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 .
Priority
The instant application, filed 04/24/2023 claims domestic benefit over two US provisional applications 63/374,646, filed on 09/06/2022 and 63/334,381, filed on 04/25/2022.
Status of Claims
The preliminary claim amendment of 11/30/2023 is acknowledged. Claims 1, 6, 9-10, 21-24, 27-29, 35, 38-39, 57, 60, 78-79, 82 and 97, amended on 11/30/2023, are currently pending and are examined under the merits herein.
Information Disclosure Statement
Applicant is advised of the following discrepancies of the information disclosure statement (IDS) filed on 11/30/2023:
Foreign Patent Document Cite No. 22 and 23 are duplicate entries in the IDS, please correct by deleting the duplicate entry. The entry cite no. 23 is lined through and marked as a duplicate entry (dup).
WO-1999012965-A3 is listed in the IDS but no copy was provided. Please provide a copy.
The examiner notes that there are several duplicate copies provided in the application file and the examiner considers only one copy as to the merits.
Applicant is advised of the following discrepancies of the IDS filed on 06/07/2024:
Where there is a strike-through, the references have not been considered as they have already been entered and considered in the IDS filed on 11/30/2023.
The examiner notes that there are several duplicate copies provided in the application file and the examiner considers only one copy as to the merits.
Doc no. FP35, or document WO-2017091683-A1, has been entered incorrectly in the IDS as “WO-2017091756-A1”, the examiner has corrected the entry.
There are several non-patent literature documents provided in the application without IDS entry filed on 06/07/2024:
Non Patent Literature document, marked as the 15 out of 112 documents filed on 06/07/2024 has 70 pages, titled “Miscellaneous Long Human Proteins Associated with the Immune System (residues 1-130)”. There is no citation of this document on the IDS. Please provide citation entry on the IDS.
Non Patent Literature document, marked as the 20 out of 112 documents filed on 06/07/2024 has 116 pages, titled “Mouse Kappa Light Chains VI”. There is no citation of this document on the IDS. Please provide citation entry on the IDS.
Non Patent Literature document, marked as the 38 out of 112 documents filed on 06/07/2024 has 185 pages, titled “Mouse Major Histocompatibility Antigen Class I K-locus Alpha-3 Region”. There is no citation of this document on the IDS. Please provide citation entry on the IDS.
Non Patent Literature document, marked as the 51 out of 112 documents filed on 06/07/2024 has 104 pages, titled “Mouse Heavy Chains Subgroup I”. There is no citation of this document on the IDS. Please provide citation entry on the IDS.
Non Patent Literature document, marked as the 59 out of 112 documents filed on 06/07/2024 has 96 pages, titled “Mouse Kappa Light Chains I”. There is no citation of this document on the IDS. Please provide citation entry on the IDS.
Non Patent Literature document, marked as the 72 out of 112 documents filed on 06/07/2024 has 112 pages, titled “THY-1 Antigens (Residues 131-143)”. There is no citation of this document on the IDS. Please provide citation entry on the IDS.
Non Patent Literature document, marked as the 80 out of 112 documents filed on 06/07/2024 has 148 pages, titled “Mouse Heavy Chains Subgroup III (D)”. There is no citation of this document on the IDS. Please provide citation entry on the IDS.
Non Patent Literature document, marked as the 94 out of 112 documents filed on 06/07/2024 has 126 pages, titled “Signal peptides of Human Heavy Chains”. There is no citation of this document on the IDS. Please provide citation entry on the IDS.
Non Patent Literature document, marked as the 103 out of 112 documents filed on 06/07/2024 has 163 pages, titled “Specific Notes: Mouse T-Lymphocyte Receptor for Antigen Variable Region (Gamma Chains)”. There is no citation of this document on the IDS. Please provide citation entry on the IDS.
Therefore, the IDS fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609.
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.
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, 6, 9-10, 21-24, 27-29, 35, 38-39, 57, 60, 78-79, 82 and 97 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 10,385,123 B2 (listed in IDS), published on 08/20/2019, herein referred to as USPat123 and further in view of NCT05248646, 2022 (Anonymous: “Trial of Sibeprenlimab in the treatment of a Nephropathy (IgAN)” website: https://clinicaltrials.gov/study/NCT05248646?tab=history&a=3#version-content-panel. NCT 05248646, version V3 (2022-03-25), available on 03/25/2022, PTO-892).
Regarding instant claim 1, USPat123 teaches a method of improving kidney function comprising administering to a human subject in need thereof an anti-APRIL antibody molecule comprising a heavy chain variable region (VH) comprising three heavy chain complementarity determining regions HCDR1 with SEQ ID NO: 11, HCDR2 with SEQ ID NO: 12, and HCDR3 with SEQ ID NO: 13 and a light chain variable region (VL) comprising three light chain complementarity determining regions LCDR1 with SEQ ID NO: 280, LCDR2 with SEQ ID NO: 285, and LCDR3 with SEQ ID NO: 16 (page 151, column 211, paragraph 209, "(a) is a humanized antibody molecule; (b) binds to human APRIL" and "the antibody molecule is suitable for use in treating a disorder in kidney, e.g., IgA nephropathy"; page 147, column 203, paragraph 181, line 15-52, CDRs recited in SEQ ID NO: 11, 12, 13, 280, 285, and 16). Further, USPat123 recites an anti-APRIL antibody molecule comprising the VH with the HCDR1 with SEQ ID NO: 17, HCDR2 with SEQ ID NO: 282, HCDR3 with SEQ ID NO: 13 and VL with the LCDR1 with SEQ ID NO: 280, LCDR2 with SEQ ID NO: 285, and LCDR3 with SEQ ID NO: 16 (page 147, column 204, paragraph 183, line 5-40, CDRs recited in SEQ ID NO: 17, 282, 13, 280, 285, 16). In addition, USPat123 teaches the method reverses or prevents progression of kidney function in the subject, thereby improving kidney function (page 158, column 225, paragraph 292, line 35-39, " The antibody molecules described herein can be used to treat or prevent different stages of IgA nephropathy. […] In an embodiment, the antibody molecule reduces aberrantly glycosylated IgA1, auto-antibody formation, deposition of nephritogenic immune complexes in the kidney, inflammation and loss of kidney function, or a combination thereof").
Regarding instant claim 82 and 97, USPat123 teaches the method of treating IgA nephropathy comprising administering anti-APRIL molecule as described in claim 1 and further teaches that the anti-APRIL molecule is administered no more than once a month (page 113, column 135, paragraph 521, line 40-45 "once every four weeks, once every eight weeks, once a month, once every two months, or once every three months") in claim 82. USPAT123 also discloses benefits of the treatment comprising the reduction of the level of galactose-deficient IgA1 (Gd-IgA1) by 60% or more, within nine-month administration of the anti-APRIL antibody molecule, compared to the subject’s baseline level of IgA1 (page 153, column 216, paragraph 241, line 62-65, " “therapeutically effective dosage” typically inhibits a measurable parameter by at least about 20%, e.g., by at least about 40%, by at least about 60%, or by at least about 80% relative to untreated subjects" and page 113, column 135, paragraph 523, line 53-56, "administration of the antibody molecule reduces the level of IgA1 with O-linked glycosylation variants (e.g., aberrant or reduced composition of galactose in CH1 hinge region)"). Further, USPat123 teaches a method of identifying a human subject who will benefit from administration of an anti-APRIL antibody molecule (page 157, column 224, paragraph 287, line 4-8, “IgA nephropathy can be diagnosed by various tests, e.g., urine test, blood tests (e.g., to show increased blood levels of the waste product creatinine), iothalamate clearance test, kidney imaging (e.g., ultrasound, X-rays, or cystoscopy), kidney biopsy, or a combination thereof”). Further, regarding instant claim 97, USPat123 teaches the method of treating IgA nephropathy with the anti-APRIL antibody as recited in claim 1 and 82, and further teaches that the subject has a proteinuria level of greater than 2.0 g/day and/or and estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73m2 (page 158, column 225, paragraph 292, line 49-53, "subject has proteinuria greater than 0.5 g/day,[...]or greater than 1 g/day. [...]subject treated for IgA nephropathy has glomerular filtration rate (GFR) less than 50 ml/min").
