light chain IgVK1-39*01/IGJK1*01. The terms rearranged germline human kappa light chain IgVk1-39*01/IGJK1*01, IGKV1-39/IGKJ1, huVk1-39 light chain or in short huVk1-39 are used interchangeably throughout the application” [0026].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to substitute the anti-FOLR1 tumor targeting binding domains of Bacac et. al. for the anti-tumor targeting EGFR and ErbB3 binding domains of Logtenberg et. al. in order to benefit from the anti-EGFR/ErbB3 tumor targeting domains of Logtenberg et. al. in the T-cell binding trispecific format of modified Bacac et. al. This would have a reasonable expectation of success because both Bacac et. al. and Logtenberg et. al. teach the benefits of a common light chain for multispecific antibodies and a person of ordinary skill in the art would be able to swap different Fab domains shown to be effective for targeting cancer antigens in order to target a desired different cancer antigen such as EGFR/ErbB3 as taught by Logtenberg et. al.
Regarding claims 28 and 31, Bacac et. al. in view of Ghayur et. al. and Holliger et. al. do not teach wherein each variable region of the trivalent multimer binds a different epitope or wherein the trivalent multimer binds three different antigens. As described above, It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to substitute the anti-EGFR and ErbB3 binding domains for the anti-FOLR1 binding domains of modified Bacac et. al.; this would result in a trivalent multimer with an anti-EGFR binding domain, and anti-ErbB3 binding domain, and an anti-CD3 binding domain for T-cell targeting to EGFR and ErbB3 tumor antigens, which reads on different epitopes because EGFR, ErbB3, and CD3 do not have shared epitopes and reads on three different antigens.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over WO2016079076 to Bacac et. al. published 26 May 2016 in view of WO2016160976 to Ghayur et. al. and Holliger, P., Hudson, P. Engineered antibody fragments and the rise of single domains. Nat Biotechnol 23, 1126–1136 (2005). https://doi.org/10.1038/nbt1142 as applied to claim 1 above, and further in view of WO2012088290 to Wu et. al. published 2 June 2012 (Of record, 892 dated 9/28/2024).
The teachings of Bacac et. al. in view of Ghayur and Holliger in regards to claim 1 are in the 103 rejection above. Bacac et. al. does not explicitly teach the trispecific binding molecule wherein the two of the variable regions of the trivalent multimer bind to different epitopes on one antigen.
This is resolved by Wu et. al.
Wu et. al. teaches a multispecific binding protein format comprising multiple VH/VL pairings (Abstract, Fig. 1). Wu et. al. that the antigen binding domains may be teaches “different parent binding proteins […] bind different epitopes on a target antigen” (page 7 line 18-19) and teaches “one or more target antigens” (starting page 8 line 12).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to substitute Fab antigen-binding domains each against different epitopes on one antigen (claim 29) as taught by Wu et. al. into the trivalent antigen-binding molecule as taught by modified Bacac et. al. in view of Ghayur et. al. and Holliger et. al. in order to benefit from making trivalent antigen-binding molecules against more than one target and with different specificities as taught by Wu et. al. This would have a predictable effect because both the Wu et. al. publication and Bacac et. al. are directed towards multivalent antigen binding molecules and Bacac et. al. teaches a method of screening for antigen-binding molecules using a common light chain of the invention; therefore, a person of ordinary skill in the art would be able to substitute the VH/VL domain to target the desired epitopes and antigens as taught by Bacac et. al. and Wu et. al. in the antibody format of modified Bacac et. al.
