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 .
Claim Status
Claims 1-5, 8, 18, 87, 91 are amended. Claim 104 is added. Claims 1-5, 8, 18, 45, 70-75, 80-81, 87, 91, 98-104 are examined on the merits.
Priority
This application is a 35 § U.S.C. 111(a) continuation application of International Application No. PCT/US2020/059265, filed on November 6, 2020, which claims the benefit of priority to U.S. Provisional Patent Application No. 62/934,695, filed on November 13, 2019 is acknowledged.
Rejection withdrawn
The rejection of claims 1-5, 8, 18, 45, 70-76, 80-81, 87, 91, 98-103 under the nonstatutory double patenting rejection are withdrawn in view of Applicant’s amendments and arguments of the claims in the reply filed 02/18/2026.
New Rejections necessitated by Claim Amendments
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 are rejected under 35 U.S.C. 103 as being obvious over Foster et al. (“Foster”, US 11,015,201 B2, cited as reference AI on IDS filed 08/05/2025) in view of Borodovsky et al. (“Borodovsky”, WO 2016/201301 A1).
The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Regarding claims 1-4, 45, 101-102, Foster teaches double stranded RNA ( dsRNA) agents, targeting the AGT gene. The invention also relates to methods of using such RNAi agents to inhibit expression of an AGT gene and to methods of preventing and treating an AGT-associated disorder, e.g., high blood pressure (e.g., abstract). Foster provides a dsRNA agent, wherein the antisense strand and the sense strand comprise the chemically modified nucleotide sequences of the duplex AD-85481 (5'-usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3' (SEQ ID NO: 11) and 5'-gsuscaucCfaCfAfAfugagaguaca-3' (SEQ ID NO: 12)) wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine- 3 'phosphate, 2'-O-methy lguanosine-3 '-phosphate, 20 and 2'-O-methyluridine-3'-phosphate, respectively; Af, Cf, Gf, and Uf are 2'-O-fluoroadenosine-3'-phosphate, 2'-Ofluorocytidine-3'-phosphate, 2'-O-fluoroguanosine-3'-phosphate, and 2'-O-fluorouridine-3'-phosphate, respectively; dT is a deoxy-thymine; s is a phosphorothioate linkage; and (Tgn) is thymidine-glycol nucleic acid (GNA) S-isomer; and wherein the 3'-end of the sense strand is optionally conjugated to an N-[tris(GaNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol (L96) ligand. (e.g., line 13, column 7).
Regarding claim 5, Foster teaches that the pharmaceutical compositions of the invention may be administered in dosages sufficient to inhibit expression of an AGT gene. In general, a suitable dose of an iRNA of the invention will be in the range of about 0.001 to about 200 milligrams per kilogram body weight of the recipient per day, generally in the range of about 1 to 50 mg per kilogram body weight per day. Typically, a suitable dose of an iRNA of the invention will be in the range of about 0.1 mg/kg to about 5.0 mg/kg, preferably about 0.3 mg/kg and about 3.0 mg/kg. A repeat-dose regimen may include administration of a therapeutic amount of iRNA on a regular basis, such as every month, once every 3-6 months, or once a year. In certain embodiments, the iRNA is administered about once per month to about once per six months (e.g., line 6, column 105).
Regarding claim 18, Foster teaches that the iRNA is preferably administered subcutaneously, i.e., by subcutaneous injection. One or more injections may be used to deliver the desired dose of iRNA to a subject. The injections may be repeated over a period of time (e.g., line 30, column 114).
Regarding claims 70-73, Foster teaches dsRNA agent further comprises a ligand. In certain embodiments, the ligand is conjugated to
the 3' end of the sense strand of the dsRNA agent. In certain
embodiments, the ligand is an N-acetylgalactosamine (GaNAc) derivative, e.g., see below (e.g., line 41, column 4). Foster teaches the ligand is one or more GaNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker (e.g., line 54, column 7).
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Regarding claims 74, 103, Foster teaches the dsRNA agent is conjugated to the ligand as shown in the schematic below and, wherein X is O or S, e.g., wherein the X is 0. (e.g., lines 1 to 30, column 5).
