DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-13, in the reply filed on 9/8/2026 is acknowledged.
Claims 14-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II-III, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/8/2026.
Claims 1-13 are examined below.
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/JP2022/032335, filed 08/29/2022. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. JP2021-140250, filed on 08/30/2021 in Japan.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement filed 2/28/2024 and the information disclosure statement filed 9/15/2025 are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in page 23 lines 14-15. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Page 50 of the specification is misaligned, i.e. in landscape orientation.
Appropriate correction is required.
Claim Objections
Claims 3 and 6-9 are objected to because of the following informalities:
In claims 3 and 6-9, line 1, it is suggested that “The antibody according to claim…, that is…” read as “The antibody according to claim…, wherein the antibody is…” (annotations added) in order to conform with conventional claim language, as in claims 4-5.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-5 and 12-13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to at least one judicial exception without significantly more.
Claim 1 recites “An antibody for use in an immunoassay method, the antibody comprising an Fc region wherein at least part of a glycan comprised in the Fc region has been removed”.
The claimed language encompasses antibodies that are themselves nature-based products that are not markedly different from their naturally occurring counterpart (namely, from the naturally occurring antibodies present in humans).
The specification suggests that the claimed antibody is a nature-based product (“It is known that proteins are subjected to various post-translational modifications after syntheses, and Glycan-modification is one of them” page 1 lines 13-15).
See also for example, Flynn et al. Molecular Immunology 47 (2010) 2074–2082 doi:10.1016/j.molimm.2010.04.006 (“Flynn”).
Flynn teaches “Naturally occurring glycan forms of human immunoglobulins G1 and G2” (Title). Flynn further teaches that human serum IgG glycan profiles “with N-linked glycans attached to Asn297 on the Fc region” change “with age, physiological states and specific disease states” (page 2074 col. 1 paras. 1 and 3). Flynn further teaches that “unglycosylated Fc peptide, ∼0.2%, were observed on both IgG isotypes” in human serum (page 2080 col. 1 para. 1, see Table 2). Therefore, Flynn teaches that mammalian IgG antibodies are naturally present with no glycans at the 297th position in the serum of humans.
See also Parekh et al. NATURE VOL. 316 1 AUGUST 1985-Cite No. 6 of IDS 2/28/2024 (“Parekh”). Parekh teaches “Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG” (Title). Parekh further teaches that patients with rheumatoid arthritis and/or primary osteoarthritis have antibodies in their serum comprising an Fc region wherein part of a glycan comprised in the Fc region has been removed (“N-glycosylation pattern of serum IgG (Fig. 1) isolated from normal individuals and from patients with either primary osteoarthritis or rheumatoid arthritis. The results…indicate…different distributions of asparagine-linked biantennary complex-type oligosaccharide structures…These two arthritis may therefore be a glycosylation diseases, reflecting changes in the intracellular processing or post-secretory degradation of N-linked oligosaccharides” Abstract).
Note that “for use in an immunoassay method” fails to impart any structural limitation to the antibody and merely recites the intended use of the claimed antibody. Therefore, this limitation fails to add a markedly difference to the nature product.
Claim 2 merely limits the antibody to it being derived from a mammal. However, Flynn addresses this limitation, teaching that human IgG is naturally present unglycosylated (Title, Table 2).
Claim 3 merely limits the antibody to it being an IgG, reduced IgG, or half IgG. However, in the present case, fragmentation or truncation does not appear to give rise to a marked difference in structure, as there is no evidence that the claimed antibody achieves or exhibits a difference in binding character. Even though fragmentation or truncation may structurally change a protein from its natural state, the resultant difference (e.g., “broken” bonds) does not alter the sequence of the protein itself. There is no evidence in the originally filed specification or remarks to support that the claimed antibody would have any structural or functional characteristics that are different from the naturally occurring antibody itself (which was already recognized in the art as being capable of undergoing post translational modifications).
Claims 4-5 merely limit the antibody to it having an asparagine at the 297th position according to Kabat, and to having no glycan bound at this position or having the glycan at this position be cleaved and removed.