Regarding instant claims 6, USPat123 teaches that method improves kidney function in the subject after a frequency of dosages and treatment time (page 156, column 221, paragraph 273, line 11-21, "The antibody molecules described herein are typically administered at a frequency that keeps a therapeutically effective level of antibody molecules in the patient's system until the patient recovers. For example, the antibody molecules may be administered at a frequency that achieves a serum concentration sufficient for at least about 1, 2, 5, 10, 20, 30, or 40 antibody molecules to bind each APRIL molecule. In an embodiment, the antibody molecules are administered every 1, 2, 3, 4, 5, 6, or 7 days, every 1, 2, 3, 4, 5, or 6 weeks, or every 1, 2, 3, 4, 5, or 6 month"). USPat123 further teaches parameters and normal ranges to test the kidney function and other measurable parameters to evaluate treatment efficacy of IgAN (page 158, column 226, paragraph 297, line 30-33, “To test kidney function, the person's estimated glomerular filtration rate (eGFR) is measured from a blood sample. Normal eGFR ranges from 90 to 120 ml/min/1.73 m2)“ and page 153, column 216, paragraph 241, line 65-67, “ The measurable parameter may be, e.g., hematuria, colored urine, foamy urine, pain, swelling (edema) in the hands and feet, or high blood pressure. The ability of an antibody molecule to inhibit a measurable parameter can be evaluated in an animal model system predictive of efficacy in treating or preventing IgA nephropathy”). Therefore, using the disclosure of USPat123, optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been obvious for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382).
Regarding instant claims 9, 10, 21, 22, and 23, the claims are drawn to the result of the administration of the anti-APRIL antibody to treat IgA nephropathy. USPat123 teaches that the antibody molecule is used to treat different stages of IgA nephropathy and that the antibody molecule preserves eGFR in the kidney, induces kidney recovery and regeneration, and reduces an autoantibody response (page 158, column 225, paragraph 292, "The antibody molecules described herein can be used to treat or prevent different stages of IgA nephropathy. In an embodiment, the antibody molecule is used to treat a symptom associated with IgA nephropathy, e.g., hematuria, proteinuria, albuminuria, hypertension, an early stage kidney disease (e.g., requiring dialysis or transplantation), or a combination thereof. In an embodiment, the antibody molecule reduces aberrantly glycosylated IgA1, auto-antibody formation, deposition of nephritogenic immune complexes in the kidney, inflammation and loss of kidney function, or a combination thereof"). As the instant claims are drawn to the result of the anti-APRIL molecule treatment, the claims do not limit the scope further and USPat123 teaches the anti-APRIL molecule with the limitations herein. See MPEP § 2112.01(II) "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Regarding instant claim 27, USPat123 teaches the antibody molecule comprises a heavy chain constant region of IgG2, and a light chain constant region of kappa (page 48, column 6, paragraph 12, line 26-30).
Regarding instant claim 29 and 35, USPat123 teaches the antibody molecule is administered no more than once a month, once a month, once every two months, once every three months, once every four weeks, or once every eight weeks (page 113, column 135, paragraph 521, line 40-45; and at a dose of 4mg/kg or 8 mg/kg (page 113, column 135, paragraph 520, line 20-21, "dose between 0.1 mg/kg and 50 mg/kg"); and is administered intravenously or subcutaneously (page 152, column 214, paragraph 233, line 64-67).
USPat123 further teaches the frequency of dosage as recited in instant claim 29 and described in instant claim 6 (page 156, column 221, paragraph 273, line 11-21). Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been obvious for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382).
USPat123 also teaches that the administration results in an increase in eGFR as recited in instant claim 35 (page 153, column 216, paragraph 241, line 62-65, “therapeutically effective dosage” typically inhibits a measurable parameter by at least about 20%, e.g., by at least about 40%, by at least about 60%, or by at least about 80% relative to untreated subjects) and teaches parameters and normal ranges to test the kidney function by measuring the subject’s estimated glomerular filtration rate in the serum (page 158, column 226, paragraph 297, line 30-33, “To test kidney function, the person's estimated glomerular filtration rate (eGFR) is measured from a blood sample. Normal eGFR ranges from 90 to 120 ml/min/1.73 m2)“ and page 153, column 216, paragraph 241, line 65-67, “ The measurable parameter may be, e.g., hematuria, colored urine, foamy urine, pain, swelling (edema) in the hands and feet, or high blood pressure. The ability of an antibody molecule to inhibit a measurable parameter can be evaluated in an animal model system predictive of efficacy in treating or preventing IgA nephropathy”). Therefore, using the disclosure from USPAT123, optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been obvious for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382).
Regarding instant claim 38 and 39, teaches the administration of the antibody molecule results in a decrease in the level of serum IgA (page 113, column 135, paragraph 523, line 50-56) by at least 50% and was sustained at least for a 1 month (page 168, column 246, paragraph 393, line 1-5, " In this study, chronic administration of a functional anti-APRIL antibody with in vitro validated blocking activity led to a reduction in serum IgA levels below 50%. Reduction was observed by day 24 and was sustained over the course of antibody treatment”).
Regarding instant claim 57, USPat123 teaches the subject has a disorder or is at risk of having a disorder, wherein the disorder is a Henloch-Schonlein purpura (page 156, column 221, paragraph 272, line 1-11 e.g. "Henoch-Schonlein purpura").
Regarding instant claim 60, USPat123 teaches that the subject is at risk of kidney failure and has proteinuria greater than or equal to a uPCR of 0.75 g/g/ or urine protein 1 g/day prior to the administration (page 158, column 225, paragraph 292, line 41-45, "the subject is at moderate to high risk, e.g., having proteinuria greater than 0.5-1 g/d and/or GFR reduced (e.g., below 30-50 ml/min) and/or hypertension").
Regarding instant claims 78 and 79, USPat123 teaches that the method further comprises administering a second therapeutic agent, like anti-CD20 monoclonal antibody to the subject (page 162, column 234, paragraph 350, line 26 - 29, "antibody molecule is administered in combination with rituximab (RITUXAN®). Rituximab is a chimeric anti-CD20 monoclonal antibody").
Regarding instant claim 24 and 28, USPat123 teaches the antibody molecule comprising a VH comprising the amino acid sequence SEQ ID NO: 296 (page 93, column 96, paragraph 345, line 50-56, see SEQ ID NO: 296 has 100% identity on Figure 1) and a VL comprising the amino acid sequence SEQ ID NO: 286 (page 93, column 96, paragraph 345, line 57-62, see SEQ ID NO: 286 has 100% identity on Figure 2). USPat123 teaches the CDRs that are recited in claim 1, 82, and 97 which are encoded in VH sequence SEQ ID NO: 296 and VL sequence SEQ ID NO: 286
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Figure 1. SEQ ID NO: 296 from instant application and SEQ ID NO: 296 from USPat123 alignment
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Figure 2. SEQ ID NOL 286 from instant application and SEQ ID NO: 286 from USPat123 alignment
While USPat123 teaches the sequences of the anti-APRIL antibody molecule as recited in claim 24, USPat123 does not teach that the anti-APRIL antibody molecule is sibeprenlimab as recited in instant claim 28. However, the applicant’s disclosure recites that the VH sequence SEQ ID NO: 296 and VL sequence SEQ ID NO: 286 encodes for the anti-APRIL antibody molecule sibeprenlimab (page 46, paragraph 2, line 20-24). Further, NCT05248646 V3, 2022 teaches that sibeprenlimab is used to treat IgA nephropathy (page 5-6, Brief summary, “evaluate effects of proteinuria and glomerular filtration rate of sibeprenlimab […] in adults with IgAN”). Therefore, it would have been obvious to the person of ordinary skill in the art to use the anti-APRIL antibody molecule sibeprenlimab for the method of treating IgAN as taught by NCT05248646 V3, 2022 and USPat123.
