Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-24 are pending.
Applicant’s election of Group I that read on (A) Tris as the species of wash buffer, (B) acetate as the species of elution buffer, (C) SEQ ID NO: 203 as the species of third domain, (D) the first domain comprises two antibody variable domain and the second domain comprises two antibody variable domain, (E) the linker having the amino acid sequence of SEQ ID NO: 187, (F) CD19 as the species of the antigen to which the first domain binds and (G) wherein the first binding domain comprising a VH comprising the CDRs of SEQ ID NOS: 105-107 and 109-111 in the reply filed on December 26, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 23 is withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1-22 and 24, drawn to a method for purifying a bispecific antigen-binding polypeptide that read on (A) Tris as the species of wash buffer, (B) acetate as the species of elution buffer, (C) SEQ ID NO: 203 as the species of third domain, (D) the first domain comprises two antibody variable domain and the second domain comprises two antibody variable domain, (E) the linker having the amino acid sequence of SEQ ID NO: 187, (F) CD19 as the species of the antigen to which the first domain binds and (G) wherein the first binding domain comprising a VH comprising the CDRs of SEQ ID NOS: 105-107 and 109-111, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 62/898,495, filed September 10, 2019, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on September 13, 2022 has been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Drawings
The drawings filed on March 9, 2022 are acceptable.
Specification
The disclosure is objected to because of the following informality: The numbering 1-210 in Table 1 is NOT clearly labeled as SEQ ID NO: for each sequences.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objection
Claim 1 is objected to because of the following informalities:
“n which” should be corrected.
Two (c), (d) should have been (c), (d), (e).
Claim 19 is objected to because of the following informality: (d) to (g) should have been (a) to (d) and indented. The same indentation issue applies to claims 16, 18 and 21.
Claim 22 is objected to because of the following informality: “a bispecific” should have been “the bispecific”.
Claim 24 is objected to because of the following informality: “A method for improving the yield of a production process for bispecific antigen-binding polypeptide, wherein in downstream processing the method according to claim 1 is applied” should have been “A method for improving the yield of a bispecific antigen-binding polypeptide, comprising applying the method according to claim 1 in downstream processing.”
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 5-9, 15-18, 20 and 21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Regarding claims 1, 5, 6, 7, 8, 9, 18, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Amending the claims by deleting “preferably”, for example, would overcome this rejection.
Regarding claims 1, 8, 9, the phrase “more preferably” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 8 recites the limitation "the dynamic loading capacity" in base claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 9 recites the limitation "the elution binding capacity" in base claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 15 recites the limitation "the CH2 domain" in base claim 12 is ambiguous because there are two CH2 domains in the hinge-CH2-CH3-linker-hinge-CH2-CH3. It is not clear which CH2 domain is being referring to. One of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention.
Claim 16 recites the limitation "…the first domain…and the second domain…" in base claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 17 recites the limitation "the first and second domain" in base claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 18 recites the limitation "…the first domain…and the second domain…" in base claim 1. There is insufficient antecedent basis for this limitation in the claim. Amending claim 18 to recites “a first domain, a peptide linker … and a second domain” would obviate this rejection.
Claim 19 recites the limitation “…the first polypeptide monomer of the third domain…the second monomer of the third domain” in base claims 17 and 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 20 recites the limitation "the first domain" in base claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 21 recites the limitation "the first domain" in base claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-22 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over WO2017134140 (Raum hereafter, published August 10, 2017; PTO 892) in view of WO2018159615 publication (Chen hereafter, published September 7, 2018; PTO 1449) and as evidenced by TOSOH BIOSCIENCE’s product flyer (PTO 892).
Claim 1 encompass a method for purifying any bispecific antigen-binding polypeptide n which binds to any extracellular epitope of the human and the Macaca CD3ε chain, wherein the method comprising:
(a) providing a separation resin comprising a polymer matrix part and a ligand part, wherein the matrix part comprises a polymer, preferably polymethacrylate, and has a particle size of at least 10 μm, preferably of at least 20 μm, more preferably about 30 to 60 μm, wherein the ligand part comprises recombinant protein L, and wherein the ligand part's protein L is covalently bound to the matrix part's particles;
(b) contacting a process fluid comprising the bispecific antigen-binding polypeptide with the separation resin;
(c) capturing the bispecific antigen-binding polypeptide by the ligand part of the separation resin, wherein the bispecific antigen-binding polypeptide reversibly binds to the ligand part of the separation resin, and wherein the remainder of the process fluid does not bind to the ligand part of the separation resin;
(c) washing the bound bispecific antigen-binding polypeptide with a wash buffer which does not elute the bispecific antigen-binding polypeptide from the ligand portion; and
(d) eluting the bispecific antigen-binding polypeptide from the ligand part with an elution buffer comprising an acidic pH.