However, Flynn addresses this limitation by teaching that IgG contains asparagine at the 297th position in the Fc region (page 2074 col. 1 para. 1) and teaching that these antibodies are also naturally unglycosylated (see Table 2 last row). Therefore, the glycan at this position must have been removed/cleaved or has not bound. Similarly, Parekh addresses this limitations (see Abstract of Parekh).
Claim 12 merely limits the antibody to it being in a composition. Therefore, this claim fails to add a marked difference to the nature-based product.
Claim 13 merely limits the antibody to it being a reagent for immunoassay. This limitation fails to impart any structural limitation to the antibody and merely recites the intended use of the claimed antibody. Therefore, this limitation fails to add a marked difference to the natural product.
For these reasons, the antibody of claims 1-5 and 12-13 is not markedly different from its naturally occurring counterparts and so is not significantly more than the judicial exception. Accordingly, the claimed subject matter is ineligible under 35 U.S.C. 101 because the claimed article is a nature-based product not markedly different than its naturally occurring constituent reagent counterparts.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-4 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Parekh et al. NATURE VOL. 316 1 AUGUST 1985-Cite No. 6 of IDS 2/28/2024 (“Parekh”).
Regarding claims 1-4, Parekh teaches an antibody for use in an immunoassay method, the antibody, that is IgG, reduced IgG, or half IgG, comprising an Fc region wherein at least part of a glycan comprised in the Fc region has been removed, wherein the Fc region is a region derived from a mammal, wherein an amino acid residue at position 297 based on Kabat numbering in the Fc region is asparagine, and part of an N-linked glycan binding to position 297 based on the Kabat numbering has been cleaved and removed (“Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG”, Title, “N-glycosylation pattern of serum IgG (Fig. 1) isolated from normal individuals and from patients with either primary osteoarthritis or rheumatoid arthritis. The results…indicate…different distributions of asparagine-linked biantennary complex-type oligosaccharide structures…These two arthritis may therefore be a glycosylation diseases, reflecting changes in the intracellular processing or post-secretory degradation of N-linked oligosaccharides” Abstract, see Fig. 1 “Asn297”). Note that the claimed limitation “for use in an immunoassay method” fails to impart any structural limitation to the antibody and merely recites the intended use of the claimed antibody; therefore, this limitation is not required to be explicitly taught in the prior art in order to address the claim over the art. Note also that although Parekh fails to use the language “wherein an amino acid residue at position 297 based on Kabat numbering in the Fc region is asparagine, and part of an N-linked glycan binding to position 297 based on the Kabat numbering has been cleaved and removed” the teaching of “post-secretory degradation of N-linked oligosaccharides” and the highlighted structures in Figure 1 showing the “Asn 297” position inherently provides the cleaving or removing of the glycan at the 297th position based on Kabat numbering.
Regarding claim 12, Parekh further teaches an antibody composition comprising the antibody according to claim 1 (“serum IgG” Title, Abstract, Fig. 1 and Table 1). Note that although Parekh fails to use the language “composition” the teaching of “serum IgG” obtained from humans inherently provides a “composition” comprising the antibody of claim 1 because serum is reasonably interpreted as a composition, that is a liquid sample that is composed of many different components comprising the claimed antibody.
Claim(s) 1-7 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ju et al. Current Opinion in Biotechnology 2014, 30:128-139-Cite No. 15 of IDS 9/15/2025 (“Ju”).
Regarding claims 1-3, Ju teaches an antibody for use in an immunoassay method, the antibody, that is IgG, comprising an Fc region wherein at least part of a glycan comprised in the Fc region has been removed, wherein the Fc region is a region derived from a mammal (“Aglycosylated full-length IgG antibodies: steps toward next-generation immunotherapeutics”, Title, “removal of Asn297 glycans of IgG…aglycosylated full-length IgG antibodies…aglycosylated antibodies have been developed and several are under clinical trials…. the aglycosylated IgG antibodies into a new class of effector functional human immunotherapeutics.” Abstract, “In this review, we overview the recent efforts to understand the impact of glycosylation on IgG antibodies and primarily highlight the recent advances in the field of the aglycosylated full-length IgG antibodies” page 129 col. 2 para. 3, “aglycosylated antibodies have been expressed in eukaryotic hosts (mammalian cells, plant cells, or yeasts) by introducing a mutation at the N-linked glycosylation site for aglycosylation” page 129 col. 1 para. 2). Note that the claimed limitation “for use in an immunoassay method” fails to impart any structural limitation to the antibody and merely recites the intended use of the claimed antibody; therefore, this limitation is not required to be explicitly taught in the prior art in order to address the claim over the art.
