DETAILED ACTION
Claims 1-9, 15-18, and 21-27 are pending in the instant application and being examined on the merit.
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 .
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). The examiner has noted that the specification at page 27, paragraph [00130] contain the amino acid sequence (Gly4-Ser)3 which is not followed by a sequence identifier.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities:
“anions exchange chromatography” should read “anion exchange chromatography” (page 33, paragraph [00165]).
“SpectraMaxR” should read “SpectraMax®” (page 36, paragraph [00175]).
Devies” should read “Devices” (page 36, paragraph [00175]).
Appropriate correction is required.
The use of the term Nanodrop, lipofectamine, FACS, and SpectraMax which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. All trademarks referenced herein should be identified as such with the appropriate notation:
NanoDrop (page 33, paragraph [00163], [00164])
Lipofectamine (page 35, paragraph [00172])
FACS (page 36, paragraph [00172], [00173], [00174])
SpectraMax i3X (page 36, paragraph [00175])
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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, 2, and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Cochrane et al (WO2008/099188A1, priority to 2/15/2007; hereinafter Cochrane), and further in view of Lehmann et al (mAbs, 2015, 7(6): 1058-1071; hereinafter Lehmann).
Regarding instant claims 1, 2, and 16-18, Cochrane teaches a single chain fragment variable (scFv) comprising a heavy chain domain, a peptide linker, and a light chain domain (page 22, section 21, lines 29-31) wherein the light chain variable region comprises four framework regions (Table 2a-2f) with Leucine (L), threonine (T), and alanine (A) at positions 104-106, respectively, and glutamic acid (E) at position 83 according to the Kabat numbering scheme as shown in the figure below (disclosed as “Antibody 5” compared to the purified human anti-IgE IgG, Antibody 33) (page 116, section 115, Table 2e, Antibody 5; page 71, section 70, SEQ ID NO:333) and comprises a human lambda(λ) light chain (page 73, section 72, lines 12-14).
Table 2e of WO2008/099188A1
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Cochrane also teaches an isolated nucleic acid encoding the scFv, an expression vector comprising the nucleic acid encoding the scFv, and a host cell comprising the expression vector comprising the nucleic acid encoding the scFv (page 43, section 42, lines 1-24).
Cochrane, however, does not teach the light chain comprising L, T, and A at positions 104-106 according to the Kabat numbering scheme is a kappa (κ) light chain.
The deficiency is resolved by Lehmann et al.
Lehmann teaches that scFvs comprising heavy chain and light chain domains tethered by a peptide linker are highly target-specific but are often limited in their stability and aggregation propensity, which negatively affects expression, purification, concentration, immunogenicity, and function (page 1058, paragraph 1). Due to this limitation, Lehmann teaches a method to exchange λ sequences with more stable κ sequences in the light chain domain to produce thermodynamically stable scFvs while maintaining comparable binding affinity (page 1058, abstract; page 1059, paragraph 3). Lehmann further teaches the manufacturing components, including the nucleotide sequences, expression vector, and host cell used for cloning, expression and purification of the scFv comprising heavy chain and light chain domains tethered by a peptide linker wherein the light chain domain is exchanged from a λ light chain to a κ light chain (page 1068, paragraph 8-9; supplementary tables 1 and 2).
Regarding instant claims 1 and 2, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the scFv comprising a heavy chain domain, a peptide linker, and a λ light chain domain wherein the light chain variable region comprises four framework regions with E, L, T, and A at positions 83 and 104-106, respectively, according to the Kabat numbering scheme as taught by Cochrane and exchange the λ light chain with the κ light chain as taught by Lehmann. This is obvious, because Cochrane teaches a scFv consisting of heavy and light chain domains joined by a peptide linker wherein the light chain is a λ light chain comprising four framework regions with E, L, T, and A at positions 83 and 104-106, respectively, according to Kabat numbering scheme, and Lehmann teaches a method to exchange λ sequences with more stable κ sequences in the light chain domain to improve thermodynamic stability while maintaining binding affinity comparable to that of the original sequence. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the scFv comprising a heavy chain domain, a peptide linker, and a λ light chain domain wherein the λ light chain variable region comprises four framework regions with E, L, T, and A at positions 83 and 104-106, respectively, according to the Kabat numbering scheme as taught by Cochrane and exchange the λ light chain to a κ light chain to improve thermodynamic stability as taught by Lehmann to form the instant scFv comprising a heavy chain variable region, a linker, and a κ light chain variable region wherein the instant κ light chain variable region comprises four framework regions and is engineered to comprise L, T, and A at instant positions 104-106, respectively (instant claim 1), and E at instant position 83 according to the Kabat numbering scheme (instant claim 2).
Regarding instant claims 16-18, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the nucleic acid molecule (wherein the nucleic acid molecule encodes the scFv comprising a heavy chain domain, a peptide linker, and a λ light chain domain, wherein the λ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme), expression vector, and host cell as taught by Cochrane and exchange the λ light chain of the scFv to a κ light chain to improve thermodynamic stability as taught by Lehmann. This is obvious, because Cochrane teaches a nucleic acid molecule, expression vector, and host cell to produce a scFv comprising a heavy chain domain, a peptide linker, and a λ light chain domain wherein the λ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme, and Lehmann teaches a nucleic acid molecule encoding a scFv comprising stable κ sequences in the light chain domain to improve thermodynamic stability while maintaining a binding affinity comparable to that of the original sequence, an expression vector comprising the nucleic acid molecule encoding the scFv comprising the stable κ sequences in the light chain domain, and a host cell comprising the expression vector comprising the nucleic acid molecule encoding the scFv comprising the stable κ sequences in the light chain domain. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the nucleic acid molecule that encodes a scFv comprising a heavy chain domain, a peptide linker, and a λ light chain domain, wherein the λ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by Cochrane and exchange λ light chain sequences with κ light chain sequences in the scFv to improve thermodynamic stability as taught by Lehmann to form the instant nucleic acid molecule encoding the instant scFv comprising a heavy chain variable region, a linker, and a κ light chain variable region wherein the instant κ light chain variable region comprises four framework regions and is engineered to comprise L, T, and A at instant positions 104-106, respectively, according to the Kabat numbering scheme (instant claim 16), the instant expression vector comprising the instant nucleic acid molecule encoding the instant scFv (instant claim 17), and the instant host cell comprising the instant expression vector comprising the instant nucleic acid molecule encoding the instant scFv (instant claim 18).
Claims 3 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Cochrane et al (WO2008/099188A1, priority to 2/15/2007; hereinafter Cochrane), and Lehmann et al (mAbs, 2015, 7(6): 1058-1071; hereinafter Lehmann) as applied to claim 1 above, and further in view of Tanaka et al (The EMBO Journal, 2003, 22(5): 1025-1035; hereinafter Tanaka).
The teachings of Cochrane and Lehmann are discussed above.
However, Cochrane and Lehmann do not teach the scFv wherein the κ light chain variable region is engineered to comprise glutamine (Q) at position 100 according to the Kabat numbering scheme, and the linker is -(G4S)3-, -(G4S)4-, or –(G4S)5-.
The deficiency is resolved by Tanaka et al.