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).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 6, 9-10, 21-24, 27-29, 35, 38-39, 57, 60, 78-79, 82 and 97 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-11, 12-14, 24, 25, 27-29 of U.S. Patent No. 10385123 B2, published on 08/20/2019, herein referred to as USPat123 in view of NCT05248646, 2022 (cited previously); Huang and Xu, 2021 (Huang X, Xu G. An Update on Targeted Treatment of IgA Nephropathy: An Autoimmune Perspective. Front Pharmacol. 2021 Aug 23;12:715253. doi: 10.3389/fphar.2021.715253, PTO-892); and Myette et al., 2019 (Myette et al. A Proliferation Inducing Ligand (APRIL) targeted antibody is a safe and effective treatment of murine IgA nephropathy. Kidney Int. 2019 Jul;96(1):104-116. doi: 10.1016/j.kint.2019.01.031. Epub 2019 Mar 16, listed in IDS).
Regarding instant claims 1, 82, and 97, USPat123 claims 1, 2 and 3 recite an anti-A PRoliferation Inducing Ligand (APRIL) antibody molecule, comprising a heavy chain variable region (VH) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) and a light chain variable region (VH) comprising three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the VH comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 11; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 13; and the VL comprises an LCDR1 comprising the amino acid sequence of SEQ ID NO: 280; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 285, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or wherein the VH comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 17; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 282, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 13; and the VL comprises an LCDR1 comprising the amino acid sequence of SEQ ID NO: 280; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 285, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
Regarding instant claim 24, USPat123 claims 4, 5, 6, 7, 8, 24, 25, and 27 recite an anti-APRIL antibody molecule, wherein the VH comprises the amino acid sequence of SEQ ID NO: 296, or an amino acid sequence that is at least 85% identical thereto and wherein the VL comprises the amino acid sequence of SEQ ID NO: 286, or an amino acid sequence that is at least 85% identical thereto.
Regarding instant claims 1, 23, 82, and 97, instant claims do not recite a synthetic antibody molecule, which is an isolated antibody molecule, which is a humanized antibody molecule as recited in USPat123 claims 9, 10, and 11. Huang and Xu, 2021 recite that the VIS649 is a humanized monoclonal antibody that targets and neutralizes human APRIL (page 4, column 1, paragraph 2, “VIS649 is a fully humanized monoclonal IgG2 antibody that targets and neutralizes human APRIL”). Huang and Xu further teach that the humanized antibody is tolerated and safe in a human clinical trial (page 4, column 1, paragraph 2, “The results suggested that a single dose of VIS649 was well-tolerated and safe in healthy adults, with no serious adverse events (SAEs) or AEs that led to study discontinuation”). Therefore, it would have been obvious to the person of ordinary skill in the art to use humanized antibodies for human subjects to make the treatment safe and well-tolerated in humans as taught by Huang and Xu, 2022.
Regarding instant claims 27, USPat123 claims 12, 13, 14, 28, and 29 recite the antibody molecule which comprises a heavy chain constant region of IgG2 and comprises a light chain constant region of kappa or lambda light chain.
Regarding instant claims 1, 6, 10, 21, 22, 23, 38, and 39, USPat123 claims do not recite the effect of treatment after administering the anti-APRIL molecule to a subject.
Myette et al., 2019 teach an anti-APRIL antibody molecule that improves the standard supportive care of IgA nephropathy (page 104, Translational statement box, “Although supportive, immunosuppressive-based therapies constitute standard clinical practice, no effective, safe, and disease-specific therapies are currently available […] findings to present the safe and effective pharmacology of humanized anti-APRIL antibody VIS649 in nonhuman primates (NHPs) in further support of its potential therapeutic use in humans for the treatment of IgA nephropathy based on its immune-mediated mechanism”). Myette et al. teach that the anti-APRIL antibody reduces serum IgA levels and pathogenic immune complex deposition to reduce kidney damage, improves kidney function as recited in instant claim 1 and 6 and reduces proteinuria as recited in instant claim 10 (page 110, column 2, paragraph 1, “mab 4540 treatment–dependent reduction in both serum IgA levels and related pathogenic immune complex formation/deposition is sufficient to both reduce kidney damage (as defined by glomerular sclerosis) and prevent resultant loss of function based on a measurement of suppressed proteinuria”).
Further, Myette teaches that the anti-APRIL antibody molecule reduces autoantibody response as recited in instant claim 23 (page 111, column 1, paragraph 1, “Implications for the downregulation of autoreactive B cells are also clear and suggest efficacy of anti-APRIL treatment in the reduction of not only autoantigenic IgA1 but also autoreactive (IgG) antibodies that drive nephritogenic immune complex formation. and recite that the IgA1 “).
Myette et al., 2019 teaches that the anti-APRIL antibody treatment induces kidney recovery and regeneration as recited in instant claims 21 and 22 (page 110, column 2, paragraph 1, “discontinuation of treatment after 4 weeks with anti-APRIL antibody 4540 led to a reversal of the reduction in key early pathogenic mechanisms of disease”).
Myette et al., 2019 teaches that the anti-APRIL antibody treatment decreases in serum IgA, serum a-g-IgA, serum IgG, serum IgM and/or uPCR as compared to baseline as recited in instant claim 38 and 39 (page 110, column 2, paragraph 1, “Targeting APRIL in this model led to a reduction in not only total IgA but also the synthesis of hypo-galactosylated IgA”).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the anti-APRIL antibody molecule as taught by Myette et al., 2019 to improve treatment options for IgAN and improve kidney function and recovery from damage.
USPat123 does not teach the anti-APRIL molecule treatment preserves estimated glomerular filtration rate (eGFR) as recited in instant claim 9, increases eGFR after anti-APRIL administration as recited in instant claim 35 and that the anti-APRIL molecule is sibeprenlimab as recited in instant claim 28. NCT05248646 V3, 2022 teaches the method of treating IgAN by administering sibeprenlimab (VIS649) wherein the eGFR is the key outcome in IgAN patients (page 5, detailed description, “The key secondary objective is to compare the annualized rate of change from baseline (slope) of estimated glomerular filtration rate (eGFR) after approximately 24 months of treatment. There will be one main cohort comprised of approximately 450 subjects with source-verified biopsy confirmed lgAN and eGFR ~ 30 ml/min/1.73 m2”). NCT05248646 V3, 2022 also discloses that the anti-APRIL treatment is evaluated for its efficacy and safety in IgAN patients who receive maximally tolerated standard of care (page 1, Brief summary). As a teaching reference, Huang and Xu 2021 teach that standard supportive treatment does not adequately treat IgAN over time (page 2, column 2, paragraph 1, “However, despite optimizing RAAS blockers, some patients cannot achieve effective alleviation of proteinuria and have a high risk of renal failure over time”) and that VIS649 can be a potential treatment of IgAN (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to improve standard supportive care for IgAN patients with high morbidity with the anti-APRIL antibody molecule sibeprenlimab.
USPat123 does not teach the reduction of the level of APRIL by 90% or more within one month of administration of the anti-APRIL molecule as recited in instant claim 82 and do not recite the dosing regimen of the anti-APRIL molecule as recited in instant claims 29 and 35.