Regarding claim 4, Ju further teaches wherein an amino acid residue at position 297 based on Kabat numbering in the Fc region is asparagine, and part of an N-linked glycan binding to position 297 based on the Kabat numbering has been cleaved and removed (“(EndoS)…digesting a glycosidic bond between the first GlcNAc and the second GlcNAc residue of the IgG N297 glycan. In a previous study, the administration of the IgGs prepared by EndoS hydrolysis relieved the symptoms of arthritis in mice” page 131 col. 1 para. 3). Note that although Ju fails to use the language “wherein an amino acid residue at position 297 based on Kabat numbering in the Fc region is asparagine, and part of an N-linked glycan binding to position 297 based on the Kabat numbering has been cleaved and removed” the teaching of treating IgG antibodies with EndoS inherently provides wherein the glycan at the 297th position based on Kabat numbering is cleaved and removed.
Regarding claim 5, Ju further teaches wherein an amino acid residue at position 297 based on Kabat numbering in the Fc region is asparagine, and an N-linked glycan has not bound to position 297 based on the Kabat numbering (“aglycosylated antibodies have been expressed in eukaryotic hosts (mammalian cells, plant cells, or yeasts) by introducing a mutation at the N-linked glycosylation site for aglycosylation” page 129 col. 1 para. 2). Note that although Ju fails to use the language “wherein an amino acid residue at position 297 based on Kabat numbering in the Fc region is asparagine, and an N-linked glycan has not bound to position 297 based on the Kabat numbering” the teaching of “introducing a mutation at the N-linked glycosylation site for aglycosylation” inherently provides wherein the glycan at the 297th position based on Kabat numbering has not bound the antibody.
Regarding claim 6, Ju further teaches that is a recombinant antibody in which an amino acid residue at position 297 based on Kabat numbering in the Fc region is replaced with an amino acid other than asparagine, and an N-linked glycan has not bound to position 297 based
on the Kabat numbering (“Hristodorov et al. introduced the mutation N297A and expressed six aglycosylated IgG antibodies in mammalian cells” page 130 col. 2 para. 3). Note that the mutation at the 297th amino acid asparagine with alanine, i.e. “N297A”, taught by Ju inherently provides the lack of binding of N-linked glycans because there is no longer an asparagine for glycans to be linked.
Regarding claim 7, Ju further teaches that is a recombinant antibody in which the amino acid residue at position 297 based on the Kabat numbering in the Fc region is replaced with one selected from the group consisting of alanine (“N297A” page 130 col. 2 para. 3).
Regarding claim 12, Ju further teaches an antibody composition comprising the antibody according to claim 1 (Title, “aglycosylated antibodies have been developed and several are under clinical trials…. the aglycosylated IgG antibodies into a new class of effector functional human immunotherapeutics” Abstract). Note that although Ju fails to use the language “composition” the teaching of aglycosylated antibodies as immunotherapeutic drugs inherently provides a “composition” comprising the antibody of claim 1 because immunotherapeutics are reasonably interpreted as a immunotherapeutic drug composition.
Claim(s) 1-4 and 12-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shields et al. The Journal of Biological Chemistry Vol. 277, No. 30, Issue of July 26, pp. 26733-26740, 2002-Cite No. 11 of IDS 2/28/2024 (“Shields”).