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Regarding claim 80, Foster teaches that the subject is a human, such as a human being treated or assessed for a disease or disorder that would benefit from reduction in AGT expression; a human at risk for a disease or disorder that would benefit from reduction in AGT expression (e.g., line 54, column 20).
Regarding claim 81, Foster teaches the AGT-associated disorder is
selected from high blood pressure, hypertension, borderline hypertension, primary hypertension, secondary hypertension isolated systolic or diastolic hypertension, pregnancy associated hypertension, diabetic hypertension, resistant hypertension, refractory hypertension, paroxysmal hypertension,
renovascular hypertension, Goldblatt hypertension, ocular hypertension, glaucoma, pulmonary hypertension, portal hypertension, systemic venous hypertension, systolic hypertension, labile hypertension; hypertensive heart disease, hypertensive nephropathy, atherosclerosis, arteriosclerosis, vasculopathy, diabetic nephropathy, diabetic retinopathy, chronic heart failure, cardiomyopathy, diabetic cardiac myopathy, glomerulosclerosis, coarctation of the aorta, aortic aneurism, ventricular fibrosis, heart failure, myocardial infarction, angina, stroke, renal disease, renal failure, systemic
sclerosis, intrauterine growth restriction (IUGR), fetal growth restriction, obesity, liver steatosis/fatty liver, nonalcoholic Steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD); glucose intolerance, type 2 diabetes (noninsulin dependent diabetes), and metabolic syndrome (e.g., line 31, column 8).
Regarding claim 87, Foster teaches iRNAs to inhibit the expression of an AGT gene as well as compositions, uses, and methods for treating subjects that would benefit from reduction of the expression of an AGT gene, e.g., subjects susceptible to or diagnosed with an AGT-associated disorder, e.g., hypertension. (e.g., line 18, column 12).
Regarding claim 91, Foster teaches that the pharmaceutical compositions containing the iRNA are useful for preventing or treating an AGT associated disorder, e.g., hypertension (e.g., line 60, column 104).
Regarding claim 98, Foster teaches the a free iRNA is administered in the absence of a pharmaceutical composition. The naked iRNA may be in a suitable buffer solution. The buffer solution may comprise acetate, citrate, prolamine, carbonate, or phosphate, or any combination thereof. In one embodiment, the buffer solution is phosphate buffered saline (PBS) (e.g., line 64, column 113-114).
Foster does not teach fixed dose of about 200 mg to about 400 mg of a double-stranded ribonucleic acid agent of the instant claims. However, this is cured by Borodovsky.
Borodovsky teaches iRNA compositions which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a C5 gene (e.g., line 30, page 2). Borodovsky teaches therapeutics and therapeutic methods suitable for treating a subject that would benefit from reduction in C5 expression, e.g., a subject having a complement component C5-associated disease, include angiotensin converting enzyme inhibitors (e.g., lines 20-36, page 153). Borodovsky teaches that the therapeutic methods of the invention include administering a fixed dose of an dsRNA agent of the invention to a subject. Borodovsky teaches that the RNAi agent is administered as a fixed dose of between about 25 mg to about 900 mg, e.g., between about 25 mg to about 850 mg, between about 25 mg to about 500 mg, between about 25 mg to about 400 mg, between about 25 mg to about 300 mg (e.g., line 6, page 104. The therapeutic methods of the invention include administering a single fixed dose of about 50 mg, 200 mg, 400 mg, 600 mg or 900 mg to the subject. The therapeutic methods of the invention include administering a weekly fixed dose of about 100 mg, 150 mg, 200 mg, 250 mg, or 400 mg to the subject. The therapeutic methods of the invention include administering a monthly fixed dose to the subject. The therapeutic methods of the invention include administering a quarterly fixed dose to the subject (e.g., lines 27-35, page 31). Borodovsky teaches an iRNA agent is administered to a subject as a fixed dose. A "fixed dose" (e.g., a dose in mg) means that one dose of an iRNA agent is used for all subjects regardless of any specific subject-related factors, such as weight. In one particular embodiment, a fixed dose of an iRNA agent of the invention is based on a predetermined weight or age (e.g., line 36, page 98; Table 24).