Tanaka teaches a method of improving solubility and function of the scFvs by using the intracellular antibody capture (IAC) technology using subgroups from the Vκ framework (page 1032, paragraph 2), wherein the scFvs comprised a 15-residue linker, (GGGGS)3, which linked the heavy chain domain with the light chain variable domain, and belonged to a Vκ1 subgroup of light chains wherein the I21 scFv clones comprised a glutamine (Q) at position 100 according to the Kabat numbering scheme as shown below (Fig. 3 and Fig. 3 legend).
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Regarding instant claims 3 and 6, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the scFv comprising a heavy chain domain, a peptide linker, and a κ light chain domain wherein the light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by the combined teachings of Cochrane and Lehmann to include a -(G4S)3- linker and engineer the κ light chain variable region to comprise glutamine (Q) at position 100 according to the Kabat numbering scheme to improve solubility and function of the scFv as taught by Tanaka. This is obvious, because the combined teachings of Cochrane and Lehmann teach a scFv consisting heavy and light chain domains joined by a peptide linker wherein the light chain is a thermodynamically stable κ light chain comprising four framework regions with L, T, and A at positions 104-106, respectively, and Tanaka teaches scFvs comprising a -(G4S)3- linker and a κ light chain variable region comprising Q at position 100 according to the Kabat numbering scheme to improve solubility and function of the scFv. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the scFv comprising a heavy chain domain, a -(G4S)3- linker (taught by Tanaka), and a κ light chain domain wherein the κ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by the combined teachings of Cochrane and Lehmann, and Q at position 100 according to the Kabat numbering scheme as taught by Tanaka to form the instant scFv comprising a heavy chain variable region, a -(G4S)3- linker (instant claim 6), and a κ light chain variable region wherein the instant κ light chain variable region comprises four framework regions and is engineered to comprise Q, L, T, and A at instant positions 100 and 104-106, respectively, according to the Kabat numbering scheme (instant claim 3).
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Cochrane et al (WO2008/099188A1, priority to 2/15/2007; hereinafter Cochrane) and Lehmann et al (mAbs, 2015, 7(6): 1058-1071; hereinafter Lehmann) as applied to claim 1 above, and further in view of Wälchli et al (US 20230355672A1, Priority to 6/24/2020; hereinafter Wälchli).
The teachings of Cochrane and Lehmann are discussed above.
However, Cochrane and Lehmann do not teach an scFv, wherein the fourth framework region comprises the amino acid sequence of instant SEQ ID NO:33, wherein X is G or Q (instant claim 4).
The deficiency is resolved by Wälchli et al.
Wälchli teaches a scFv comprising the following structure:
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wherein SEQ ID NO:13 comprise the light chain domain with the fourth framework region comprising amino acid sequence FGGGTKLTVKR (page 12, paragraphs [0088-0092]).
Wälchli teaches that the antibody framework sequences may tolerate some variations without destroying the specificity and affinity to the antigen (page 16, paragraph [0116])
Regarding instant claim 4, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the scFv comprising a heavy chain domain, a peptide linker, and a κ light chain domain comprising four framework regions as taught by the combined teachings of Cochrane and Lehmann to include the fourth framework sequence as taught by SEQ ID NO:13 of Wälchli, wherein the fourth framework region comprises L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by Cochrane. This is obvious, because the combined teachings of Cochrane and Lehmann teach a scFv comprising heavy and light chain domains joined by a peptide linker wherein the light chain is a thermodynamically stable κ light chain comprising four framework regions, Wälchli teaches SEQ ID NO:13 wherein the fourth framework region comprises the amino acid sequence FGGGTKLTVKR, and Cochrane teaches a fourth framework region comprising L, T, and A at positions 104-106, respectively. Further Wälchli teaches that the framework sequences may be varied without affect antigen binding and an antibody comprising SEQ ID NO:13 is a functional antibody. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the scFv comprising a heavy chain domain, a peptide linker, and a κ light chain domain comprising four framework regions as taught by the combined teachings of Cochrane and Lehmann to include the fourth framework sequence as taught by SEQ ID NO:13 of Wälchli, wherein the fourth framework region comprises L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by Cochrane to form the instant scFv comprising a heavy chain domain, a peptide linker, and a κ light chain domain comprising four framework regions wherein fourth framework region comprises L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme (instant claim 1), and comprises of the amino acid sequence instant SEQ ID NO:33, wherein X is G (instant claim 4).
Claims 5, 7, 9, 21-27 are rejected under 35 U.S.C. 103 as being unpatentable over Cochrane et al (WO2008/099188A1, priority to 2/15/2007; hereinafter Cochrane), and Lehmann et al (mAbs, 2015, 7(6): 1058-1071; hereinafter Lehmann) as applied to claim 1 above, and further in view of Li et al (WO2022/134645A1, priority to 12/23/2020; hereinafter Li).
The teachings of Cochrane and Lehmann are discussed above.
However, Cochrane and Lehmann do not teach an scFv, capable of binding to CD20 or TIGIT (instant claim 5), wherein the scFv comprises a -(G4S)4- linker, a heavy chain variable region comprising VH-CDR1-3 comprising instant SEQ ID NOs:7-9, respectively, and a light chain variable region comprising VL-CDR1-3 comprising instant SEQ ID NOs:10-12, respectively (instant claim 7). Additionally, the combined teachings of Cochrane and Lehmann do not teach a bispecific antibody capable of binding CD3 and CD20, comprising an anti-CD3 Fab, an anti-CD20 Fab, and an anti-CD20 scFv (instant claim 9) wherein the bispecific antibody comprises:
an anti-CD3 Fab comprising the amino acid sequences that are the same as instant heavy and light chain variable region comprising SEQ ID NOs:13 and 14 (instant claim 22), which comprises CDR sequences of SEQ ID NOs 1-3 and 4-6 (instant claim 21).
an anti-CD20 Fab comprising the amino acid sequences that are the same as instant heavy and light chain variable region comprising SEQ ID NO:15 (comprising the CDR sequences that are the same as instant SEQ ID NOs:7-9) and SEQ ID NO:16, wherein X1-X5 of instant SEQ ID NO:16 is comprised of V, G, V, E, and I, respectively (comprising the same CDR sequences as instant SEQ ID NOs:10-12) (instant claims 21 and 22).
Furthermore, the combined teachings of Cochrane and Lehmann do not teach the structural components of the bispecific antibody wherein:
the first polypeptide chain comprises an anti-CD20 heavy chain variable region and a heavy chain constant region, wherein the heavy chain constant region comprises, from N-terminus to C-terminus, CH1, CH2 and CH3,
the second polypeptide chain comprises, from N-terminus to C-terminus, an anti-CD20 light chain variable region and a light chain constant region,
the third polypeptide chain, from N-terminus to C-terminus, comprises an anti-CD20 scFv, an anti-CD3 heavy chain variable region, and a heavy chain constant region wherein the heavy chain constant region comprises CH1, CH2 and CH3, and
the fourth polypeptide chain comprises, from N-terminus to C-terminus, an anti-CD3 light chain variable region and a light chain constant region,
wherein the anti-CD20 heavy chain variable region and the heavy chain constant region CH1 in the first polypeptide chain associate with the anti-CD20 light chain variable region and the light chain constant region in the second polypeptide chain to form the anti-CD20 Fab, the anti-CD3 heavy chain variable region and the heavy chain constant region CH1 in the third polypeptide chain associate with the anti-CD3 light chain variable region and the light chain constant region in the fourth polypeptide chain to form the anti-CD3 Fab (instant claims 23 and 25), and the heavy chain constant region in the first polypeptide chain is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366S/L368A/Y407V mutations, and the heavy chain constant region in the third polypeptide chain is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366W mutations (instant claim 24). Finally, the combined teachings of Cochrane and Lehmann do not teach a pharmaceutical composition comprising the bispecific antibody (instant claim 26) for treating or alleviating a B-cell associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition wherein the B-cell associated disease is B-cell lymphoma, B-cell leukemia, or B-cell mediated autoimmune disease (instant claim 27).