Regarding claims 1-3, Shields teaches an antibody for use in an immunoassay method, the antibody, that is IgG, reduced IgG, or half IgG, comprising an Fc region wherein at least part of a glycan comprised in the Fc region has been removed, wherein the Fc region is a region derived from a mammal (“Lack of Fucose on Human IgG1 N-Linked Oligosaccharide Improves Binding to Human FcyRIII and Antibody-dependent Cellular Toxicity”, Title, “Lec13 cells, a variant Chinese hamster ovary cell line, were used to produce human IgG1 that were deficient in fucose attached to the Asn297-linked carbohydrate… Antibody-dependent cellular cytotoxicity assays using purified peripheral blood monocytes or natural killer cells from several donors showed enhanced cytotoxicity, especially evident at lower antibody concentrations” Abstract, “cDNA Constructs for Stable Cell Lines…Transfection and Culturing of Lec13…Cells…Parental lines were Pro- (proline auxotroph) and GAT- (glycine, adenosine, thymidine auxotroph)…Cell lines were transfected with cDNA…Selection of stably transfected Lec13 cells expressing mAbs” page 26734 col. 1 paras. 1-2).
Regarding claim 4, Shields further teaches wherein an amino acid residue at position 297 based on Kabat numbering in the Fc region is asparagine, and part of an N-linked glycan binding to position 297 based on the Kabat numbering has been cleaved and removed (“Treatment of fucosylated IgG with fucosidases (65) may be useful for generating enough afocosyl IgG to use for assays” page 26739 bridge paragraph cols. 1-2). Note that although Shields fails to use the language “wherein an amino acid residue at position 297 based on Kabat numbering in the Fc region is asparagine, and part of an N-linked glycan binding to position 297 based on the Kabat numbering has been cleaved and removed” the teaching of treating IgG antibodies with fucosidases inherently provides wherein the glycan at the 297th position based on Kabat numbering is cleaved and removed.
Regarding claim 12, Shields further teaches an antibody composition comprising the antibody according to claim 1 (Title, Abstract, “On average, the Lecl3 cells generated 10µg of mAb per 15-cm plate; expression in control CHO cells for all antibodies was 4--5 times higher than in the Lecl3 cells. Antibodies generated from CHO-DP12 grown on plates will be denoted as CHO-P” page 26734 col. 2 para. 1). Note that although Shields fails to use the language “composition” the teaching of using the “antibodies generated from CHO-DP12 grown on plates…denoted as CHO-P” inherently provides a “composition” comprising the antibody of claim 1 because the antibody solution obtained from a cell culture is reasonably interpreted as a composition.
Regarding claim 13, Shields further teaches a reagent for immunoassay, comprising the antibody according to claim 1 (Abstract, “Antibody-dependent Cell Cytotoxicity Assays…used to measure binding” page 26734 col. 2 para. 3, “afocosyl IgG to use for assays” page 26739 col. 2 para. 1).
Claim(s) 1-3, 5-7 and 10-13 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Crowe (WO 2020/061159 A1)-Cite No. 3 of IDS 2/28/2024.
Regarding claims 1-3, Crowe teaches an antibody for use in an immunoassay method (“The present disclosure is directed to antibodies binding to and neutralizing Zika virus and methods for use thereof. In accordance with the present disclosure, provided are methods comprising: a method of detecting a Zika virus infection in a subject” Abstract, “Detection may comprise ELISA” page 2 lines 8-9), the antibody, that is IgG, reduced IgG, or half IgG, comprising an Fc region wherein at least part of a glycan comprised in the Fc region has been removed, wherein the Fc region is a region derived from a mammal (“The antibody may be an IgG…comprising an Fc portion mutated to alter (eliminate or enhance) FcR interactions, to increase half-life and/or increase therapeutic efficacy…or glycan modified to alter (eliminate or enhance) FcR interactions such as enzymatic or chemical addition or removal of glycans or expression in a cell line engineered with a defined glycosylating pattern.” page 2 lines 20-25, “Recombinant full-length IgG antibodies can be generated by subcloning heavy and light chain Fv DNAs from the cloning vector into an IgG plasmid vector, transfected into 293 (e.g., Freestyle) cells or CHO cells, and antibodies can be collected and purified from the 293 or CHO cell supernatant” page 32 lines 27-30).