Huang and Xu, 2021 teach a phase I clinical trial with the anti-APRIL molecule VIS649 that demonstrated safety in healthy adults and suppresses serum APRIL and teaches the dosing regimen for VIS649 (page 3, Table 1, Intervention/Treatment under VIS649, first row, “VIS649 0.5 mg/kg-20 mg/kg, single dose, IV”. Huang and Xu, 2021 further teach the anti-APRIL molecule VIS649 reduces the free serum APRIL to the lower level of quantification (page 4, column 1, paragraph 1). Huang and Xu also teaches that the treatment reduces IgA which may be a potential treatment for IgAN (page 5, column 1, paragraph 1, “Serum IgA, Gd-IgA1, IgG, and IgM were reversibly suppressed in a dose-dependent manner with VIS649. Meanwhile, VIS649 was able to suppress free serum APRIL to the lower level of quantification. These data support the clinical development of VIS649 as a potential treatment for IgAN ”). Therefore, it would have been obvious to the person of ordinary skill in the art to use the dosing regimen taught by Huang and Xu to establish a tolerable and safe treatment for subjects with IgAN.
USPat123 claims do not recite the characteristics of the subject having the disorders as listed in instant claim 57 or at risk of kidney failure, is a pediatric patient, is not immunocompromised; and/or has proteinuria greater than or equal to a uPCR of 0.75 g/g or urine protein 1 g/day prior to administration as recited in instant claim 60. NCT05248646 V3, 2022 discloses the inclusion criteria in the clinical study of sibeprenlimab, VIS469, an anti-APRIL antibody molecule to treat subjects with IgAN wherein the subject’s urine protein/creatinine ratio (uPCR) is less than 0.75 g/g or urine protein is greater than 1.0 g/day (page 8, Inclusion Criteria).
USPat123 claims do not recite administering a secondary therapeutic agent as recited in instant claim 78 and 79. Huang and Xu 2021 discloses rituximab, an anti-CD20 antibody to treat IgAN and teaches that the B cell depletion may be a potential therapy of IgAN because it would reduce autoantibodies (page 5, column 1, paragraph 1, “depleting antibody-producing B-cells may be a potential therapy in IgAN because it would presumably reduce the production of pathogenic autoantibodies. B-cell depletion with the monoclonal antibody rituximab is well-tolerated and effective in several glomerular diseases. “Notably, another randomized, controlled, single-blind study (NCT04525729) on rituximab in treating primary IgAN is now recruiting participants in China, and the results are expected in 2023”). Therefore, it would have been obvious to the person of ordinary skill in the art to combine anti-APRIL antibodies with secondary therapeutic agents like rituximab to improve reduction of pathogenic autoantibodies in IgAN as taught by Huang and Xu, 2021.
Claims 1, 6, 9-10, 21-24, 27-29, 35, 38-39, 57, 60, 78-79, 82 and 97 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 4, 5, 6, 12, 13, 14, 15, 16, 17, 18, 19, 20, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 42, 44, 45, 46, 47, 48, 49, 50, and 51 of U.S. Patent No. 10954296 B2 published on 03/23/2021 herein referred to as USPat296, in view of NCT05248646, 2022 (cited previously); Huang and Xu, 2021 (cited previously); and Myette et al., 2019 (cited previously).
Regarding instant claims 1, 82, 97, USPat296 claims 1, 12, 13, and 37 recite a method of reducing the level of IgA in a cell or subject, the method comprising contacting the cell or subject with an anti-A PRoliferation-Inducing Ligand (APRIL) antibody molecule, wherein the VH comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 11; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 13; and the VL comprises an LCDR1 comprising the amino acid sequence of SEQ ID NO: 280; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 285, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or wherein the VH comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 17; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 282, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 13; and the VL comprises an LCDR1 comprising the amino acid sequence of SEQ ID NO: 280; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 285, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16, thereby reducing the level of IgA.
Regarding instant claim 38 and 39, USPat296 claims 15, 27, 28, and 39 recite the method of reducing the level of aberrantly glycosylated IgA1 in a subject comprising administering the anti-APRIL molecule with the same limitations as recited in USPat296 claim 1 above. USPat296 claims 9 and 10 recite the method of claim 1, wherein the level of IgA comprises: (a) the level of IgA in a peripheral tissue chosen from serum, mucosal tissue, or bone marrow; (b) the level of a variant of IgA chosen from IgA1, IgA1 in polymeric form (pIgA1), or IgA1 with an O-linked glycosylation variant and wherein the level of IgA comprises the level of aberrantly glycosylated IgA1.
Regarding instant claims 24, USPat296 claims 2, 3, 14, 16, 17, 37, and 39 recite the method wherein a) the VH comprises the amino acid sequence of SEQ ID NO: 296; (b) the VL comprises the amino acid sequence of SEQ ID NO: 286.
Regarding instant claims 1, 23, 82, and 97, instant claims do not recite a synthetic antibody molecule, which is an isolated antibody molecule, which is a humanized antibody molecule as recited in USPat296 claims 4 and 18. As described previously, Huang and Xu recite that the VIS649 is a humanized monoclonal antibody that targets and neutralizes human APRIL (page 4, column 1, paragraph 2). Huang and Xu further teach that the humanized antibody is tolerated and safe in a human clinical trial (page 4, column 1, paragraph 2). Therefore, it would have been obvious to the person of ordinary skill in the art to use humanized antibodies for human subjects to make the treatment safe and well-tolerated in humans as taught by Huang and Xu, 2022.
Regarding instant claim 27, USPat296 Claims 5, 6, 19, 20, and 40 recite the method of claim 1, wherein the antibody molecule comprises a heavy chain constant region of IgG2 and a light chain region of kappa.
Regarding instant claims 29 and 35, USPat296 claims 24, 29, 30, 31, 32, 33, 34, 42, 44, 45, 46, 47, 48, and 49 recite the method wherein the antibody molecule is administered to the subject at a dose between 0.1 mg/kg and 50 mg/kg, between 0.5 mg/kg and 10 mg/kg, between 0.5 mg/kg and 2 mg/kg, between 1 mg/kg and 3 mg/kg, between 1 mg/kg and 5 mg/kg, between 1 mg/kg and 10 mg/kg, wherein the antibody molecule is administered to the subject at a dose of 1 mg/kg, 2 mg/kg, 4 mg/kg, or 8 mg/kg. Claims 25 and 43 recite the method of claim 15, wherein the antibody molecule is administered once a week, twice a week, once every two weeks, or once every four weeks, or once a month, once every two months, or once every three months. Claims 23, 35, 36, 50, 51, and 41 recite the method wherein the antibody molecule is administered to the subject intravenously or subcutaneously.
Regarding instant claims 1, 6, 10, 21, 22, 23, 38, and 39, USPat296 claims do not recite the effect of treatment after administering the anti-APRIL molecule to a subject.
As described previously, Myette et al., 2019 teach an anti-APRIL antibody molecule that improves the standard supportive care of IgA nephropathy (page 104, Translational statement box). Myette et al. teach that the anti-APRIL antibody reduces serum IgA levels and pathogenic immune complex deposition to reduce kidney damage, improves kidney function as recited in instant claim 1 and 6 and reduces proteinuria as recited in instant claim 10 (page 110, column 2, paragraph 1). Further, Myette teaches that the anti-APRIL antibody molecule reduces autoantibody response as recited in instant claim 23 (page 111, column 1, paragraph 1) and teaches that the anti-APRIL antibody treatment induces kidney recovery and regeneration as recited in instant claims 21 and 22 (page 110, column 2, paragraph 1). Further, Myette et al., 2019 teaches that the anti-APRIL antibody treatment decreases in serum IgA, serum a-g-IgA, serum IgG, serum IgM and/or uPCR as compared to baseline as recited in instant claim 38 and 39 (page 110, column 2, paragraph 1).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the anti-APRIL antibody molecule as taught by Myette et al., 2019 to improve treatment options for IgAN and improve kidney function and recovery from damage.