The deficiency is resolved by Li et al.
Li teaches a bispecific antibody capable of binding CD3 and CD20 (page 7, paragraph [0032]), comprising an anti-CD3 Fab, an anti-CD20 Fab, and an anti-CD20 scFv (FIG. 14) wherein:
the first polypeptide chain comprises an anti-CD20 heavy chain variable region and a heavy chain constant region, wherein the heavy chain constant region comprises, from N-terminus to C-terminus, a CH1, CH2, and CH3 (FIG. 14; page 7, paragraph [0033]; page 8, paragraph [0038]),
the second polypeptide chain comprises, from N-terminus to C-terminus, an anti-CD20 light chain variable region and a light chain constant region (FIG 14; page 7, paragraph [0033]),
the third polypeptide chain, from N-terminus to C-terminus, comprises an anti-CD20 scFv, an anti-CD3 heavy chain variable region, and a heavy chain constant region, wherein the heavy chain constant region comprises CH1, CH2 and CH3 (FIG. 14; page 7, paragraph [0033]; page 8, paragraph [0038]), and
the fourth polypeptide chain comprises, from N-terminus to C-terminus, an anti-CD3 light chain variable region and a light chain constant region (FIG. 14; page 7, paragraph [0033]),
wherein the anti-CD20 heavy chain variable region and the heavy chain constant region CH1 in the first polypeptide chain associate with the anti-CD20 light chain variable region and the light chain constant region in the second polypeptide chain to form the anti-CD20 Fab, the anti-CD3 heavy chain variable region and the heavy chain constant region CH1 in the third polypeptide chain associate with the anti-CD3 light chain variable region and the light chain constant region in the fourth polypeptide chain to form the anti-CD3 Fab (FIG. 14; page 7, paragraph [0033]), and the heavy chain constant region in the first polypeptide chain is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366S/L368A/Y407V mutations (FIG. 14; page 7, paragraph [0035]-page 8, paragraph [0035]), and the heavy chain constant region in the third polypeptide chain is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366W mutations (FIG. 14; page 7, paragraph [0035]-page 8, paragraph [0035]; page 42, paragraph [00236]). Li also teaches the scFv wherein the heavy chain variable region comprising SEQ ID NO:26 (identical to instant SEQ ID NO:15) comprising VH-CDR1-3 comprising amino acid sequences identical to instant SEQ ID NOs:7-9, respectively, and the light chain variable region comprising SEQ ID NO:27(identical to instant SEQ ID NO:16 wherein X1-X5 is V, G, V, E, and I, respectively) comprising VL-CDR1-3 comprising amino acid sequences identical to instant SEQ ID NOs:10-12, respectively (page 55, paragraph [00277], SEQ ID NOs:26 and 27; page 44, paragraph [00246]; Claim 11), and SEQ ID NO:29, which is identical to instant SEQ ID NO:20. Li further teaches the bispecific antibody wherein:
the anti-CD3 Fab comprises:
a heavy chain variable region CDR1 (VH-CDR1), a VH-CDR2, a VH-CDR3, a light chain variable region (VL-CDR1), a VL-CDR2 and a VL-CDR3 comprising SEQ ID NOs:1, 2, 3 (wherein X1=L and X2=Y), 4, 5 (wherein X1=K, X2=Q, and X3=R), and 6, respectively, wherein amino acid sequences SEQ ID NOs:1-6 recited above are identical to instant SEQ ID NOs:1-6, respectively (pages 50-51, paragraph [00277], SEQ ID NOs:1-6), and
a heavy chain variable region and a light chain variable region comprising SEQ ID NO:10 (identical to instant SEQ ID NO:13) and SEQ ID NO:18 (identical to instant SEQ ID NO:14), respectively (page 52, paragraph [00277], SEQ ID NOs:10 and 18), and
the anti-CD20 Fab comprises:
VH-CDR1-3 and VL-CDR1-3 comprising the CDR amino acid sequences listed in SEQ ID NO:26 and 27, respectively, which are identical to instant SEQ ID NOs:7-12, respectively (page 7, paragraph [0031]; page 44, paragraph [00246]; and page 55, paragraph [00277], SEQ ID NOs:26 and 27), and
amino acid sequences SEQ ID NO:26 (identical to instant SEQ ID NO: 15) and SEQ ID NO:27 (identical to instant SEQ ID NO:16 wherein X1, X2, X3, X4 and X5 are V, G, V, E and I, respectively), respectively (page 55, paragraph [00277], SEQ ID NOs:26 and 27).
Finally, Li teaches a pharmaceutical composition comprising the bispecific antibody (page 10, paragraph [0048]), and a method for treating or alleviating a B cell associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition, wherein the B cell associated disease is B-cell lymphoma, B-cell leukemia, or a B cell-mediated autoimmune disease (page 11, paragraph [0055]).
In regards to the -(G4S)4- linker (instant SEQ ID NO:28) recited in instant claim 7, using a (GGGGS)4 linker, a 20-mer glycine-serine rich flexible linker, in a scFv is a widely known and common practice in the art to provide flexibility, enhance solubility, and prevent secondary structure formation.
Regarding instant claims 5 and 7, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the scFv comprising a heavy chain domain, a peptide linker, and a κ light chain domain wherein the light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by the combined teachings of Cochrane and Lehmann wherein the linker is -(G4S)4- and comprises a heavy chain variable region comprising VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26, and a light chain variable region comprising VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27, wherein the scFv is capable of binding to CD20 as taught by Li. This is obvious, because the combined teachings of Cochrane and Lehmann teach a scFv comprising heavy and light chain domains joined by a peptide linker wherein the light chain is a thermodynamically stable κ light chain comprising four framework regions with L, T, and A at positions 104-106, respectively, and Li teaches a scFv comprising a heavy chain variable region comprising VH-CDR1-3 comprising CDR amino acid sequences of SEQ ID NO:26, and a light chain variable region comprising VL-CDR1-3 comprising CDR amino acid sequences of SEQ ID NO:27 wherein the scFv is capable of binding to CD20. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the scFv capable of binding CD20 comprising a heavy chain domain, a -(G4S)4- linker, and a κ light chain domain wherein the κ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by the combined teachings of Cochrane and Lehmann, wherein the heavy chain variable region comprises VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26, and the light chain variable region comprises VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27 as taught by Li to form the instant scFv capable of binding CD20 (instant claim 5) comprising a heavy chain variable region, a -(G4S)4- linker, and a κ light chain variable region wherein:
the instant κ light chain variable region comprises four framework regions and is engineered to comprise L, T, and A at instant position 104-106, respectively, according to the Kabat numbering scheme (instant claim 1), and
the instant heavy chain variable region comprises VH-CDR1-3 comprising instant SEQ ID NOs:7-9, respectively, and the instant light chain variable region comprises VL-CDR1-3 comprising instant SEQ ID NOs:10-12, respectively (instant claim 7).