Response to Arguments
Applicant’s arguments filed 8/13/2026 have been fully considered but are not persuasive in view of the new rejection, necessitated by amendment, above. Applicant argues that Bacac et. al. does not teach the trivalent multimer lacks a CH2 and/or CH3 region (Remarks 8/13/2026 p. 8). However, as described in the 103 rejection above, Bacac et. al. in view of Ghayur et. al. and Holliger et. al. makes obvious the trivalent multimer lacking a CH2 and/or CH3 region because Bacac et. al. and Ghayur et. al. teach fragments of the antibodies of the invention, and Ghayur et. al. explicitly teaches the fragment having only the VH/VL and CH1/CL domains; Holliger et. al. teaches that antibody fragments may be made by pepsin digestion and that they are less immunogenic than full-length antibodies. Applicant argues that “a general disclosure that antibodies may include fragments such as Fab, Fab’, Fab’SH, F(ab’)2, diabodies, linear antibodies, single-chain antibody molecule, or single domain antibodies does not teach the claimed trivalent multimer. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). MPEP §2144.08 describes obviousness of species when prior art teaches a genus, as Bacac et. al. teaches a genus of potential antibody structures, and notes that among the considerations are teachings of structural similarity and teachings of similar properties or uses. As described in the 103 rejection above, a person of ordinary skill in the art would know that protease cleavage to remove the Fc domain preserves the entire structure of the variable regions of the antibody, such as in a F(ab’)2 fragment, and would have been readily able to visualize how that would apply to the antibody of Bacac et. al. As described in the 103 rejection above, Holliger et. al. and Ghayur et. al. teach motivation and reasonable expectation of success for an Fc-less version of the antibody of Bacac et. al., and therefore would particular motivate selection of a the antibody fragment, resulting in a F(ab’)3 fragment as claimed.
Applicant further argues that Ghayur does not supply the missing limitation relied upon in the rejection because “all exemplary binding proteins disclosed in Ghayur include CH2 and CH3 domains”. This is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As disclosed in the 103 rejection above, Ghayur et. al. explicitly discloses an antibody fragment as the invention: ““Examples of binding fragments encompassed within the term ‘antigen-binding portion’ of an antibody with regard to the trivalent molecules of the present disclosure include fragments that comprise (i) a trivalent fragment consisting of one VH-VH-CH1, one VL-VL-CL, one VH-CH1, and one VL-CL where the anti TNF binder is on the monovalent arm; (ii) a trivalent fragment consisting of one VH-VH-CH1, one VL-VL-CL, one VH-CH1, and one VL-CL, where the anti TNF binder is on the bivalent arm” (p. 9 line 28- p. 10 line 2)”. Therefore, a person of ordinary skill in the art would understand that the antibody fragment of the invention explicitly does not require an Fc region CH2-CH3. This is further supported by the fact that Ghayur et. al. teaches that “a labeled binding protein of the invention can be derived by functionally linking a binding protein or binding protein portion of the invention (by chemical coupling, genetic fusion, non-covalent association or otherwise) to one or more other molecular entities[…]” (p. 22 lines 3-10). Thus, it would have been clear to a person of ordinary skill in the art that the invention encompassed the antigen-binding portions, even in the absence of an Fc domain. Ghayur et. al. serves as additional evidence antibody fragments were commonly known to include Fc-less fragments, and it would have be evident to a person of ordinary skill in the art, as mentioned in both Ghayur et. al. and Bacac et. al., that a trivalent antibody fragment could be made from the working embodiments of antibodies described in the disclosure. Applicant is further reminded that the disclosure of alternate embodiments of the invention do not teach away from a broader disclosure or nonpreferred embodiments: “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)” (MPEP §2123).
Applicant further argues that Holliger does not support the conclusion that a person of ordinary skill in the art would understand that an Fc-less fragment would benefit from lacking Fc functions the are unnecessary or undesirable in some circumstances. Applicant argues that Bacac et. al. does not teach or suggest a trivalent multimer lacking a CH2 and/or CH3 region “let alone a method of generating such a construct” (Remarks p. 11-12). This is not persuasive. MPEP §2121 teaches that prior art is presumed to be operable/enabling, and further that "Even if a reference discloses an inoperative device, it is prior art for all that it teaches." Beckman Instruments v. LKB Produkter AB, 892 F.2d 1547, 1551, 13 USPQ2d 1301, 1304 (Fed. Cir. 1989). Regardless, both Bacac et. al. and Bayur et. al. show that antibody fragments were entirely routine and obvious in the art, regardless of the trivalent structure of the antibody. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a method for selectively removing CH2 and/or CH3 regions by proteolysis) 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).