Raum teaches various methods of purifying bispecific antibody. Example of purification methods include affinity chromatography, see p. 57, para. [188]. The bispecific antibody comprising a first domain that binds to a target cell surface antigen (para. 95]), a second domain binds to an extracellular epitope of the human and Macaca CD3ε chain (para. [96]); and a third domain comprises two polypeptide monomers, each comprising a hinge domain, a CH2 domain and a CH3 domain, wherein said two polypeptide monomers are fused to each other via a peptide linker and comprises hinge-CH2-CH3-linker-hinge-CH2-CH3 (para. 157]) as per claims 1, 11 and 12, see entire document, abstract, p. 4, para. [15], in particular. Raum teaches that the bispecific antibody exhibiting cross-species specificity to non-chimpanzee primates, for instance macaques, can be advantageously used in identical form in preclinical testing and as drug in humans, see p. 73, para. [238].
Regarding claims 13-14, Raum teaches that each polypeptide monomers in the third domain comprises the amino acid sequence of SEQ ID NO: 17, which is identical to the claimed SEQ ID NO: 203, see reference SEQ ID NO: 17 at p. 109, in particular.
ALIGNMENT:
Query Match 100.0%; Score 1242; Length 227;
Best Local Similarity 100.0%;
Matches 227; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 60
Qy 61 GVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK 120
Qy 121 GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 180
Qy 181 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 227
|||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 227
Regarding claim 15, Raum teaches that the CH2 domain comprises intra domain cysteine disulfide bridge, see p. 49, para. [158], in particular.
Regarding claim 16, Raum teaches that an antibody construct, wherein: (i) the first domain comprises two antibody variable domains and the second domain comprises two antibody variable domains, see p. 49, para. [162], in particular.
Regarding claims 17-19, Raum teaches that the first and second domain are fused to the third domain via a peptide linker. Preferred peptide linker have been described herein above and are characterized by the amino acid sequence Gly-Gly-Gly-GlySer, i.e. Gly4Ser (SEQ ID NO: 1), which is identical to the claimed SEQ ID NO: 187, see p. 50, para. [164], in particular.
Regarding claim 20, Raum teaches that the first domain binds to a tumor antigen, e.g., CD19, see p. 50-51, para. [0166] to [0167], p. 78, in particular.
Regarding claim 21, Raum teaches that the first binding domain that binds to CD19 and comprises the heavy chain CDRs comprise SEQ ID NO: 1389, 1390 and 1391, which identical to the claimed SEQ ID NO: 105, 106 and 107, respectively; the light chain CDRs comprise SEQ ID NO: 1392, 1393 and 1394, which are identical to the claimed SEQ ID NO: 109, 110 and 111, respectively, See p. 290-291, and sequence alignment below:
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248
825
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187
818
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Query Match 86.8%; Score 162.4; Length 122;
Best Local Similarity 43.2%;
Matches 35; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 SYGMH--------------VISYEGSNKYYAESVKG------------------------ 22
||||| |||||||||||||||||
Db 31 SYGMHWVRQAPGKCLEWVAVISYEGSNKYYAESVKGRFTISRDNSKNTLYLQMNSLRDED 90
Qy 23 --------DRGTIFGNYGLEV 35
|||||||||||||
Db 91 TAVYYCARDRGTIFGNYGLEV 111
Query Match 84.7%; Score 136.3; Length 112;
Best Local Similarity 40.5%;
Matches 32; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 RSSQSLLHKNAFNYLD---------------LGSNRAS---------------------- 23
|||||||||||||||| |||||||
Db 24 RSSQSLLHKNAFNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRV 83
Qy 24 ----------MQALQTPFT 32
|||||||||
Db 84 EAEDVGVYYCMQALQTPFT 102
Regarding claim 22, Raum teaches that pharmaceutical composition comprising the reference bispecific antibody for treating cancer, see p. 57, para. [189], p. 70, [229], p. 71, para. [233].