Regarding instant claims 9 and 21-25, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the scFv comprising a heavy chain domain, a peptide linker, and a κ light chain domain wherein the κ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by the combined teachings of Cochrane and Lehmann, and include it in a bispecific antibody capable of binding CD3 and CD20, comprising:
an anti-CD3 Fab comprising a heavy chain variable region and a light chain variable region comprising SEQ ID NOs:10 and 18, respectively, wherein the VH-CDR1-3 and VL-CDR1-3 comprise SEQ ID NOs:1-6, respectively,
an anti-CD20 Fab comprising a heavy chain variable region comprising VH-CDR1-3 and a light chain variable region comprising VL-CDR1-3 comprising SEQ ID NOs:26 and 27, respectively,
a scFv capable of binding CD20 comprising a heavy chain variable region comprising VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26, and a light chain variable region comprising VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27,
a bispecific antibody structure wherein:
the first polypeptide chain, from N-terminus to C-terminus, comprises an anti-CD20 heavy chain variable region and a heavy chain constant region comprising CH1, CH2, and CH3,
the second polypeptide chain comprises, from N-terminus to C-terminus, an anti-CD20 light chain variable region and a light chain constant region,
the third polypeptide chain, from N-terminus to C-terminus, comprises an anti-CD20 scFv, an anti-CD3 heavy chain variable region, and a heavy chain constant region, wherein the heavy chain constant region comprises CH1, CH2, and CH3, and
the fourth polypeptide chain comprises, from N-terminus to C-terminus, an anti-CD3 light chain variable region and a light chain constant region,
wherein the anti-CD20 heavy chain variable region and the heavy chain constant region CH1 in the first polypeptide chain associate with the anti-CD20 light chain variable region and the light chain constant region in the second polypeptide chain to form the anti-CD20 Fab, the anti-CD3 heavy chain variable region and the heavy chain constant region CH1 in the third polypeptide chain associate with the anti-CD3 light chain variable region and the light chain constant region in the fourth polypeptide chain to form the anti-CD3 Fab, and
a heavy chain constant region in the first and third polypeptide chains wherein the heavy chain constant region in the first polypeptide is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366S/L368A/Y407V mutations, and the heavy chain constant region in the third polypeptide chain is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366W mutations
as taught by Li. This is obvious, because the combined teachings of Cochrane and Lehmann teach a scFv consisting of heavy and light chain domains joined by a peptide linker wherein the light chain is a thermodynamically stable κ light chain comprising four framework regions with L, T, and A at positions 104-106, respectively, and Li teaches a bispecific antibody capable of binding CD3 and CD20, comprising an anti-CD3 Fab, anti-CD20 Fab, and scFv capable of binding CD20, wherein:
the anti-CD3 Fab comprises a heavy chain variable region comprising amino acid sequence SEQ ID NO:10 and a light chain variable region comprising amino acid sequence SEQ ID NO:18, wherein the VH-CDR1-3 and VL-CDR1-3 comprise SEQ ID NOs:1-6, respectively,
the anti-CD20 Fab comprises a heavy chain variable region comprising VH-CDR1-3 comprising amino acid sequence SEQ ID NO:26 and a light chain variable region comprising VL-CDR1-3 comprising amino acid sequence SEQ ID NO:27,
the anti-CD20 scFv comprises a heavy chain variable region comprising VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26, and a light chain variable region comprising VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27,
the structure of the bispecific antibody comprises:
a first polypeptide chain, from N-terminus to C-terminus, comprising an anti-CD20 heavy chain variable region and a heavy chain constant region wherein the heavy chain constant region comprises CH1, CH2 and CH3,
a second polypeptide chain comprising, from N-terminus to C-terminus, an anti-CD20 light chain variable region and a light chain constant region,
a third polypeptide chain, from N-terminus to C-terminus, comprising an anti-CD20 scFv, an anti-CD3 heavy chain variable region, and a heavy chain constant region wherein the heavy chain constant region comprises CH1, CH2 and CH3, and
a fourth polypeptide chain comprising, from N-terminus to C-terminus, an anti-CD3 light chain variable region and a light chain constant region,
wherein the anti-CD20 heavy chain variable region and the heavy chain constant region CH1 in the first polypeptide chain associate with the anti-CD20 light chain variable region and the light chain constant region in the second polypeptide chain to form the anti-CD20 Fab, the anti-CD3 heavy chain variable region and the heavy chain constant region CH1 in the third polypeptide chain associate with the anti-CD3 light chain variable region and the light chain constant region in the fourth polypeptide chain to form the anti-CD3 Fab, and
the heavy chain constant region in the first polypeptide is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366S/L368A/Y407V mutations, and the heavy chain constant region in the third polypeptide chain is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366W mutations.
Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the bispecific antibody capable of binding CD3 and CD20, comprising an anti-CD3 Fab, anti-CD20 Fab, and scFv capable of binding CD20, wherein:
the anti-CD3 Fab comprises a heavy chain variable region comprising SEQ ID NO:10 and a light chain variable region comprising SEQ ID NO:18, wherein the VH-CDR1-3 and VL-CDR1-3 comprise SEQ ID NOs:1-6, respectively,
the anti-CD20 Fab comprises a heavy chain variable region comprising VH-CDR1-3 comprising SEQ ID NO:26 and a light chain variable region comprising VL-CDR1-3 comprising SEQ ID NO:27,
the anti-CD20 scFv comprises a heavy chain variable region comprising VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26 and a light chain variable region comprising VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27,
the bispecific antibody structure comprises:
a first polypeptide chain, from N-terminus to C-terminus, comprising an anti-CD20 heavy chain variable region and a heavy chain constant region, wherein the heavy chain constant region comprises CH1, CH2 and CH3,
a second polypeptide chain comprising, from N-terminus to C-terminus, an anti-CD20 light chain variable region and a light chain constant region,
a third polypeptide chain, from N-terminus to C-terminus, comprising an anti-CD20 scFv, an anti-CD3 heavy chain variable region, and a heavy chain constant region, wherein the heavy chain constant region comprises CH1, CH2 and CH3, and
a fourth polypeptide chain comprising, from N-terminus to C-terminus, an anti-CD3 light chain variable region and a light chain constant region,
wherein the anti-CD20 heavy chain variable region and the heavy chain constant region CH1 in the first polypeptide chain associate with the anti-CD20 light chain variable region and the light chain constant region in the second polypeptide chain to form the anti-CD20 Fab, the anti-CD3 heavy chain variable region and the heavy chain constant region CH1 in the third polypeptide chain associate with the anti-CD3 light chain variable region and the light chain constant region in the fourth polypeptide chain to form the anti-CD3 Fab, and
the heavy chain constant region in the first polypeptide is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366S/L368A/Y407V mutations, and the heavy chain constant region in the third polypeptide chain is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366W mutations
as taught by Li wherein the scFv comprises a heavy chain domain, a peptide linker, and a κ light chain domain, wherein the κ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by the combined teachings of Cochrane and Lehmann to form the instant bispecific antibody capable of binding CD3 and CD20, comprising an anti-CD3 Fab, anti-CD20 Fab, and anti-CD20 scFv (instant claim 9), wherein:
the instant anti-CD3 Fab comprises a heavy chain variable region comprising instant SEQ ID NO:13 and a light chain variable region comprising instant SEQ ID NO:14, wherein the VH-CDR1-3 and VL-CDR1-3 comprise instant SEQ ID NOs:1-6, respectively (instant claims 21 and 22),
the instant anti-CD20 Fab comprises a heavy chain variable region comprising instant SEQ ID NO:15 wherein VH-CDR1-3 comprise instant SEQ ID NOs:7-9 and a light chain variable region comprising instant SEQ ID NO:16, wherein X1, X2, X3, X4, and X5 are V, G, V, E, I, respectively, wherein VL-CDR1-3 comprise instant SEQ ID NOs:10-12 (instant claims 21 and 22),
the instant anti-CD20 scFv comprises a heavy chain variable region, a -(G4S)4- linker, and a κ light chain variable region wherein:
the instant κ light chain variable region comprises four framework regions with L, T, and A at instant positions 104-106, respectively, according to the Kabat numbering scheme (instant claim 1),
the instant heavy chain variable region comprises VH-CDR1-3 comprising instant SEQ ID NOs:7-9, respectively, and the instant light chain variable region comprises VL-CDR1-3 comprising instant SEQ ID NOs:10-12, respectively (instant claim 7).