Applicant further argues that Holliger does not teach or suggest applying proteolysis to Bacac et. al. or that such proteolysis would yield a trivalent multimer and “It does not teach or suggest that such proteolysis would preserve the claimed Fab2-Fab3 linker arrangement” (Remarks p. 11) and that these conclusory statements by the office must have a rational underpinning and be grounded in evidence. This is not persuasive. MPEP §2144.02 states that the rationale to support a rejection may rely on log and sound scientific principle. As described in the 103 rejection, both Holliger and Bacac et. al. teach that the effects of the Fc domain can be undesired to a person of ordinary skill in the art, and Holliger et. al. teaches that enzymes such as papain and pepsin are specific for the removing the Fc domain through proteolysis. It is not relevant that there is no explicit discussion of the Fab2-Fab3 linker as claimed because Bacac et. al. suggests the claimed linker sequences and a person of ordinary skill in the art would have a reasonable expectation of applying to the IgG antibody of Bacac et. al. the pepsin digests of “IgG antibodies” as taught by Holliger because there is a reasonable expectation that the pepsin is specific for the IgG hinge, and Bacac et. al. teaches linkers of Fab2-Fab3 that are not the IgG hinge. Holliger teaches that the generation of fragments is broadly applicable to generating multispecific antibody fragments, such as all of those taught in Fig. 1 and Fig. 2. As described in the rejection, the reason for the proposed modification is because Bacac, Bayur, and Holliger all teach antibody fragments; Bacac and Bayur et. al. teach trivalent antibodies as claimed and suggest making antibody fragments; and Holliger teaches that a person of ordinary skill in the art, at the time of filing, was motivated to make antibody fragments by cleaving the Fc domain with Fc-specific proteases in order to remove undesirable Fc effector functions. Applicant is further remind that the instant claims are directed towards a single molecule (“A trivalent multimer”), and therefore, the Applicant’s instant method for generating the fragments as described in the specification is not imported onto the claims because a person of ordinary skill in the art would understand, with a reasonable expectation of success, that one of the fragments generated from applying the method as described by Holliger et. al. to the fragment of Bacac et. al. in order to obtain the fragment as described by Bayur et. al. would result in the instantly claimed fragment.
As described above, MPEP §2121 states that prior art is presumed to be enabled, and further that prior art is a reference for all that it teaches, even if it is not enabled. As described in the 103 rejection above, both Bacac et. al. and Bayur et. al. disclose that antibody fragments of the multispecific antibodies disclosed are part of the invention, and Bayur et. al. explicitly discloses an antibody fragment comprising the identical variable domain structure of the instant trivalent multimer. A person of ordinary skill in the art, reading Bacac et. al. and Bayur et. al. in view of Holliger et. al., would be motivated to cleave the Fc domain from the trispecific IgG antibody using pepsin in order to generate a fragment identical to the one explicitly described by Bayur et. al. in order to benefit from a multispecific fragment lacking undesirable Fc-domain functions as taught by Holliger. Applicant is reminded that “the fact that an author of a publication did not attempt to make the compound disclosed, without more, will not overcome a rejection based on that publication” (MPEP §2121.02) and that Applicant’s arguments cannot be substituted for evidence. If Applicant has evidence that attempts to prepare the instant trivalent molecule would using pepsin would have been inoperable at the relevant time (MPEP §2121), Applicant is invited to make that evidence of record.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning (Remarks 7/13/2026 p. 12-13), it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In particular, as described in the 103 rejection above, the Examiner relies on the teaching of a fragment of the trivalent multispecific of Bacac et. al., wherein the trivalent fragment consists of only the VH and VL and CH1 and CL domains of the trivalent antibody as taught by Ghayur et. al., which would result in a multispecific antibody fragment consisting of, for example, one VH-CH1-VH-CH1, one VH-CH1, and three VL-CLs and lacking the Fc CH2/CH3 portion as generated by a proteolytic enzyme as taught by Bacac et. al. and Holliger et. al. A person of ordinary skill in the art would understand that such a fragment benefit from reduced immunogenicity and shorter half-life as taught by Holliger. This would have a reasonable expectation of success because both Bacac et. al. and Ghayur et. al. teach that a person of ordinary skill in the art would recognize “antibody” to include fragments of the described antibody structures and Ghayur et. al. explicitly discloses trivalent antibody fragments for a similar trivalent antibody; and further, a person of ordinary skill in the art would recognize as taught by Bacac et. al. and Holliger et. al. that the Fc domain of an antibody may be removed using a proteolytic enzyme such a pepsin, and that this would result in a trivalent fragment similar to that described by Ghayur et. al. when proteolysis was applied to the antibody of Bacac et. al.
Regarding claim 23, Applicant argues that claim 23 is not obvious over Bacac et. al. in view of Ghayur et. al. and Holliger et. al. because of the reasons described above (Remarks p. 13-14). This is not persuasive for the reasons described above.