Regarding claim 5, Crowe further teaches wherein an amino acid residue at position 297 based on Kabat numbering in the Fc region is asparagine, and an N-linked glycan has not bound to position 297 based on the Kabat numbering (“the Fc region is that of the EU index in Kabat” page 36 lines 25-26, “The glycosylation pattern may be altered, for example, by deleting one or more glycosylation site(s) found in the polypeptide…change of Asn 297 to Ala can remove one of the glycosylation sites” page 38 lines 23-25 and 31). Note that although Crowe fails to use the language “an N-linked glycan has not bound to position 297 based on the Kabat numbering” the teaching of changing asparagine to alanine at the 297th position to remove the glycosylation site inherently provides wherein the glycan at the 297th position based on Kabat numbering has not bound the antibody because there is no longer an asparagine for glycans to be “N-linked”.
Regarding claim 6, Crowe further teaches that is a recombinant antibody in which an amino acid residue at position 297 based on Kabat numbering in the Fc region is replaced with
an amino acid other than asparagine, and an N-linked glycan has not bound to position 297 based on the Kabat numbering (“change of Asn 297 to Ala can remove one of the glycosylation sites” page 38 lines 23-25 and 31).
Regarding claim 7, Crowe further teaches that is a recombinant antibody in which the amino acid residue at position 297 based on the Kabat numbering in the Fc region is replaced with one selected from the group consisting of alanine (“change of Asn 297 to Ala can remove one of the glycosylation sites” page 38 lines 23-25 and 31).
Regarding claim 10, Crowe further teaches an immobilized antibody comprising: an insoluble carrier; and the antibody according to claim 1 supported on the insoluble carrier (“the antibodies of the disclosure are immobilized onto a selected surface exhibiting protein affinity, such as a well in a polystyrene microtiter plate” page 65 lines 32-33).
Regarding claim 11, Crowe further teaches wherein the insoluble carrier is at least one selected from the group consisting of a plate carrier (“plate” page 65 lines 32-33).
Regarding claim 12, Crowe further teaches an antibody composition comprising the antibody of claim 1 (“composition described herein” page 6 line 1, “antibodies can be collected and purified from the 293 or CHO cell supernatant” page 32 lines 27-30, “The isolated monoclonal antibody, or antigen binding fragment thereof, comprising a substantially homogenous composition” page 38 lines 7-8, “the antibodies of the present disclosure may be purified. The term "purified," as used herein, is intended to refer to a composition, isolatable from other components, wherein the protein is purified to any degree relative to its naturally-obtainable state” page 55 lines 31-34).
Regarding claim 13, Crowe further teaches a reagent for immunoassay, comprising the antibody of claim 1 (Abstract, “Detection may comprise ELISA” page 2 lines 8-9).
Claim(s) 1, 3 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu et al. Journal of Biological Chemistry, February 7, 2014•Volume 289•Number 6 10.1074/jbc.M113.513366 (“Liu”).
Regarding claims 1, 3 and 12, Liu teaches an antibody for use in an immunoassay method and an antibody composition, the composition comprising the antibody, the antibody, that is IgG, comprising an Fc region wherein at least part of a glycan comprised in the Fc region has been removed (“One of important strategies to improve the next generation of anti-cancer therapeutics is aiming to build antibodies with enhanced effector functions…This has been accomplished by two general approaches. The fucose attached to the N-linked glycan at Asn-297 of Fc sterically hinders the interaction of Fc with FcγRIIIA, and removal of fucose by glyco-engineering can increase the binding to FcγRIIIA, which translates into >50-fold higher ADCC activity compared with wild type IgG1 controls (10, 11). Protein engineering, through amino acid mutations in the Fc portion of IgG1, has generated multiple variants that increase the affinity of Fc binding” bridge paragraph pages 3571-3572). Note that the limitation “for use in an immunoassay method” of claim 1 fails to impart any structural limitation to the antibody and merely recites the intended use of the claimed antibody; therefore, this limitation is not required to be explicitly taught in the prior art in order to address the claim over the art. Note also that although Liu fails to use the language “composition” the teaching of “anti-cancer therapeutics” inherently provides the claimed antibody composition because an immunotherapeutic is reasonably interpreted as a composition.
Claim Rejections - 35 USC § 103
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.
Claims 1-3, 5-7 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Gao et al. (WO 2015157595 A1) (“Gao”).