The instant bispecific antibody structure comprises:
a first polypeptide chain, from N-terminus to C-terminus, comprising an anti-CD20 heavy chain variable region and a heavy chain constant region, wherein the heavy chain constant region comprises CH1, CH2 and CH3,
a second polypeptide chain comprising, from N-terminus to C-terminus, an anti-CD20 light chain variable region and a light chain constant region,
a third polypeptide chain, from N-terminus to C-terminus, comprising an anti-CD20 scFv, an anti-CD3 heavy chain variable region, and a heavy chain constant region wherein the heavy chain constant region comprises CH1, CH2 and CH3, and
a fourth polypeptide chain comprising, from N-terminus to C-terminus, an anti-CD3 light chain variable region and a light chain constant region,
wherein the instant anti-CD20 heavy chain variable region and the instant heavy chain constant region CH1 in the instant first polypeptide chain associate with the instant anti-CD20 light chain variable region and the instant light chain constant region in the instant second polypeptide chain to form the instant anti-CD20 Fab, the instant anti-CD3 heavy chain variable region and the instant heavy chain constant region CH1 in the instant third polypeptide chain associate with the instant anti-CD3 light chain variable region and the instant light chain constant region in the instant fourth polypeptide chain to form the instant anti-CD3 Fab (instant claims 23 and 25), and
the instant heavy chain constant region in the instant first polypeptide is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366S/L368A/Y407V mutations, and the instant heavy chain constant region in the instant third polypeptide chain is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366W mutations (instant claim 24).
Regarding claims 26 and 27, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the bispecific antibody capable of binding CD3 and CD20, wherein the bispecific antibody comprises an anti-CD3 Fab, anti-CD20 Fab, and scFv capable of binding CD20, wherein the anti-CD20 scFv comprises a heavy chain variable region comprising VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26 and a light chain variable region comprising VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27 as taught by Li, wherein the scFv comprises a heavy chain domain, a peptide linker, and a κ light chain domain, wherein the κ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by the combined teachings of Cochrane and Lehmann, and include it in a pharmaceutical composition comprising the bispecific antibody wherein the pharmaceutical composition is used in a method for treating or alleviating a B cell associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition, wherein the B cell associated disease is B-cell lymphoma, B-cell leukemia, or a B cell-mediated autoimmune disease as taught by Li. This is obvious, because the combined teachings of Cochrane and Lehmann teach a scFv comprising heavy and light chain domains joined by a peptide linker wherein the light chain is a thermodynamically stable κ light chain comprising four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme, and Li teaches a method for treating or alleviating a B cell associated disease (e.g. B-cell lymphoma, B-cell leukemia, or a B cell-mediated autoimmune disease) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition wherein the pharmaceutical composition comprises a bispecific antibody capable of binding CD3 and CD20, wherein the bispecific antibody comprises an anti-CD3 Fab, anti-CD20 Fab, and scFv capable of binding CD20, wherein the anti-CD20 scFv comprises a heavy chain variable region comprising VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26 and a light chain variable region comprising VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the pharmaceutical composition comprising the bispecific antibody capable of binding CD3 and CD20, comprising an anti-CD3 Fab, anti-CD20 Fab, and scFv capable of binding CD20, wherein the anti-CD20 scFv comprises a heavy chain variable region comprising VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26 and a light chain variable region comprising VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27, and use it in a method for treating a B cell associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition, wherein the B cell associated disease is B-cell lymphoma, B-cell leukemia, or a b cell-mediated autoimmune disease as taught by Li wherein the scFv comprises a heavy chain domain, a peptide linker, and a κ light chain domain, wherein the κ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by the combined teachings of Cochrane and Lehmann to form the instant method for treating or alleviating a B cell associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the instant pharmaceutical composition comprising the instant bispecific antibody (instant claim 26) capable of binding CD3 and CD20, comprising an anti-CD3 Fab, anti-CD20 Fab, and scFv capable of binding CD20 (instant claim 9), wherein the instant anti-CD20 scFv comprises a heavy chain variable region, a -(G4S)4- linker, and a κ light chain variable region wherein:
the instant κ light chain variable region comprises four framework regions with L, T, and A at instant positions 104-106, respectively, according to the Kabat numbering scheme (instant claim 1), and
the instant heavy chain variable region comprises VH-CDR1-3 comprising instant SEQ ID NOs:7-9, respectively, and the instant light chain variable region comprises VL-CDR1-3 comprising instant SEQ ID NOs:10-12 (instant claim 7), respectively,
wherein the B cell associated disease is B-cell lymphoma, B-cell leukemia, or a B cell-mediated autoimmune disease (instant claim 27).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Cochrane et al (WO2008/099188A1, priority to 2/15/2007; hereinafter Cochrane), Lehmann et al (mAbs, 2015, 7(6): 1058-1071; hereinafter Lehmann), and Li et al (WO2022/134645A1, priority to 12/23/2020; hereinafter Li) as applied to claim 1 above, and further in view of Sasisekharan et al (US Patent No. 11,459,405B2; hereinafter Sasisekharan).
The teachings of Cochrane, Lehmann, and Li are discussed above.
However, Cochrane, Lehmann, and Li do not teach an scFv comprising a heavy chain variable region, a linker, and a κ light chain wherein the κ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme, the instant heavy chain variable region comprises instant SEQ ID NO:15 comprising VH-CDR1-3 comprising instant SEQ ID NOs:7-9, respectively, and the instant light chain variable region comprises instant SEQ ID NO:16, wherein X1-X5 are V, G, L, T, and A, respectively, wherein VL-CDR1-3 comprises instant SEQ ID NOs:10-12, respectively.