USPat296 does not teach the anti-APRIL molecule treatment preserves estimated glomerular filtration rate (eGFR) as recited in instant claim 9, increases eGFR after anti-APRIL administration as recited in instant claim 35 and that the anti-APRIL molecule is sibeprenlimab as recited in instant claim 28. As described previously, NCT05248646 V3, 2022 teaches the method of treating IgAN by administering sibeprenlimab (VIS649) wherein the eGFR is the key outcome in IgAN patients (page 5, detailed description). NCT05248646 V3, 2022 also discloses that the anti-APRIL treatment is evaluated for its efficacy and safety in IgAN patients who receive maximally tolerated standard of care (page 1, Brief summary). As a teaching reference, Huang and Xu 2021 teach that standard supportive treatment does not adequately treat IgAN over time (page 2, column 2, paragraph 1) and that VIS649 can be a potential treatment of IgAN (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to improve standard supportive care for IgAN patients with high morbidity with the anti-APRIL antibody molecule sibeprenlimab.
USPat296 does not teach the reduction of the level of APRIL by 90% or more within one month of administration of the anti-APRIL molecule as recited in instant claim 82.
As described previously, Huang and Xu, 2021 teach the anti-APRIL molecule VIS649 reduces the free serum APRIL to the lower level of quantification (page 4, column 1, paragraph 1). Huang and Xu also teaches that the treatment reduces IgA which may be a potential treatment for IgAN (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to use the dosing regimen taught by Huang and Xu to establish a tolerable and safe treatment for subjects with IgAN.
USPat296 claims do not recite the characteristics of the subject having the disorders as listed in instant claim 57 or at risk of kidney failure, is a pediatric patient, is not immunocompromised; and/or has proteinuria greater than or equal to a uPCR of 0.75 g/g or urine protein 1 g/day prior to administration as recited in instant claim 60. NCT05248646 V3, 2022 discloses the inclusion criteria in the clinical study of sibeprenlimab, VIS469, an anti-APRIL antibody molecule to treat subjects with IgAN wherein the subject’s urine protein/creatinine ratio (uPCR) is less than 0.75 g/g or urine protein is greater than 1.0 g/day (page 8, Inclusion Criteria).
USPat296 claims do not recite administering a secondary therapeutic agent as recited in instant claim 78 and 79. As described previously, Huang and Xu 2021 discloses rituximab, an anti-CD20 antibody to treat IgAN and teaches that the B cell depletion may be a potential therapy of IgAN because it would reduce autoantibodies (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to combine anti-APRIL antibodies with secondary therapeutic agents like rituximab to improve reduction of pathogenic autoantibodies in IgAN as taught by Huang and Xu, 2021.
Claims 1, 6, 9-10, 21-24, 27-29, 35, 38-39, 57, 60, 78-79, 82 and 97 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 8, 9, 10, 25, 26, and 29 of U.S. Patent No. 10968270 B2, published on 04/06/2021 and herein referred to as USPat270 in view of in view of NCT05248646, 2022 (cited previously); Huang and Xu, 2021 (cited previously); and Myette et al., 2019 (cited previously).
Regarding instant claims 1, 82, and 97, USPat270 claims 1, 2, and 3 recite an anti-A PRoliferation Inducing Ligand (APRIL) antibody molecule, comprising: (i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the VH comprises: an HCDR1 comprises the amino acid sequence of SEQ ID NO: 11, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 12, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 13, the LCDR1 comprises the amino acid sequence of any of SEQ ID NO: 280, the LCDR2 comprises the amino acid sequence of any of SEQ ID NO: 285, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 16.
Regarding instant claim 24, USPat270 claims 8, 9, 10, and 29 recite the antibody molecule of claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO: 296 or an amino acid that is at least 85% identical thereto and the VL comprises the amino acid sequence of SEQ ID NO: 286 or an amino acid that is at least 85% identical thereto.
Regarding instant claims 1, 23, 82, and 97, instant claims do not recite a synthetic antibody molecule, which is an isolated antibody molecule, which is a humanized antibody molecule as recited in USPat270 claim 25. Huang and Xu, 2021 recite that the VIS649 is a humanized monoclonal antibody that targets and neutralizes human APRIL (page 4, column 1, paragraph 2, “VIS649 is a fully humanized monoclonal IgG2 antibody that targets and neutralizes human APRIL”). Huang and Xu further teach that the humanized antibody is tolerated and safe in a human clinical trial (page 4, column 1, paragraph 2, “The results suggested that a single dose of VIS649 was well-tolerated and safe in healthy adults, with no serious adverse events (SAEs) or AEs that led to study discontinuation”). Therefore, it would have been obvious to the person of ordinary skill in the art to use humanized antibodies for human subjects to make the treatment safe and well-tolerated in humans as taught by Huang and Xu, 2022.
Regarding instant claims 27, USPat270 claim 26 recites the antibody molecule wherein the antibody molecule comprises: (a) a heavy chain constant region of IgG2 (b) a light chain constant region of kappa light chain.
Regarding instant claims 1, 6, 10, 21, 22, 23, 38, and 39, USPat270 claims do not recite the effect of treatment after administering the anti-APRIL molecule to a subject.
As described previously, Myette et al., 2019 teach an anti-APRIL antibody molecule that improves the standard supportive care of IgA nephropathy (page 104, Translational statement box). Myette et al. teach that the anti-APRIL antibody reduces serum IgA levels and pathogenic immune complex deposition to reduce kidney damage, improves kidney function as recited in instant claim 1 and 6 and reduces proteinuria as recited in instant claim 10 (page 110, column 2, paragraph 1). Further, Myette teaches that the anti-APRIL antibody molecule reduces autoantibody response as recited in instant claim 23 (page 111, column 1, paragraph 1) and teaches that the anti-APRIL antibody treatment induces kidney recovery and regeneration as recited in instant claims 21 and 22 (page 110, column 2, paragraph 1). Further, Myette et al., 2019 teaches that the anti-APRIL antibody treatment decreases in serum IgA, serum a-g-IgA, serum IgG, serum IgM and/or uPCR as compared to baseline as recited in instant claim 38 and 39 (page 110, column 2, paragraph 1).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the anti-APRIL antibody molecule as taught by Myette et al., 2019 to improve treatment options for IgAN and improve kidney function and recovery from damage.
USPat270 does not teach the anti-APRIL molecule treatment preserves estimated glomerular filtration rate (eGFR) as recited in instant claim 9, increases eGFR after anti-APRIL administration as recited in instant claim 35 and that the anti-APRIL molecule is sibeprenlimab as recited in instant claim 28. As described previously, NCT05248646 V3, 2022 teaches the method of treating IgAN by administering sibeprenlimab (VIS649) wherein the eGFR is the key outcome in IgAN patients (page 5, detailed description). NCT05248646 V3, 2022 also discloses that the anti-APRIL treatment is evaluated for its efficacy and safety in IgAN patients who receive maximally tolerated standard of care (page 1, Brief summary). As a teaching reference, Huang and Xu 2021 teach that standard supportive treatment does not adequately treat IgAN over time (page 2, column 2, paragraph 1) and that VIS649 can be a potential treatment of IgAN (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to improve standard supportive care for IgAN patients with high morbidity with the anti-APRIL antibody molecule sibeprenlimab.
USPat270 does not teach the reduction of the level of APRIL by 90% or more within one month of administration of the anti-APRIL molecule as recited in instant claim 82 and do not recite the dosing regimen of the anti-APRIL molecule as recited in instant claims 29 and 35.