Regarding claim 7, Applicant argues that the rejections of claims 7, 28, and 29 fail to remedy the deficiencies as described for the references of Bacac in view of Ghayur and Holliger (Remarks p. 14-17). This is not persuasive for the reasons described above.
Double Patenting- Maintained
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 1, 4, 5, 7, 14-15, 23, 25, and 28-32 are rejected on the ground of nonstatutory double patenting as being anticipated by claims 1, 2, 5-8, 12, 17, 38-43 of U.S. Patent No. US 11,952,424 B2 in view of WO2016160976 to Ghayur et. al. and Holliger, P., Hudson, P. Engineered antibody fragments and the rise of single domains. Nat Biotechnol 23, 1126–1136 (2005). https://doi.org/10.1038/nbt1142.
The instant claims at their broadest recite a trivalent multimer comprising 3 Fab domains, each comprising a VH and CH1 paired with a VL and CL, wherein Fab2 and Fab3 are connected via a linker at a heavy chain variable region of Fab2 and a CH1 domain of Fab3 and Fab1 and Fab2 are paired via a hinge comprising at least two disulfide bonds present at the C-terminus of the heavy chain of Fab1 and Fab2, wherein the multimer lacks all or a portion of an Fc region. Claims 4-6 are drawn to common variable heavy chain regions and common light chain regions and specific a particular light chain SEQ ID No:1. Claims 9-11 describe wherein the linker is specific sequence (claim 9) or comprises middle hinge region sequence; an upper and a lower hinge sequence; or a helix-forming sequence (claim 11). Claim 14-15 recite the multimer binding different epitopes or different antigens. Claim 25 recites a pharmaceutically acceptable composition comprising the multimer.
The ‘424 patent recites:
Regarding claims 1, and 4-5, “A multivalent antibody which comprises: a base antibody portion which comprises two binding domains; and one or two additional binding domains, wherein the base antibody portion is a full length immunoglobulin, wherein the one or two additional binding domains are Fab domains comprising a CH1 region, each Fab domain being connected to the base antibody portion by a linker, linking a variable region of the base antibody portion and the CH1 region, wherein each binding domain of the base antibody portion and each of the one or two additional binding domains all have the same light chain, the light chain comprising the complementarity determining regions (CDRs) of IGKV1-39/jk1 or IGKV1-39/jk5, and wherein the multivalent antibody binds to at least three different epitopes or antigens” (Claim 1). Claims 2 and 17 recite specific linker sequences including a SEQ ID NO: 4 identical to instant SEQ ID NO: 5.
The embodiment of two binding domains plus one additional binding domain reads on the instant “trivalent multimer”.
Regarding claim 25, claim 12 recites a pharmaceutically acceptable composition of the antibody.
Regarding claim 7, Claims 38-40 recite specific common light chain CDRs (SEQ ID NO 254, 255, and 256) or variable regions sequences (SEQ ID NO: 37); SEQ ID NO: 37 is 100% identical to the VL in instant SEQ ID NO: 1 but does not teach the CL region; in order to determine the scope of the claims directed towards the common light chain CDRs of IGKV1-39/jk1 or IGKV1-39/jk5 the specification was consulted (MPEP 804.II.B.1); an embodiment of the common light chain as claimed is SEQ ID NO: 35, which is 100% identical to instant SEQ ID NO: 1 (Fig. 11).
Regarding instant claims 14-15 and 28-31, claims 41-43 recite binding three or more, or four or more epitopes or antigens, or at least three epitopes on two different antigens.
The claims of ‘424 do not recite the trivalent binding protein lacks a CH2 and/or a CH3 region. This is resolved by Ghayur et. al. and Holliger et. al.
Ghayur et. al. teaches trivalent molecules with anti-TNF binding properties for enhanced pharmacokinetic characteristics (p. 6 lines 10-19). Ghayur et. al. teaches the proteins in exemplary formats comprising a monovalent arm and a bivalent arm. Ghayur et. al. teaches that the invention includes the antigen-binding portion of the antibodies of the invention and that “Examples of binding fragments encompassed within the term ‘antigen-binding portion’ of an antibody with regard to the trivalent molecules of the present disclosure include fragments that comprise (i) a trivalent fragment consisting of one VH-VH-CH1, one VL-VL-CL, one VH-CH1, and one VL-CL where the anti TNF binder is on the monovalent arm; (ii) a trivalent fragment consisting of one VH-VH-CH1, one VL-VL-CL, one VH-CH1, and one VL-CL, where the anti TNF binder is on the bivalent arm” (p. 9 line 28- p. 10 line 2).