The deficiency is resolved by Sasisekharan et al.
Sasisekharan teaches a bispecific antibody that binds to CD20 comprising the light chain of Obinutuzumab having substitutions set forth in SEQ ID NO:21, wherein the fourth framework of the light chain variable region comprises amino acid sequence “FGGGTKVEIK” (page 50, section 55, lines 30-32; Table 8). Sasisekharan teaches that the framework sequences of an antibody can be varied (column 15).
Regarding instant claim 8, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the scFv comprising a heavy chain domain, a peptide linker, and a κ light chain domain wherein the light chain variable region comprises four framework regions as taught by the combined teachings of Cochrane and Lehmann wherein the linker is -(G4S)4- and comprises a heavy chain variable region comprising VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26, and a light chain variable region comprising VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27 as taught by Li to comprise SEQ ID NO:21 in the light chain variable region as taught by Sasisekharan wherein the fourth framework region comprises L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by Cochrane. This is obvious, because the combined teachings of Cochrane and Lehmann teach a scFv comprising heavy and light chain domains joined by a peptide linker wherein the light chain is a thermodynamically stable κ light chain comprising four framework regions, Li teaches a scFv comprising a heavy chain variable region comprising VH-CDR1-3 comprising CDR amino acid sequences of SEQ ID NO:26, and a light chain variable region comprising VL-CDR1-3 comprising CDR amino acid sequences of SEQ ID NO:27, Sasisekharan teaches SEQ ID NO:21 wherein the fourth framework region of the light chain variable region comprises amino acid sequence FGGGTKVEIK, and Cochrane teaches a fourth framework region comprising L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the scFv comprising a heavy chain domain, a peptide linker, and a κ light chain domain wherein the light chain variable region comprises four framework regions as taught by the combined teachings of Cochrane and Lehmann wherein the linker is -(G4S)4- and comprises a heavy chain variable region comprising CDR amino acid sequences of SEQ ID NO:26, and a light chain variable region comprising CDR amino acid sequences of SEQ ID NO:27 as taught by Li to comprise SEQ ID NO:21 in the light chain variable region as taught by Sasisekharan wherein the fourth framework region comprises L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by Cochrane to form the instant scFv comprising a heavy chain variable region, a -(G4S)4- linker, and a κ light chain variable region wherein:
the instant κ light chain variable region comprises SEQ ID NO:16 wherein X1-X5 comprises V, G, L, T, A, respectively (instant claim 8), wherein the light chain variable region comprises four framework regions and is engineered to comprise L, T, and A at instant position 104-106, respectively, according to the Kabat numbering scheme (instant claim 1), and
the instant heavy chain variable region comprises instant SEQ ID NO:15 comprising VH-CDR1-3 comprising instant SEQ ID NOs:7-9, respectively, and the instant light chain variable region comprises VL-CDR1-3 comprising instant SEQ ID NOs:10-12, respectively (instant claim 7).
Double Patenting
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).
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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.
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Claims 1, 7, 9, 16-18, and 21-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-15 of U.S. Patent No. 12,180,280B2 (hereinafter Patent ‘280) in view of Cochrane et al (WO2008/099188A1, priority to 2/15/2007; hereinafter Cochrane) and Lehmann et al (mAbs, 2015, 7(6): 1058-1071; hereinafter Lehmann).
Claims 6 and 7 of Patent ‘280 teach a bispecific antibody comprising an antigen binding domain against CD3 and CD20 wherein the CD3 binding domain comprises an isolated monoclonal antibody or the antigen binding portion thereof wherein the isolated monoclonal antibody comprises a heavy chain variable region comprising VH-CDR1-3 comprising SEQ ID NOs:1-3 (identical to instant SEQ ID NOs:1-3), respectively and a light chain variable region comprising VL-CDR1-3 comprising SEQ ID NOs:4-6 (identical to instant SEQ ID NOs:4-6), respectively, and the CD20 binding domain comprises a heavy chain and light chain variable region. Additionally, Patent ‘280 teaches the bispecific antibody comprising one antigen binding domain against CD3 and two antigen binding domains against CD20. Claims 9-15 of Patent ‘280 further teach the structure of the bispecific antibody comprising:
a first polypeptide, from N terminus to C terminus, comprising an anti-CD20 heavy chain variable region and a heavy chain constant region, wherein:
the heavy chain variable region comprises SEQ ID NO:26 (identical to instant SEQ ID NO:15),
the heavy chain constant region comprises SEQ ID NO:33 (identical to instant SEQ ID NO:19, wherein X1, X2, and X3 comprise S, A, and V, respectively),
a second polypeptide comprising an anti-CD20 light chain variable region wherein:
the anti-CD20 light chain variable region comprises SEQ ID NO:27 (identical to instant SEQ ID NO:16),
the anti-CD20 light chain constant region comprises SEQ ID NO:31 (identical to instant SEQ ID NO:18),
a third polypeptide, from N terminus to C terminus, comprising an anti-CD20 heavy chain variable region, an anti-CD20 light chain variable region, an anti-CD3 heavy chain variable region, and a heavy chain constant region, wherein:
the third polypeptide comprises SEQ ID NO:29 (identical to instant SEQ ID NO:20),
the anti-CD20 heavy chain variable region comprises SEQ ID NO:26,
the heavy chain constant region comprises SEQ ID NO:34 (identical to instant SEQ ID NO:19, wherein X1, X2, and X3 comprise W, L, and Y, respectively),
the anti-CD20 light chain variable region comprises SEQ ID NO:27,
the linker sequence is GGGGSGGGGSGGGGS (identical to instant SEQ ID NO:27), and
a fourth polypeptide comprising an anti-CD3 light chain variable region and a light chain constant region, wherein the light chain constant region comprises SEQ ID NO:32,
wherein the anti-CD20 heavy chain variable region in the first polypeptide and the anti-CD20 light chain variable region in the second polypeptide associate to form the antigen binding fragment against CD20 protein, the anti-CD20 heavy chain variable region and the anti-CD20 light chain variable region in the third polypeptide associate to form the antigen binding fragment against CD20 protein, the anti-CD3 heavy chain variable region in the third polypeptide and the anti-CD3 light chain variable region in the fourth polypeptide associate to form an antigen binding fragment against CD3, wherein the heavy chain constant region in the first polypeptide and the heavy chain constant region in the third polypeptide are associated together. Regarding the third polypeptide, the anti-CD20 heavy chain variable region and the anti-CD20 light chain variable region is described as being linked via a linker to form a scFv (page 26, section 20, lines 13-15; FIG. 14). The specification also describes a pharmaceutical composition comprising the bispecific antibody (page 21, section 9, lines 36-40) wherein the pharmaceutical composition is administered to the subject in need thereof for treating a B cell associated disease e.g. B-cell lymphomas, B-cell leukemia, or a B-cell mediated autoimmune disease (page 21, section 10, lines 27-33).
Patent ‘280, however, does not teach a bispecific antibody wherein the scFv on the third polypeptide chain comprises a heavy chain domain, a peptide linker, and a κ light chain domain, wherein the κ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme.