Regarding claim 1, Gao teaches an antibody for use in an immunoassay method (“Conjugated compounds comprising cysteine-engineered antibodies” Title, “The conjugate
compounds comprise cysteine-engineered antibodies…with…detection labels such as radionuclides or fluorophores. The disclosure also provides methods of using the disclosed conjugate compounds for in vitro, in situ, ex vivo, and in vivo diagnosis” Abstract), the antibody, comprising an Fc region (“The terms "antibody" or "immunoglobulin," as used interchangeably herein, include whole antibodies” para. 35) wherein at least part of a glycan comprised in the Fc region has been removed (“other amino acids can be modified at additional EU positions disclosed in the art. Accordingly, in some aspects the conjugate compounds disclosed herein further comprise at least one engineered cysteine residue selected from cysteine amino acid substitutions at amino acid positions 239, 248, 254, 273, 279, 282, 286, 287, 289, 297, 298, 312, 324, 326, 330, 335, 337, 339, 350, 355, 356, 359, 360, 361, 375, 383, 384, 389, 398, 400, 413, 415, 418, 422, 440, 441, 442, 443 and 446” para. 110). Note that although Gao fails to use the language “wherein at least part of a glycan comprised in the Fc region has been removed” the teaching of substituting the 297th amino acid according to Kabat with cysteine inherently provides the removing of at least part of a glycan comprised in the Fc region because this substitution would effectively remove the N-linked glycans. Gao further suggests that removing at least part of the glycan comprised in the Fc region improves the antibody’s stability in serum, which is useful for the treatment of cancer (“The use of antibody-drug conjugates (ADC), i.e., immunoconjugates, for the local delivery of cytotoxic or cytostatic agents, i.e., drugs to kill or inhibit tumor cells in the treatment of cancer… theoretically allows targeted delivery of the drug moiety to tumors, where they bind to the target and may be internalized resulting in intracellular
accumulation therein, where systemic administration of these unconjugated drug agents can
result in unacceptable levels of toxicity to normal cells as well as the tumor cells sought to be
eliminated” para. 2) . Gao further teaches “nucleic acids, vectors and host cells for
the generation of antibodies” (para. 8).
Gao teaches the antibody of claim 1 from a list of other 38 antibodies.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have tried picking the antibody wherein at least part of a glycan comprised in the Fc region has been removed, i.e. the antibody with the N297C, from the finite list of 38 other antibodies taught by Gao because Gao teaches that said antibody has improved serum stability, which can help in the treatment of cancer. A person having ordinary skill in the art would have had a reasonable expectation of success because Gao further teaches “nucleic acids, vectors and host cells for the generation of antibodies” (para. 8).
Regarding claim 2, Gao further suggests wherein the Fc region is a region derived from a mammal (“Examples of suitable mammalian host cell lines include HEK-293 and HEK-293T, the COS-7 lines of monkey kidney cells, described by Gluzman (Cell 23:175, 1981), and other cell lines including, for example, L cells, C127, 3T3, Chinese hamster ovary (CHO), NSO, HeLa and BHK cell lines” para. 190).
Regarding claim 3, Gao further suggests the antibody according to claim 1, that is IgG, reduced IgG, or half IgG (“Thus Fc refers to the last two constant region immunoglobulin domains of …IgG” para. 48).
Regarding claims 5-7, Gao suggests wherein an amino acid residue at position 297
based on Kabat numbering in the Fc region is asparagine (Fig. 1A, see position 297 according to EU (Kabat) showing amino acid “N”, i.e. asparagine), and an N-linked glycan has not bound
to position 297 based on the Kabat numbering, that is a recombinant antibody in which an
amino acid residue at position 297 based on Kabat numbering in the Fc region is replaced with
an amino acid other than asparagine, and an N-linked glycan has not bound to position 297 based
on the Kabat numbering, that is a recombinant antibody in which the amino acid residue at position 297 based on the Kabat numbering in the Fc region is replaced with one selected from the group consisting of cysteine (“other amino acids can be modified at additional EU positions disclosed in the art. Accordingly, in some aspects the conjugate compounds disclosed herein further comprise at least one engineered cysteine residue selected from cysteine amino acid substitutions at amino acid positions 239, 248, 254, 273, 279, 282, 286, 287, 289, 297, 298, 312, 324, 326, 330, 335, 337, 339, 350, 355, 356, 359, 360, 361, 375, 383, 384, 389, 398, 400, 413, 415, 418, 422, 440, 441, 442, 443 and 446” para. 110). Note that although Gao fails to use the language “an N-linked glycan has not bound to position 297 based on the Kabat numbering” the teaching of substituting the asparagine at the 297th position for cysteine inherently provides the lack of binding of N-linked glycans.