Raum does not teach the method comprises
(a) providing a separation resin comprising a polymer matrix part and a ligand part, wherein the matrix part comprises a polymer, preferably polymethacrylate, and has a particle size of at least 10 μm, preferably of at least 20 μm, more preferably about 30 to 60 pm, wherein the ligand part comprises recombinant protein L, and wherein the ligand part's protein L is covalently bound to the matrix part's particles;
(b) contacting a process fluid comprising the bispecific antigen-binding polypeptide with the separation resin;
(c) capturing the bispecific antigen-binding polypeptide by the ligand part of the separation resin, wherein the bispecific antigen-binding polypeptide reversibly binds to the ligand part of the separation resin, and wherein the remainder of the process fluid does not bind to the ligand part of the separation resin;
(d) washing the bound bispecific antigen-binding polypeptide with a wash buffer which does not elute the bispecific antigen-binding polypeptide from the ligand portion; and
(d) elute eluting the bispecific antigen-binding polypeptide from the ligand part with an elution buffer at-comprising an acidic pH as per claim 1, wherein the matrix part has a particle size of about 45 μm as per claim 2, wherein the recombinant protein L comprises a modified B4 domain with an alkali-stable tetramer ligand having multiple coupling sites as per claim 3, wherein the recombinant protein L reversibly binds to a bispecific antigen-binding polypeptide's κ-light chain outside of the antigen binding site, wherein the process fluid is passed through the separation resin at least one time (purification cycle) allowing the bispecific antigen-binding polypeptide to contact with the protein L (residence time), wherein bispecific antigen-binding polypeptide residence time before elution is at least about 2 minutes, preferably about 2.5 to 4 minutes as per claim 5, wherein the dynamic loading capacity is at least 10 mg/ml resin, preferably at least 15 mg/ml resin, more preferably at least 18 mg/ml resin as per claim 8 and wherein the elution binding capacity is at least 7.5 mg/ml resin, preferably at least 9 mg/ml resin, more preferably 16 mg/ml resin as per claim 9.
However, Chen teaches a method purifying protein, e.g., bispecific antibody having one arm that binds to HER2 and arm B binds to CD3 (see p. 30, Table 1, Fig. 1, p. 12-13, 15, para. [0049], reference claim 7) or bispecific T cell Engager (BiTE) antibodies comprising two scFv (p. 15, para. [0049], Example 12, p. 35, p. 13) using recombinant protein L ligand affinity chromatography, see entire document, Example 3, in particular.
The method comprises (a) providing a separation resin comprising a polymer matrix, e.g., polymethacrylate recombinant protein L ligand covalently conjugated to the resin or matrix, e.g., agarose or polymethacrylate for purification of protein of interest. The commercially available matrix with Protein L ligands include, for example, HiTrap™ Protein L (GE Healthcare), Capto™ L (GE Healthcare), Pierce™ Protein L Agarose (Thermo Scientific), Protein L-Agarose HC (ProteNova), TOYOPEARL(registered trademark) AF rProtein L-650F (Tosoh Bioscience), KanCap™ L (Kaneka), Protein L Resin (Genscript), MabAffinity(registered trademark) Protein L High Flow Beads (ACRO Biosystems), Amintra Protein L Resin (Expedeon), and ProL™ rProtein L Agarose Resin (Amicogen), see p. 27, para. [0083], in particular. Methods of binding affinity ligands to a matrix are well known in the purification art, see p. 28. The conventional method of purifying a protein using recombinant Protein L, a protein is usually bound to a Protein L matrix at a certain pH and then eluted by lowering the pH. For example,
(b) contacting or applying a solution comprising bispecific antibodies (Example 5) with a Protein L matrix to
(c) capture the bispecific antibodies kappa light chain constant region (LC), e.g., Cκ (Fig. 1) that bound to the Protein L matrix,
(d) washing the Protein L-matrix with 1x D-PBS, see para. [0095], then
(f) eluting the bound antibodies from the Protein L matrix with a buffer, e.g., Na-acetate at acidic pH, e.g., 2.4 and pH 3.3 as per claim 1, see p. 4, para. [0022], [0085], [0096], Examples 5, 8, 12, 13, reference claim 12, in particular.