As described previously, Huang and Xu, 2021 teach a phase I clinical trial with the anti-APRIL molecule VIS649 that demonstrated safety in healthy adults and suppresses serum APRIL and teaches the dosing regimen for VIS649 (page 3, Table 1, Intervention/Treatment under VIS649, first row, “VIS649 0.5 mg/kg-20 mg/kg, single dose, IV”). Huang and Xu, 2021 further teach the anti-APRIL molecule VIS649 reduces the free serum APRIL to the lower level of quantification (page 4, column 1, paragraph 1). Huang and Xu also teaches that the treatment reduces IgA which may be a potential treatment for IgAN (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to use the dosing regimen taught by Huang and Xu to establish a tolerable and safe treatment for subjects with IgAN.
USPat270 claims do not recite the characteristics of the subject having the disorders as listed in instant claim 57 or at risk of kidney failure, is a pediatric patient, is not immunocompromised; and/or has proteinuria greater than or equal to a uPCR of 0.75 g/g or urine protein 1 g/day prior to administration as recited in instant claim 60. NCT05248646 V3, 2022 discloses the inclusion criteria in the clinical study of sibeprenlimab, VIS469, an anti-APRIL antibody molecule to treat subjects with IgAN wherein the subject’s urine protein/creatinine ratio (uPCR) is less than 0.75 g/g or urine protein is greater than 1.0 g/day (page 8, Inclusion Criteria).
USPat270 claims do not recite administering a secondary therapeutic agent as recited in instant claim 78 and 79. As described previously, Huang and Xu 2021 discloses rituximab, an anti-CD20 antibody to treat IgAN and teaches that the B cell depletion may be a potential therapy of IgAN because it would reduce autoantibodies (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to combine anti-APRIL antibodies with secondary therapeutic agents like rituximab to improve reduction of pathogenic autoantibodies in IgAN as taught by Huang and Xu, 2021.
Claims 1, 6, 9-10, 21-24, 27-29, 35, 38-39, 57, 60, 78-79, 82 and 97 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 28, 29, 30, 31, 32, 33, and 34 of U.S. Patent No. 10981982 B2, published on 04/20/2021, herein referred to as USPat982 in view of NCT05248646, 2022 (cited previously); Huang and Xu, 2021 (cited previously); and Myette et al., 2019 (cited previously).
Regarding instant claim 1, 82, and 97, USPat982 claims 1, 10, 11, 16, 28, and 29 recite a nucleic acid molecule encoding three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) of an anti-A PRoliferation Inducing Ligand (APRIL) antibody molecule, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 11; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 12, and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 13; and the LCDR1 comprises the amino acid sequence of SEQ ID NO: 280; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 285, and the LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or wherein the HCDR1 comprising the amino acid sequence of SEQ ID NO: 17; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 282, and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 13; and the CDR1 comprises the amino acid sequence of SEQ ID NO: 280; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 285, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 16.
Regarding instant claim 24, USPat982 claims 2, 3, 12, 13, 14, 15, 17, 18, 30, 31, 32, 33, and 34 recite the nucleic acid molecule of claim 2, wherein: (a) the VH comprises the amino acid sequence of SEQ ID NO: 296, or an amino acid sequence that is at least 85%, 90%, 95%, 99% identical thereto; (b) the VL comprises the amino acid sequence of SEQ ID NO: 286, or an amino acid sequence that is at least 90%, 95%, 99% identical thereto.
Regarding instant claims 1, 23, 82, and 97, instant claims do not recite a synthetic antibody molecule, which is an isolated antibody molecule, which is a humanized antibody molecule as recited in USPat982 claims 4 and 19. As described previously, Huang and Xu recite that the VIS649 is a humanized monoclonal antibody that targets and neutralizes human APRIL (page 4, column 1, paragraph 2). Huang and Xu further teach that the humanized antibody is tolerated and safe in a human clinical trial (page 4, column 1, paragraph 2). Therefore, it would have been obvious to the person of ordinary skill in the art to use humanized antibodies for human subjects to make the treatment safe and well-tolerated in humans as taught by Huang and Xu, 2022.
Regarding instant claims 27, USPat982 claims 5, 6, 7, 20, 21, and 22 recite the nucleic acid molecule of claim 1, wherein the anti-APRIL antibody molecule comprises a heavy chain constant region of IgG2 and comprises a light chain constant region of kappa light chain.
Regarding instant claims 1, 6, 10, 21, 22, 23, 38, and 39, USPat982 claims do not recite the effect of treatment after administering the anti-APRIL molecule to a subject.
As described previously, Myette et al., 2019 teach an anti-APRIL antibody molecule that improves the standard supportive care of IgA nephropathy (page 104, Translational statement box). Myette et al. teach that the anti-APRIL antibody reduces serum IgA levels and pathogenic immune complex deposition to reduce kidney damage, improves kidney function as recited in instant claim 1 and 6 and reduces proteinuria as recited in instant claim 10 (page 110, column 2, paragraph 1). Further, Myette teaches that the anti-APRIL antibody molecule reduces autoantibody response as recited in instant claim 23 (page 111, column 1, paragraph 1) and teaches that the anti-APRIL antibody treatment induces kidney recovery and regeneration as recited in instant claims 21 and 22 (page 110, column 2, paragraph 1). Further, Myette et al., 2019 teaches that the anti-APRIL antibody treatment decreases in serum IgA, serum a-g-IgA, serum IgG, serum IgM and/or uPCR as compared to baseline as recited in instant claim 38 and 39 (page 110, column 2, paragraph 1).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the anti-APRIL antibody molecule as taught by Myette et al., 2019 to improve treatment options for IgAN and improve kidney function and recovery from damage.
USPat296 does not teach the anti-APRIL molecule treatment preserves estimated glomerular filtration rate (eGFR) as recited in instant claim 9, increases eGFR after anti-APRIL administration as recited in instant claim 35 and that the anti-APRIL molecule is sibeprenlimab as recited in instant claim 28. As described previously, NCT05248646 V3, 2022 teaches the method of treating IgAN by administering sibeprenlimab (VIS649) wherein the eGFR is the key outcome in IgAN patients (page 5, detailed description). NCT05248646 V3, 2022 also discloses that the anti-APRIL treatment is evaluated for its efficacy and safety in IgAN patients who receive maximally tolerated standard of care (page 1, Brief summary). As a teaching reference, Huang and Xu 2021 teach that standard supportive treatment does not adequately treat IgAN over time (page 2, column 2, paragraph 1) and that VIS649 can be a potential treatment of IgAN (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to improve standard supportive care for IgAN patients with high morbidity with the anti-APRIL antibody molecule sibeprenlimab.
USPat982 does not teach the reduction of the level of APRIL by 90% or more within one month of administration of the anti-APRIL molecule as recited in instant claim 82 and do not recite the dosing regimen of the anti-APRIL molecule as recited in instant claims 29 and 35.
As described previously, Huang and Xu, 2021 teach a phase I clinical trial with the anti-APRIL molecule VIS649 that demonstrated safety in healthy adults and suppresses serum APRIL and teaches the dosing regimen for VIS649 (page 3, Table 1, Intervention/Treatment under VIS649, first row, “VIS649 0.5 mg/kg-20 mg/kg, single dose, IV”). Huang and Xu, 2021 further teach the anti-APRIL molecule VIS649 reduces the free serum APRIL to the lower level of quantification (page 4, column 1, paragraph 1). Huang and Xu also teaches that the treatment reduces IgA which may be a potential treatment for IgAN (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to use the dosing regimen taught by Huang and Xu to establish a tolerable and safe treatment for subjects with IgAN.
USPat982 claims do not recite the characteristics of the subject having the disorders as listed in instant claim 57 or at risk of kidney failure, is a pediatric patient, is not immunocompromised; and/or has proteinuria greater than or equal to a uPCR of 0.75 g/g or urine protein 1 g/day prior to administration as recited in instant claim 60. NCT05248646 V3, 2022 discloses the inclusion criteria in the clinical study of sibeprenlimab, VIS469, an anti-APRIL antibody molecule to treat subjects with IgAN wherein the subject’s urine protein/creatinine ratio (uPCR) is less than 0.75 g/g or urine protein is greater than 1.0 g/day (page 8, Inclusion Criteria).