Regarding claim 12, Gao further suggests an antibody composition comprising the antibody according to claim 1 (Title, Abstract, “the disclosure provides compositions comprising the conjugate compounds of the disclosure” para. 12).
Regarding claim 13, Gao further suggests a reagent for immunoassay, comprising the antibody according to claim 1 (Title, Abstract, “The present disclosure provides an assay for detecting the binding of a cysteine engineered antibody or Fc fusion protein disclosed herein, or a conjugate compound disclosed herein to a target cell” para. 165).
Claim(s) 8-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gao (WO 2015157595 A1) as applied to claims 1 and 6 above, and further in view of Liu et al. Journal of Biological Chemistry, February 7, 2014•Volume 289•Number 6 10.1074/jbc.M113.513366 (“Liu”).
Regarding claims 8-9, Gao suggests the antibody of claims 1 and 6 as discussed above.
Gao further suggests that is a recombinant antibody in which the amino acid residue at position 297 based on the Kabat numbering in the Fc region is replaced with cysteine (para. 110), and an amino acid residue at position capable of forming a disulfide bond with the cysteine is also replaced with cysteine, that is a recombinant antibody in which an amino acid residue at position 298 based on the Kabat numbering in the Fc region is replaced with cysteine (“other amino acids can be modified at additional EU positions disclosed in the art. Accordingly, in some aspects the conjugate compounds disclosed herein further comprise at least one engineered cysteine residue selected from cysteine amino acid substitutions at amino acid positions 239, 248, 254, 273, 279, 282, 286, 287, 289, 297, 298, 312, 324, 326, 330, 335, 337, 339, 350, 355, 356, 359, 360, 361, 375, 383, 384, 389, 398, 400, 413, 415, 418, 422, 440, 441, 442, 443 and 446” para. 110 emphasis added). Note that Gao suggests the antibody of claims 8-9 when teaching that at least one cysteine may be inserted into the antibody (by substitution) at positions 297 and 298 based on Kabat, i.e. a double cysteine substitution at positions 297 and 298.
Gao teaches the recombinant antibody in which an amino acid residue at position 297 and 298 based on the Kabat numbering in the Fc region is replaced with cysteine from a finite list of other antibodies in paragraph 110. There appears to be not enough motivation in Gao to try picking the recombinant antibody of claims 8-9 from the list of antibodies taught in paragraph 110 of Gao.
Liu teaches “Asymmetrical Fc Engineering Greatly Enhances Antibody-dependent
Cellular Cytotoxicity (ADCC) Effector Function and Stability of the Modified Antibodies” (Title). Liu teaches the antibody of claim 1 as discussed above. Liu further suggests that replacing an amino acid residue at position 298 based on the Kabat numbering in the Fc region with cysteine increases the antibody stability (“A genetic algorithm for protein design (EGAD) (18) was used to search beneficial residue(s) at positions Ser-298, Ala-327, and Ala-330 in the Fc region, which could enhance the binding to FcγRIIIA and stabilize the Fc-FcγRIIIA complex using the available Fc-Fcγ receptor crystal structures. EGAD was also used to analyze some of combinations of mutations that had very favorable binding to Fγreceptors. Examples of the EGAD-predicted mutations include S298C” page 3573 col. 1 para. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have tried picking the recombinant antibody in which the amino acid residue at positions 297 and 298 based on the Kabat numbering in the Fc region is replaced with cysteine taught in paragraph 110 of Gao because Liu suggests this increases antibody stability, and Gao is interested in increasing antibody stability. A person having ordinary skill in the art would have had a reasonable expectation of success because both Gao and Liu teach the antibody of claim 1.
Conclusion
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/Fernando Ivich/ Examiner, Art Unit 1678
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