The deficiency is resolved by Cochrane et al and Lehmann et al.
As described in the 103 rejections above, the teachings of Cochrane, Lehmann, and Li (which is the same reference as Patent ‘280) are described above.
Regarding instant claims 1, 7, 9 and 21-25, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the scFv comprising a heavy chain domain, a peptide linker, and a κ light chain domain, wherein the κ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by the combined teachings of Cochrane and Lehmann, and include it in a bispecific antibody capable of binding CD3 and CD20, comprising:
an anti-CD3 Fab comprising a heavy chain variable region and a light chain variable region comprising SEQ ID NOs:10 and 18, respectively, wherein the VH-CDR1-3 and VL-CDR1-3 comprise SEQ ID NOs:1-6, respectively,
an anti-CD20 Fab comprising a heavy chain variable region comprising VH-CDR1-3 and a light chain variable region comprising VL-CDR1-3 comprising SEQ ID NOs:26 and 27, respectively,
a scFv capable of binding CD20, wherein the anti-CD20 scFv comprises a heavy chain variable region comprising VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26 and a light chain variable region comprising VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27,
a bispecific antibody structure wherein:
the first polypeptide chain, from N-terminus to C-terminus, comprises an anti-CD20 heavy chain variable region and a heavy chain constant region comprising CH1, CH2, and CH3,
the second polypeptide chain comprises, from N-terminus to C-terminus, an anti-CD20 light chain variable region and a light chain constant region,
the third polypeptide chain, from N-terminus to C-terminus, comprises an anti-CD20 scFv, an anti-CD3 heavy chain variable region, and a heavy chain constant region wherein the heavy chain constant region comprises CH1, CH2, and CH3, and
the fourth polypeptide chain comprises, from N-terminus to C-terminus, an anti-CD3 light chain variable region and a light chain constant region,
wherein the anti-CD20 heavy chain variable region and the heavy chain constant region CH1 in the first polypeptide chain associate with the anti-CD20 light chain variable region and the light chain constant region in the second polypeptide chain to form the anti-CD20 Fab, the anti-CD3 heavy chain variable region and the heavy chain constant region CH1 in the third polypeptide chain associate with the anti-CD3 light chain variable region and the light chain constant region in the fourth polypeptide chain to form the anti-CD3 Fab, and
a heavy chain constant region in the first and third polypeptide chains wherein the heavy chain constant region in the first polypeptide is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366S/L368A/Y407V mutations, and the heavy chain constant region in the third polypeptide chain is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366W mutations
as taught by Patent ‘280. This is obvious, because the combined teachings of Cochrane and Lehmann teach a scFv consisting of heavy and light chain domains joined by a peptide linker wherein the light chain is a thermodynamically stable κ light chain comprising four framework regions with L, T, and A at positions 104-106, respectively, and Patent ‘280 teaches a bispecific antibody capable of binding CD3 and CD20, comprising an anti-CD3 Fab, anti-CD20 Fab, and scFv capable of binding CD20, wherein:
the anti-CD3 Fab comprises a heavy chain variable region comprising SEQ ID NO:10 and a light chain variable region comprising SEQ ID NO:18, wherein the VH-CDR1-3 and VL-CDR1-3 comprise SEQ ID NOs:1-6, respectively,
the anti-CD20 Fab comprises a heavy chain variable region comprising VH-CDR1-3 comprising SEQ ID NO:26 and a light chain variable region comprising VL-CDR1-3 comprising SEQ ID NO:27, and
the anti-CD20 scFv comprises a heavy chain variable region comprising VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26 and a light chain variable region comprising VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27,
the structure of the bispecific antibody comprises:
a first polypeptide chain, from N-terminus to C-terminus, comprising an anti-CD20 heavy chain variable region and a heavy chain constant region wherein the heavy chain constant region comprises CH1, CH2, and CH3,
a second polypeptide chain comprising, from N-terminus to C-terminus, an anti-CD20 light chain variable region and a light chain constant region,
a third polypeptide chain, from N-terminus to C-terminus, comprising an anti-CD20 scFv, an anti-CD3 heavy chain variable region, and a heavy chain constant region, wherein the heavy chain constant region comprises CH1, CH2, and CH3, and
a fourth polypeptide chain comprising, from N-terminus to C-terminus, an anti-CD3 light chain variable region and a light chain constant region,
wherein the anti-CD20 heavy chain variable region and the heavy chain constant region CH1 in the first polypeptide chain associate with the anti-CD20 light chain variable region and the light chain constant region in the second polypeptide chain to form the anti-CD20 Fab, the anti-CD3 heavy chain variable region and the heavy chain constant region CH1 in the third polypeptide chain associate with the anti-CD3 light chain variable region and the light chain constant region in the fourth polypeptide chain to form the anti-CD3 Fab, and
the heavy chain constant region in the first polypeptide is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366S/L368A/Y407V mutations, and the heavy chain constant region in the third polypeptide chain is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366W mutations.
Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the bispecific antibody capable of binding CD3 and CD20, comprising an anti-CD3 Fab, anti-CD20 Fab, and scFv capable of binding CD20, wherein:
the anti-CD3 Fab comprises a heavy chain variable region comprising SEQ ID NO:10 and a light chain variable region comprising SEQ ID NO:18, wherein the VH-CDR1-3 and VL-CDR1-3 comprise SEQ ID NOs:1-6, respectively,
the anti-CD20 Fab comprises a heavy chain variable region comprising VH-CDR1-3 comprising SEQ ID NO:26 and a light chain variable region comprising VL-CDR1-3 comprising SEQ ID NO: 27, and
the anti-CD20 scFv comprises a heavy chain variable region comprising VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26 and a light chain variable region comprising VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27,
the bispecific antibody structure comprises:
a first polypeptide chain, from N-terminus to C-terminus, comprising an anti-CD20 heavy chain variable region and a heavy chain constant region, wherein the heavy chain constant region comprises CH1, CH2 and CH3,
a second polypeptide chain comprising, from N-terminus to C-terminus, an anti-CD20 light chain variable region and a light chain constant region,
a third polypeptide chain, from N-terminus to C-terminus, comprising an anti-CD20 scFv, an anti-CD3 heavy chain variable region, and a heavy chain constant region, wherein the heavy chain constant region comprises CH1, CH2 and CH3, and
a fourth polypeptide chain comprising, from N-terminus to C-terminus, an anti-CD3 light chain variable region and a light chain constant region,
wherein the anti-CD20 heavy chain variable region and the heavy chain constant region CH1 in the first polypeptide chain associate with the anti-CD20 light chain variable region and the light chain constant region in the second polypeptide chain to form the anti-CD20 Fab, the anti-CD3 heavy chain variable region and the heavy chain constant region CH1 in the third polypeptide chain associate with the anti-CD3 light chain variable region and the light chain constant region in the fourth polypeptide chain to form the anti-CD3 Fab, and
the heavy chain constant region in the first polypeptide is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366S/L368A/Y407V mutations, and the heavy chain constant region in the third polypeptide chain is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366W mutations
as taught by Patent ‘280 wherein the scFv comprises a heavy chain domain, a peptide linker, and a κ light chain domain, wherein the κ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by the combined teachings of Cochrane and Lehmann to form the instant bispecific antibody capable of binding CD3 and CD20, comprising an anti-CD3 Fab, anti-CD20 Fab, and anti-CD20 scFv, wherein:
the instant anti-CD3 Fab comprises a heavy chain variable region comprising instant SEQ ID NO:13 and a light chain variable region comprising instant SEQ ID NO:14, wherein the VH-CDR1-3 and VL-CDR1-3 comprise instant SEQ ID NOs:1-6, respectively,
the instant anti-CD20 Fab comprises a heavy chain variable region comprising instant SEQ ID NO:15 wherein VH-CDR1-3 comprise instant SEQ ID NOs:7-9 and a light chain variable region comprising instant SEQ ID NO:16, wherein X1, X2, X3, X4, and X5 are V, G, V, E, I, respectively, wherein VL-CDR1-3 comprise instant SEQ ID NOs:10-12,
the instant anti-CD20 scFv comprises a heavy chain variable region, a -(G4S)4- linker, and a κ light chain variable region wherein:
the instant κ light chain variable region comprises four framework regions and is engineered to comprise L, T, and A at instant positions 104-106, respectively, according to the Kabat numbering scheme,
the instant heavy chain variable region comprises VH-CDR1-3 comprising instant SEQ ID NOs:7-9, respectively, and the instant light chain variable region comprises VL-CDR1-3 comprising instant SEQ ID NOs:10-12, respectively.
