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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3 March 2026 has been entered.
Response to Amendment
The amendment filed 3 March 2026 is acknowledged. Claim 1 is amended. Claims 9 and 11 are cancelled. Claim 32 is new.
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 Claims 16-18, 20-22, 24, and 26 are withdrawn as drawn to an unelected invention or species as previously described.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.
Withdrawal of Rejections
The rejection of claims 1, 4-5, 9, 14-15, 25, and 30 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO2016079076 to Bacac et. al. published 26 May 2016 is withdrawn in view of the amendment to the claims.
The rejection of claim 7 under 35 U.S.C. 103 as being unpatentable over WO2016079076 to Bacac et. al. published 26 May 2016 as applied to claim 1 above, and further in view of US 20100172917 published 07/08/2010 (Of Record, Examiner 892 dated 9/28/2024) is withdrawn in view of the amendment to the claims.
The rejection of claim 11 under 35 U.S.C. 103 as being unpatentable over WO2016079076 to Bacac et. al. published 26 May 2016 as applied to claim 1 above, and further in view of US Patent 11,471,490 (effectively filed July 3, 2017, published October 18, 2022, of record in 892 dated 9/28/2024) is withdrawn in view of the amendment to the claims.
The rejection of claim 23 under 35 U.S.C. 103 as being unpatentable over WO2016079076 to Bacac et. al. published 26 May 2016 in view of WO 2012/088290 published 2 June 2012 (Of record, 892 dated 9/28/2024, hereinafter “the ‘290 publication”) and Sjogren et. al. “Rapid and improved characterization of therapeutic antibodies and antibody related products using IdeS digestion and subunit analysis”. Analyst 2016 141, 3114-3125. http://dx.doi.org/10.1039/C6AN00071A. Published 04 May 2016 (Of record) is withdrawn in view of the amendment to the claims.
The rejection of claims 28, 29, and 31 under 35 U.S.C. 103 as being unpatentable over WO2016079076 to Bacac et. al. published 26 May 2016 as applied to claim 1 above in view of WO 2012/088290 published 2 June 2012 (Of record, 892 dated 9/28/2024, hereinafter “the ‘290 publication”) is withdrawn in view of the amendment to the claims.
The rejection of claims 1, 4-5, 7-9, 11, 14-15, 23, 25, and 28-31 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 as evidenced by “Correspondence between the IMGT unique numbering for C-DOMAIN, the IMGT exon numbering, the Eu and Kabat numberings: Human IGHG”, www.imgt.org accessed by the examiner on 20 June 2025 is withdrawn in view of the amendment to the claims.
The rejection of claim 23 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5-8, 12, 17, 38-43 of U.S. Patent No. US 11,952,424 B2 in view of WO2016079076 to Bacac et. al. published 26 May 2016 and Sjogren et. al. “Rapid and improved characterization of therapeutic antibodies and antibody related products using IdeS digestion and subunit analysis”. Analyst 2016 141, 3114-3125. http://dx.doi.org/10.1039/C6AN00071A. Published 04 May 2016 (Of record) is withdrawn in view of the amendment to the claims.
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- New
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 3/3/3036 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 3/3/2026 p. 7). 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 “Of note, contrary to the Office’s allegation, Ter Meulen does not teach a common light chain of instant SEQ ID NO: 1” (Remarks 3/3/2026). This argument is moot in view of the new rejection of claim 7 in view of Logtenberg et. al. However, for clarity of the record, the Examiner would like to note that Applicant appears to have inadvertently aligned SEQ ID NO: 1 with SEQ ID NO: 129 from WO2012088290 to Wu et. al. The Examiner has thoroughly checked the available databases through STN (USGENE database, see search notes) and through STIC, and SEQ ID NO: 129 of Ter Meulen is 100% identical to instant SEQ ID NO: 1 as shown below:
Title: US-17-417-288-1
Perfect score: 1102
Sequence: 1 DIQMTQSPSSLSASVGDRVT..........EVTHQGLSSPVTKSFNRGEC 214
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 214 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 50 summaries
Database : US-12-590-973-129.fasta:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 1102 100.0 214 1 US-12-590-973-129 Binding molecules
ALIGNMENTS
RESULT 1
US-12-590-973-129
Query Match 100.0%; Score 1102; DB 1; Length 214;
Best Local Similarity 100.0%;
Matches 214; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIKRTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIKRTVAAPSVFIFPP 120
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
Applicant argues “To arrive at the current invention, a skilled person will have to combine the multimer as allegedly taught by Bacac, provide suitable linkers for connecting Fab2 and Fab3 as allegedly taught by Andresen et. al., and then cleave of the CH2/CH3 region using the method as allegedly taught by Sjogren. This combination is not, however, suggested by the combination of cited references”; and that there is not motivation to combine Bacac, Andresen, and Sjogren et. al. (Remarks p. 10). These arguments are moot in view of the new 103 rejection above, which does not rely on Andresen. The Examiner notes that, as described in the 103 rejection above, the linker of SEQ ID NO: 305 of Bacac et. al. linking the Fab heavy chain VH is 100% identical to instant SEQ ID NO: 13.