Claim 2 is included because evidentiary reference TOSOH BIOSCIENCE’s product teaches that TOYOPEARL AF-rProtein L-650F resin has an average particle size of 45 μm, see last page.
Regarding claim 3, evidentiary reference TOSOH BIOSCIENCE’s product teaches TOYOPEARL® AF-rProtein L-650 F is an affinity chromatography resin that combines a rigid polymer polymethacrylate matrix with a recombinant tetramer ligand, which is derived from the B4 domain of native protein L from Peptostreptococcus magnus and has been optimized with improved alkaline stability having multiple coupling sites enables multipoint attachment,
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311
449
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see Figure 2, in particular.
Regarding claim 4, Chen teaches that the recombinant Protein L reversibly blinds to the bispecific antibody’s kappa light chain, e.g., V kappa 1-Constant region and lambda LC on both arms (aka outside the antigen binding site, Fig. 1), see Example 5.
Claim 5 is included because the adjustment of particular working conditions (such as residence time is at least about 2 minutes before elution) is deemed merely a matter of judicious selection and routine optimization, which is well within the purview of the skilled artisan and therefore obvious under 35 U.S.C. § 103(a). Discovering an optimum value of a result effective variable involves only routine skills in the art. In re Boesch, 617, F.2d, 272,205 USPQ 215 (CCPA 1980).
Regarding claim 6, Chen teaches that the wash buffer is 1xD-PBS (aka phosphate buffered saline), see Example 12.
Regarding claim 7, Chen teaches that the elution buffer is Na-acetate in the range of 100 to 150 mM, which is within the claimed range of 50 to 150 mM and at acidic pH such as 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, and 3.3, which is within the claimed range of about 3 to 7.5, see para. [0018], [0085], Example 13.
Claim 8 is included as the TOYOPEARL AF-rProtein L-650F resin provides the highest binding capacity available on the market, e.g., about 50 mg/ml, which is at least 10, 15 or 18 mg/ml, see Fig. 3, in particular.
Claim 9 is included as the reference TOYOPEARL AF-rProtein L-650F resin intrinsically has elution binding capacity of at least 7.5 mg/ml resin.
Regarding claim 10, Chen teaches that BITE antibodies (para. [0049], [0090]) are fusion proteins consisting of two single-chain variable fragments (scFv) of different antibodies, see Example 12, Fig. 1, in particular.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skilled in the art before the effective filling date of the claimed invention to have used any one of the commercially available affinity chromatography resin, e.g., high binding capacity TOYOPEARL AF-rProtein L-650F that binds to kappa light chain constant region of the bispecific antibody in the method of Chen to purify any Raum’s bispecific antibody that binds to CD19 and an extracellular epitope of the human and the Macaca CD3ε chain in order to improve the yield of the bispecific antibody in the production process.
One of ordinary skill in the art would have a reasonable expectation of success, because Chen demonstrates the successful use of Protein L affinity chromatography to purify bispecific antibody.
One of ordinary skill in the art would have been motivated to do so because Chen teaches that methods of binding affinity ligands to a matrix are well known in the purification art (see p. 28) and bispecific antibody such as BITE without or with Fc can be purified using any commercially available affinity chromatography resin comprising recombinant Protein L ligand, including the high binding capacity TOYOPEARL AF-rProtein L-650F for the sake of convenience.
One of ordinary skill in the art would have been motivated to do so because Raum teaches the bispecific antibody exhibiting cross-species specificity to non-chimpanzee primates, for instance macaques, can be advantageously used in identical form in preclinical testing and as drug in humans, see p. 73, para. [238].
Claim 24 is included because one of ordinary skill in the art would have been motivated to use TOYOPEARL AF-rProtein L-650F affinity resin in downstream processing because of its high binding capacity, improved process economics in the production of antibody molecules and reduced host cell proteins in the final product.
In this case, the simple substitution of one known element, bispecific antibody in the method for purifying bispecific antibody of Chen for another, e.g., Raum’s bispecific antibody would obtain predictable results.
In addition, the claims would have been obvious because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641