The instant bispecific antibody structure comprises:
a first polypeptide chain, from N-terminus to C-terminus, comprising an anti-CD20 heavy chain variable region and a heavy chain constant region, wherein the heavy chain constant region comprises CH1, CH2 and CH3,
a second polypeptide chain comprising, from N-terminus to C-terminus, an anti-CD20 light chain variable region and a light chain constant region,
a third polypeptide chain, from N-terminus to C-terminus, comprising an anti-CD20 scFv, an anti-CD3 heavy chain variable region, and a heavy chain constant region wherein the heavy chain constant region comprises CH1, CH2 and CH3, and
a fourth polypeptide chain comprising, from N-terminus to C-terminus, an anti-CD3 light chain variable region and a light chain constant region,
wherein the instant anti-CD20 heavy chain variable region and the instant heavy chain constant region CH1 in the instant first polypeptide chain associate with the instant anti-CD20 light chain variable region and the instant light chain constant region in the instant second polypeptide chain to form the instant anti-CD20 Fab, the instant anti-CD3 heavy chain variable region and the instant heavy chain constant region CH1 in the instant third polypeptide chain associate with the instant anti-CD3 light chain variable region and the instant light chain constant region in the instant fourth polypeptide chain to form the instant anti-CD3 Fab, and
the instant heavy chain constant region in the instant first polypeptide is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366S/L368A/Y407V mutations, and the instant heavy chain constant region in the instant third polypeptide chain is an IgG1 heavy chain constant region with L234A/L235A/N297A/T366W mutations.
Regarding claims 26 and 27, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the bispecific antibody capable of binding CD3 and CD20, wherein the bispecific antibody comprises an anti-CD3 Fab, anti-CD20 Fab, and scFv capable of binding CD20, wherein the anti-CD20 scFv comprises a heavy chain variable region comprising VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26 and a light chain variable region comprising VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27 as taught by Patent ‘280, wherein the scFv comprises a heavy chain domain, a peptide linker, and a κ light chain domain, wherein the κ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by the combined teachings of Cochrane and Lehmann, and include the bispecific antibody in a pharmaceutical composition wherein the pharmaceutical composition is used in a method for treating or alleviating a B cell associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition, wherein the B cell associated disease is B-cell lymphoma, B-cell leukemia, or a B cell-mediated autoimmune disease as taught by Patent ‘280. This is obvious, because the combined teachings of Cochrane and Lehmann teach a scFv consisting of heavy and light chain domains joined by a peptide linker wherein the light chain is a thermodynamically stable κ light chain comprising four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme, and Patent ‘280 teaches a method for treating or alleviating a B cell associated disease (e.g. B-cell lymphoma, B-cell leukemia, or a B cell-mediated autoimmune disease) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition wherein the pharmaceutical composition comprises a bispecific antibody capable of binding CD3 and CD20, wherein the bispecific antibody comprises an anti-CD3 Fab, anti-CD20 Fab, and scFv capable of binding CD20, wherein the anti-CD20 scFv comprises a heavy chain variable region comprising VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26 and a light chain variable region comprising VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the pharmaceutical composition comprising the bispecific antibody capable of binding CD3 and CD20, comprising an anti-CD3 Fab, anti-CD20 Fab, and scFv capable of binding CD20, wherein the anti-CD20 scFv comprises a heavy chain variable region comprising VH-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:26 and a light chain variable region comprising VL-CDR1-3 comprising the CDR amino acid sequences of SEQ ID NO:27, and use it in a method for treating or alleviating a B cell associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition, wherein the B cell associated disease is B-cell lymphoma, B-cell leukemia, or a b cell-mediated autoimmune disease as taught by Patent ‘280 wherein the scFv comprises a heavy chain domain, a peptide linker, and a κ light chain domain, wherein the κ light chain variable region comprises four framework regions with L, T, and A at positions 104-106, respectively, according to the Kabat numbering scheme as taught by the combined teachings of Cochrane and Lehmann to form the instant method for treating or alleviating a B cell associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the instant pharmaceutical composition comprising the instant bispecific antibody capable of binding CD3 and CD20, comprising an anti-CD3 Fab, anti-CD20 Fab, and scFv capable of binding CD20, wherein the instant anti-CD20 scFv comprises a heavy chain variable region, a -(G4S)4- linker, and a κ light chain variable region wherein:
the instant κ light chain variable region comprises four framework regions and is engineered to comprise L, T, and A at instant positions 104-106, respectively, according to the Kabat numbering scheme, and
the instant heavy chain variable region comprises VH-CDR1-3 comprising instant SEQ ID NOs:7-9, respectively, and the instant light chain variable region comprises VL-CDR1-3 comprising instant SEQ ID NOs:10-12, respectively,
wherein the B cell associated disease is B-cell lymphoma, B-cell leukemia, or a B cell-mediated autoimmune disease.
Allowable Subject Matter
Claim 15 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
The sequences of instant claim 15 (e.g. instant SEQ ID NOs:21 and 22) have been searched and found to be free of the prior art (see STIC search results and STNext sequence search results).
The current state of the art is that there are multiple bispecific antibodies that target CD3 and CD20 for clinical use (Salvaris et al, J. Pers. Med., 2021, 11(355):1-15), though none of these constitute prior art for the instant application as the specific amino acid sequences claimed are novel. While methods developing new bispecific antibodies are known in the art, it is not a trivial task to generate a novel bispecific antibody that binds with specificity to the antigens and has high binding affinity and specificity to the desired species. Therefore, it is not obvious in the art to modify the amino acid sequences of a known CD3/CD20 bispecific antibodies to arrive at the instant claimed amino acid sequences comprising the bispecific antibody. Therefore, the amino acid sequences described above for instant claim 15 are novel and allowable.
Conclusion
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643