Holliger et. al. teaches “There is a range of applications, however, in which the Fc-mediated effects are not required and are even undesirable. For example, a long serum half-life results in poor contrast in imaging applications, and inappropriate activation of Fc receptor–expressing cells can lead to massive cytokine release and associated toxic effects. To remove the Fc domain (and associated effects), IgGs have been dissected into constituent domains, initially through proteolysis (with such enzymes as papain and pepsin) and later genetically engineered into either monovalent (Fab, scFv, single variable VH and VL domains) or bivalent fragments (Fab′2, diabodies, minibodies, etc.)(Figs. 1 and 2)” (p. 1127, left column ¶1).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to make a fragment of the trivalent multispecific of ‘424 claims, wherein the trivalent fragment consists of only the VH and VL and CH1 and CL domains of the trivalent antibody as taught by Ghayur et. al., which would result in a multispecific antibody fragment consisting of, for example, one VH-CH1-VH-CH1, one VH-CH1, and three VL-CLs and lacking the Fc CH2/CH3 portion as generated by pepsin, as taught by Holliger. A person of ordinary skill in the art would understand that such a fragment benefit from less immunogenicity as taught by Holliger et. al. This would have a reasonable expectation of success because Ghayur et. al. teaches that a person of ordinary skill in the art would recognize “antibody” to include fragments of the described antibody structures and Ghayur et. al. explicitly discloses trivalent antibody fragments for a similar trivalent antibody.
Regarding claim 23, as described in the claim interpretation section above, the claim requires the only the product that would be generated by the process as described. Modified ‘424 in view of Ghayur et. al. and Holliger et. al. would result in the fragment of the invention as taught by Bacac et. al. in view of Ghayur et. al. generated by the enzyme as taught by Bates et. al., and linked by the disulfide bonds as taught by Bacac et. al. and Holliger et. al., and therefore reads on claim 23.
Response to Arguments
Applicant’s arguments dated 8/13/2026 have been fully considered but are not persuasive. Applicant argues that the non-statutory double patenting rejection relies upon the same rationale as the obviousness rejection, namely that the full-length multivalent antibody of the ‘424 patent would have been modified in view of Ghayur and Holliger to arrive at the presently claimed trivalent multimer lacking a CH2 and/or CH3 region is deficient for the reasons as discussed in the 103 rejection (Remarks p. 17). Applicant argues that, in particular, the claims are directed towards the multivalent antibody in which “the base antibody portion is a full length immunoglobulin”. This is not persuasive for the reasons discussed in the NSDP rejection above. As disclosed in the NSDP rejection above, Ghayur et. al. explicitly discloses an antibody fragment as the invention. Therefore, a person of ordinary skill in the art would understand that the antibody fragment of the invention explicitly does not require an Fc region CH2-CH3. This is further supported by the fact that Ghayur et. al. teaches that “a labeled binding protein of the invention can be derived by functionally linking a binding protein or binding protein portion of the invention (by chemical coupling, genetic fusion, non-covalent association or otherwise) to one or more other molecular entities[…]” (p. 22 lines 3-10). Thus, it would have been clear to a person of ordinary skill in the art that the invention encompassed the antigen-binding portions, even in the absence of an Fc domain. Ghayur et. al. serves as additional evidence antibody fragments were commonly known to include Fc-less fragments, and it would have be evident to a person of ordinary skill in the art, as mentioned in both Ghayur et. al. and Bacac et. al., that a trivalent antibody fragment could be made from the working embodiments of antibodies described in the disclosure. Applicant is further reminded that the disclosure of alternate embodiments of the invention do not teach away from a broader disclosure or nonpreferred embodiments: “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)” (MPEP §2123). As described in the NSDP rejection, Holliger discusses the removal of CH2/CH3 domains in general and motivates why it would benefit a person of ordinary skill in the art and connects the removal of Fc domain in the context of the generation of multispecific antibody fragments. As set forth in the response to the obviousness arguments section above, Holliger provides motivation to combine and both Ghayur et. al. and Holliger et. al. teach a reasonable expectation of success at arriving at a trivalent antibody fragment from the trivalent antibody of the claims of ‘424.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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