In regards to claims 23, 28, 29, and 31, Applicant argues that there is no suggestion in the cited references to motivate a skilled artisan to combine Bacac with Wu or Sjogren et. al. and that Bacac et. al. teaches Fab fragments, generically. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, this is not persuasive because the disclosure of Bacac et. al. suggests that the instant antibody is defined as broadly as possible and the disclosure of Fab’2 fragments suggest that Bacac et. al., and a person of ordinary skill in the art was aware of various types of fragments made by cleaving off the Fc domain. As described in the new 103 rejection above, it is clear that a person of ordinary skill would understand that trivalent fragments may be made from the antibody of Bacac et. al. because Ghayur et. al. explicitly discloses trivalent fragments comprising only the VH/VL and CH1/CL domains; additionally, Holliger et. al. explicitly teaches why an artisan may contemplate fragments of an antibody (e.g. to reduce immunogenicity, as described above), and that the fragments may be made using pepsin to remove the Fc domain. MPEP 2144 states “The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992); see also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000)”. Thus, as described in the 103 rejection above, 1) Bacac et. al. suggests the general knowledge of a person of ordinary skill in the art of antibody fragments in the broadest sense of the definition; 2) Ghayur et. al. suggests the knowledge of a person of ordinary skill in the art would extend to trivalent antibody fragments; and 3) Holliger et. al. demonstrates that a person of ordinary skill had both a method to cleave off the CH2/CH3 domain and the expectation of a benefit from making and Fc-less antibody fragments; all of these offer motivation to combine and a reasonable expectation of success as described in the 103 rejection above.
Applicant argues that Wu et. al. does not teach or suggest the F(ab’)3 format (Remarks p. 11). 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).
Applicant also argues “a skilled artisan would understand that the IdeS protease could be used for analytical characterization of antibodies, for instance mass spectrometry related methods. Nowhere in Sjögren is it suggested that their protease can also be used for the generation of therapeutic trivalent antibodies” (Remarks p. 11-12). This is moot in view of the new rejection above which does not rely on Sjogren. However, the Examiner would like to note the recited limitation of “therapeutic trivalent antibodies” is not recited in the claims, and that even if it were it is unclear how this would patentably distinguish the instantly claimed structure because there is no claimed feature that would make the therapeutic multimer patentably distinct from the multimer generally (for example, if the therapeutic multimer requires a composition comprising therapeutically effective dose, there are no amounts required in the claims); there is no amount of stability or amount of product required by the claims. Additionally, a person of ordinary skill in the art, based on the stability of the antibodies of Bacac et. al. and the known properties of Fab’2 fragments would have a reasonable expectation of success at generating the trivalent multimer as instantly claimed. As described in the 103 rejection above, Bacac et. al. in view of Ghayur et. al. and Holliger et. al. would suggest to a person of ordinary skill in the art a reasonable expectation of success of generating a trivalent fragment of the multimer of Bacac et. al.
Lastly, Applicant argues that because the IdeS antibody of Sjogren cleaves the hinge region, a person of ordinary skill in the art would not use an immunological hinge-derived linker to connect the domains. This is not persuasive in view of the new 103 rejection above because a person of ordinary skill in the art, at the time of filing, would know which parts of the hinge were cleaved by which enzymes (as evidenced by Brezski RJ, Jordan RE. Cleavage of IgGs by proteases associated with invasive diseases: an evasion tactic against host immunity? MAbs. 2010 May-Jun;2(3):212-20. doi: 10.4161/mabs.2.3.11780. Epub 2010 May 23; See Fig. 1); and therefore would be able to determine what linkers to use between the Fab domains of Bacac et. al.; or to determine that the exemplary linker between heavy chain Fab domains of Bacac et. al. does not contain a pepsin cleavage site.
Double Patenting- New
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
Applicants’ argument dated 3/3/2026 have been fully considered but are moot due to the withdrawal of the previous NSDP rejection and the new NSDP rejection, above, or are not persuasive. Applicant argues that Sjogren et. al. does not provide any teaching that would motivate a skilled artisan to arrive at the claimed invention because Sjogren does not teach therapeutic trivalent multimers lacking a CH2 and/or CH3 region. As described for the 103 rejection above, this is unpersuasive because the limitation of a therapeutic trivalent multimer is not claimed. As described in the previous rejection, a person of ordinary skill in the art would have been motivated to generate the fragments of Bacac et. al. to analyze their binding properties as taught by Sjogren. Additionally, the new NSDP rejection above does not rely on Sjogren as described. Applicant argues that applying Sjogren to the ‘424 patent could only be the result of impermissible hindsight (Remarks p. 13). Although this argument is moot in view of the new NSDP rejection above, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, 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). As described in the new NSDP rejection above, a person of ordinary skill in the art would understand from ‘424 in view of Ghayur et. al. and Holliger et. al. that fragments could be generated, for example by pepsin digestion, and are included in the understanding of a person of ordinary skill in contemplating an antibody; and further, an artisan would understand that these fragments have an advantage of reduced immunogenicity as taught by Holliger et. al.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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