USPat982 claims do not recite administering a secondary therapeutic agent as recited in instant claim 78 and 79. As described previously, Huang and Xu 2021 discloses rituximab, an anti-CD20 antibody to treat IgAN and teaches that the B cell depletion may be a potential therapy of IgAN because it would reduce autoantibodies (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to combine anti-APRIL antibodies with secondary therapeutic agents like rituximab to improve reduction of pathogenic autoantibodies in IgAN as taught by Huang and Xu, 2021.
Claims 1, 6, 9-10, 21-24, 27-29, 35, 38-39, 57, 60, 78-79, 82 and 97 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, and 38 of U.S. Patent No. 11136385 B2, published on 10/05/2021, herein referred to as USPat385, in view of NCT05248646, 2022 (cited previously); Huang and Xu, 2021 (cited previously); and Myette et al., 2019 (cited previously).
Regarding instant claims 1, 82, and 97, USP385 claims 1, 2, and 3, recite a method of treating IgA nephropathy, the method comprising administering to a subject in need thereof an effective amount of an anti-A PRoliferation Inducing Ligand (APRIL) antibody molecule, wherein the antibody molecule comprises a heavy chain variable region (VH) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) and a light chain variable region (VL) comprising three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the VH comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 11; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 13; and the VL comprises an LCDR1 comprising the amino acid sequence of SEQ ID NO: 280; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 285, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or wherein the VH comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 17; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 282, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 13; and the VL comprises an LCDR1 comprising the amino acid sequence of SEQ ID NO: 280; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 285, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16, thereby treating IgA nephropathy.
Regarding instant claim 24, USPat385 claims 4, 5, 6, 7, 8, 9, 10, and 32 recite the method of claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO: 296, or an amino acid sequence that is at least 85% identical thereto, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 286, or an amino acid sequence that is at least 85% identical thereto.
Regarding instant claims 1, 23, 82, and 97, instant claims do not recite a synthetic antibody molecule, which is an isolated antibody molecule, which is a humanized antibody molecule as recited in USPat385 claim 11. As described previously, Huang and Xu recite that the VIS649 is a humanized monoclonal antibody that targets and neutralizes human APRIL (page 4, column 1, paragraph 2). Huang and Xu further teach that the humanized antibody is tolerated and safe in a human clinical trial (page 4, column 1, paragraph 2). Therefore, it would have been obvious to the person of ordinary skill in the art to use humanized antibodies for human subjects to make the treatment safe and well-tolerated in humans as taught by Huang and Xu, 2022.
Regarding instant claim 27, USPat385 claims 12, 13, 14, and 33. The method of claim 1, wherein the antibody molecule comprises a heavy chain constant region of IgG2 and wherein the antibody molecule comprises a light chain constant region of kappa light chain.
Regarding instant claims 38 and 39, USPat385 claim 20 recites the method of claim 1, wherein administration of the antibody molecule reduces (a) the level of IgA in a peripheral tissue chosen from serum, mucosal tissue, or bone marrow; (b) the level of a variant of IgA chosen from IgA1, IgA1 in polymeric form (pIgA1), or IgA1 with an O-linked glycosylation variant; or (c) both (a) and (b).
Regarding instant claim 78 and 79, USPat385 claim 21 recites the method further comprising administering to the subject a second therapy for IgA nephropathy but does recite anti-CD20 antibody as the second therapeutic agent. As described previously, Huang and Xu 2021 discloses rituximab, an anti-CD20 antibody to treat IgAN and teaches that the B cell depletion may be a potential therapy of IgAN because it would reduce autoantibodies (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to combine anti-APRIL antibodies with secondary therapeutic agents like rituximab to improve reduction of pathogenic autoantibodies in IgAN as taught by Huang and Xu, 2021.
Regarding instant claims 29 and 35, USPat385 claims 24 and 38 recite the method wherein the antibody molecule is administered to the subject at a dose of 1 mg/kg, 2 mg/kg, 4 mg/kg, or 8 mg/kg. USPat385 claims 19, 25, and 36 recite the method wherein the antibody molecule is administered to the subject once a month, once every two months, or once every three months. USPat385 claims 19, 26, 27, and 34 recite the method wherein the antibody molecule is administered to the subject intravenously or subcutaneously. USPat385 claims 19, 23, 28, 29, 30, 31, and 37 recite the method, wherein the antibody molecule is administered to the subject at a dose between 0.5 mg/kg and 10 mg/kg, between 0.5 mg/kg and 2 mg/kg, between 1 mg/kg and 3 mg/kg, between 1 mg/kg and 5 mg/kg, between 1 mg/kg and 10 mg/kg, between 0.1 mg/kg and 50 mg/kg.
Regarding instant claims 1, 6, 10, 21, 22, 23, 38, and 39, USPat385 claims do not recite the effect of treatment after administering the anti-APRIL molecule to a subject.
As described previously, Myette et al., 2019 teach an anti-APRIL antibody molecule that improves the standard supportive care of IgA nephropathy (page 104, Translational statement box). Myette et al. teach that the anti-APRIL antibody reduces serum IgA levels and pathogenic immune complex deposition to reduce kidney damage, improves kidney function as recited in instant claim 1 and 6 and reduces proteinuria as recited in instant claim 10 (page 110, column 2, paragraph 1). Further, Myette teaches that the anti-APRIL antibody molecule reduces autoantibody response as recited in instant claim 23 (page 111, column 1, paragraph 1) and teaches that the anti-APRIL antibody treatment induces kidney recovery and regeneration as recited in instant claims 21 and 22 (page 110, column 2, paragraph 1). Further, Myette et al., 2019 teaches that the anti-APRIL antibody treatment decreases in serum IgA, serum a-g-IgA, serum IgG, serum IgM and/or uPCR as compared to baseline as recited in instant claim 38 and 39 (page 110, column 2, paragraph 1).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the anti-APRIL antibody molecule as taught by Myette et al., 2019 to improve treatment options for IgAN and improve kidney function and recovery from damage.
USPat385 does not teach the anti-APRIL molecule treatment preserves estimated glomerular filtration rate (eGFR) as recited in instant claim 9, increases eGFR after anti-APRIL administration as recited in instant claim 35 and that the anti-APRIL molecule is sibeprenlimab as recited in instant claim 28. As described previously, NCT05248646 V3, 2022 teaches the method of treating IgAN by administering sibeprenlimab (VIS649) wherein the eGFR is the key outcome in IgAN patients (page 5, detailed description). NCT05248646 V3, 2022 also discloses that the anti-APRIL treatment is evaluated for its efficacy and safety in IgAN patients who receive maximally tolerated standard of care (page 1, Brief summary). As a teaching reference, Huang and Xu 2021 teach that standard supportive treatment does not adequately treat IgAN over time (page 2, column 2, paragraph 1) and that VIS649 can be a potential treatment of IgAN (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to improve standard supportive care for IgAN patients with high morbidity with the anti-APRIL antibody molecule sibeprenlimab.
USPat385 does not teach the reduction of the level of APRIL by 90% or more within one month of administration of the anti-APRIL molecule as recited in instant claim 82. As described previously, Huang and Xu, 2021 further teach the anti-APRIL molecule VIS649 reduces the free serum APRIL to the lower level of quantification (page 4, column 1, paragraph 1). Huang and Xu also teaches that the treatment reduces IgA which may be a potential treatment for IgAN (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to use the dosing regimen taught by Huang and Xu to establish a tolerable and safe treatment for subjects with IgAN.
USPat385 claims do not recite the characteristics of the subject having the disorders as listed in instant claim 57 or at risk of kidney failure, is a pediatric patient, is not immunocompromised; and/or has proteinuria greater than or equal to a uPCR of 0.75 g/g or urine protein 1 g/day prior to administration as recited in instant claim 60. NCT05248646 V3, 2022 discloses the inclusion criteria in the clinical study of sibeprenlimab, VIS469, an anti-APRIL antibody molecule to treat subjects with IgAN wherein the subject’s urine protein/creatinine ratio (uPCR) is less than 0.75 g/g or urine protein is greater than 1.0 g/day (page 8, Inclusion Criteria).
Claims 1, 6, 9-10, 21-24, 27-29, 35, 38-39, 57, 60, 78-79, 82 and 97 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26, 27, 28, 29, 30, 32, 38, 39, 40, 41, 42, 43, 45, 49, 50, 51, 52, and 53, of copending Application No. 18/899,795, filed on 01/17/2025, herein referred to as USApp795 in view of NCT05248646, 2022 (cited previously); Huang and Xu, 2021 (cited previously); and Myette et al., 2019 (cited previously).
Regarding instant claims 1, 82, 97, 29, 35, 38, and 39, USApp795 claim 26 recites a method of treating IgA nephropathy in a population of human subjects in need thereof comprising subcutaneously administering the population of human subjects 400 mg of an anti-APRIL antibody molecule, which comprises a heavy chain variable region (VH) and a light chain variable region (VL),wherein the VH comprises a heavy chain complementarity determining region (HCDR) 1 comprising the amino acid sequence as set forth in SEQ ID NO: 11, a HCDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 12, and a HCDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 13, and the VL comprises a light chain complementarity determining region (LCDR) 1 comprising the amino acid sequence as set forth in SEQ ID NO: 280; a LCDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 285; and an LCDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 16, by the Chothia numbering system, wherein the anti-APRIL antibody molecule is administered once in every four weeks, and wherein the administration suppresses total IgA by up to 60% from the baseline value obtained from the human subjects before the administration.
Regarding instant claim 24, 29, 35, 38, and 39, USApp795 claims 27, 28, 29, 42, and 51 recite a method of treating IgA nephropathy in a population of human subjects in need thereof comprising subcutaneously administering the population of human subjects 400 mg of an anti-APRIL antibody molecule, which comprises a heavy chain variable region (VH) comprising the amino acid sequence as set forth in SEQ ID NO: 296 and a light chain variable region (VL) comprising the amino acid sequence as set forth in SEQ ID ON: 286, wherein the anti-APRIL antibody molecule is administered once in every four weeks, and wherein the administration suppresses total IgA by up to 60% from the baseline value obtained from the human subjects before the administration.
Regarding instant claim 27, USApp795 claims 39 and 51 recite the method wherein the anti-APRIL antibody molecule comprises a heavy chain constant region of IgG2 and a light chain constant region of kappa light chain.
Regarding instant claims 29 and 35, USApp795 claims 40, 41, 49, 50, 52, and 53 recite the method wherein the subjects in the population are administered the anti-APRIL antibody molecule at a concentration of about 200 mg/ml and wherein the subjects in the population are administered a total volume of 2 mL of a pharmaceutical composition comprising the anti-APRIL antibody molecule. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been obvious for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382).
Regarding instant claims 38 and 39, USApp795 claims 30, 32, 43, and 45 recite subjects in the population have a level of a-g IgA higher than the level of a-g IgA in a healthy subject, prior to the administration. USApp795 claims 34 and 47 recite the level of a-g IgA prior to the administration is reduced by at least by 40% after the administration.
Regarding instant claims 78 and 79, USApp795 claim 38 recite the method further comprising administering to a subject in the population a second therapeutic agent but does not teach the second therapeutic agent is anti-CD20 antibody. As described previously, Huang and Xu 2021 discloses rituximab, an anti-CD20 antibody to treat IgAN and teaches that the B cell depletion may be a potential therapy of IgAN because it would reduce autoantibodies (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to combine anti-APRIL antibodies with secondary therapeutic agents like rituximab to improve reduction of pathogenic autoantibodies in IgAN as taught by Huang and Xu, 2021.
Regarding instant claims 1, 6, 10, 21, 22, 23, 38, and 39, USApp795 claims do not recite the effect of treatment after administering the anti-APRIL molecule to a subject.
As described previously, Myette et al., 2019 teach an anti-APRIL antibody molecule that improves the standard supportive care of IgA nephropathy (page 104, Translational statement box). Myette et al. teach that the anti-APRIL antibody reduces serum IgA levels and pathogenic immune complex deposition to reduce kidney damage, improves kidney function as recited in instant claim 1 and 6 and reduces proteinuria as recited in instant claim 10 (page 110, column 2, paragraph 1). Further, Myette teaches that the anti-APRIL antibody molecule reduces autoantibody response as recited in instant claim 23 (page 111, column 1, paragraph 1) and teaches that the anti-APRIL antibody treatment induces kidney recovery and regeneration as recited in instant claims 21 and 22 (page 110, column 2, paragraph 1). Further, Myette et al., 2019 teaches that the anti-APRIL antibody treatment decreases in serum IgA, serum a-g-IgA, serum IgG, serum IgM and/or uPCR as compared to baseline as recited in instant claim 38 and 39 (page 110, column 2, paragraph 1).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the anti-APRIL antibody molecule as taught by Myette et al., 2019 to improve treatment options for IgAN and improve kidney function and recovery from damage.
USApp795 does not teach the anti-APRIL molecule treatment preserves estimated glomerular filtration rate (eGFR) as recited in instant claim 9, increases eGFR after anti-APRIL administration as recited in instant claim 35 and that the anti-APRIL molecule is sibeprenlimab as recited in instant claim 28. As described previously, NCT05248646 V3, 2022 teaches the method of treating IgAN by administering sibeprenlimab (VIS649) wherein the eGFR is the key outcome in IgAN patients (page 5, detailed description). NCT05248646 V3, 2022 also discloses that the anti-APRIL treatment is evaluated for its efficacy and safety in IgAN patients who receive maximally tolerated standard of care (page 1, Brief summary). As a teaching reference, Huang and Xu 2021 teach that standard supportive treatment does not adequately treat IgAN over time (page 2, column 2, paragraph 1) and that VIS649 can be a potential treatment of IgAN (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to improve standard supportive care for IgAN patients with high morbidity with the anti-APRIL antibody molecule sibeprenlimab.
USApp795 does not teach the reduction of the level of APRIL by 90% or more within one month of administration of the anti-APRIL molecule as recited in instant claim 82.
As described previously, Huang and Xu, 2021 teach the anti-APRIL molecule VIS649 reduces the free serum APRIL to the lower level of quantification (page 4, column 1, paragraph 1). Huang and Xu also teaches that the treatment reduces IgA which may be a potential treatment for IgAN (page 5, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to use the dosing regimen taught by Huang and Xu to establish a tolerable and safe treatment for subjects with IgAN.
USApp795 claims do not recite the characteristics of the subject having the disorders as listed in instant claim 57 or at risk of kidney failure, is a pediatric patient, is not immunocompromised; and/or has proteinuria greater than or equal to a uPCR of 0.75 g/g or urine protein 1 g/day prior to administration as recited in instant claim 60. NCT05248646 V3, 2022 discloses the inclusion criteria in the clinical study of sibeprenlimab, VIS469, an anti-APRIL antibody molecule to treat subjects with IgAN wherein the subject’s urine protein/creatinine ratio (uPCR) is less than 0.75 g/g or urine protein is greater than 1.0 g/day (page 8, Inclusion Criteria).
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lam Thuy Vi Tran Ho whose telephone number is (571)272-9135. The examiner can normally be reached Monday-Friday 7:30-3.
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/LAM THUY VI TRAN HO/Examiner, Art Unit 1647 /L.T./Examiner, Art Unit 1647
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683