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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 modify the teachings of Foster -suitable dose of an iRNA in the range of about 0.001 to about 200 milligrams per kilogram body weight of the recipient per day, such as every month, once every 3-6 months as to target AGT gene in subjects with an angiotensinogen (AGT)-associated disorder, with the teachings of Borodovsky -administering a fixed dose of an dsRNA agent to a subject by administering a single fixed dose of about 200 mg to 400 mg regardless of any specific subject- related factors, such as weight; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of developing a method for inhibiting the expression of an AGT gene in an AGT-associated disorder, e.g., high blood pressure by using a pharmaceutical composition comprising of a modified dsRNA agent (SEQ ID NOs 11 and 12) with a fixed dose of about 200 to 400 mg of modified double-stranded RNA every month, once every 3-6 months.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to obtain a pharmaceutical composition of modified dsRNA (antisense/sense strands) of a fixed-dose regardless of the subject-related factors such as weight or age for the treatment of AGT-associated disorder human disease e.g., high blood pressure by inhibiting AGT gene expression.
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 1-5, 8, 18, 45, 70-75, 80-81, 87, 91, 98-104 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-18, 22-23, 28-36, of U.S. Patent No. U.S. Patent No. US 11,834,661 B2 (“661”, December, 2023, cited as reference AZ on IDS filed 08/05/2025) in view of Foster et al. ("Foster", US 2017/0189541 A1, July 2017, cited as reference AO on IDS filed 08/05/2025) and Borodovsky et al. (“Borodovsky”, WO 2016/201301 A1).
This rejection is made to address the amendment to the claims in the reply filed 02/18/2026.
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to the same method of RNAi agents, e.g., double-stranded RNAi agents, targeting the angiotensinogen (AGT) gene, and methods of using such RNAi agents to inhibit expression of AGT and methods of treating subjects having an AGT-associated disorder, e.g., hypertension. The difference is that “661” claims are directed to inhibition of expression of AGT by at least 50%, whereas the instant claims are directed to fixed dose of dsRNA agent. However, one of ordinary skills in the art would recognize that if he/she knew how to make the instant claimed limitation, then it is obvious that the instant claims was known at the time of the filing.
Regarding claims 1-4, 45, 80, 99-102, “661” teaches a method for treating a subject having an angiotensinogen-(AGT-)associated disorder, the method comprising administering to the subject a dsRNA agent, or salt
thereof, wherein the dsRNA agent, or salt thereof, comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises the nucleotide sequence 5'-gsuscaucCfaCfAfAfugagaguaca-3' (SEQ ID NO:482) and the antisense strand comprises the nucleotide sequence 5'-usGfsuac(Tgn)cucauugUfgGfaugacsgsa- 3' (SEQ ID NO:666), (SEQ ID NO 482 and SEQ ID NO 666 corresponds to SEQ ID NO 12 and SEQ ID NO 11 respectively of the instant claims) wherein a, g, c, and u are 2'-O-methyl (2'-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2'-fluoro A, G, C and U, respectively; s is a phosphorothioate
linkage; and (Tgn) is a thymidineglycol nucleic acid (GNA)S-Isomer, thereby treating the subject having an AGT-associated disorder, wherein a, g, c, and u are 2'-O-methyl (2'-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2'-fluoro A, G, C and U, respectively; s is a phosphorothioate linkage; and (Tgn) is a thymidine-glycol nucleic acid (GNA)S-Isomer, thereby inhibiting expression of the AGT gene in the cell (claim 16). The method of claim 16, wherein the subject is human (claim 17).
Regarding claim 18, “661” teaches the method of claim 16, wherein the dsRNA agent, or salt thereof, is administered to the subject subcutaneously, (claim 23).
Regarding claim 70, “661” teaches the method of claim 16, wherein the dsRNA agent, or salt thereof, further comprises a ligand (claim 28).
Regarding claim 71, “661” teaches the method of claim 28, wherein the ligand is conjugated to the 3' end of the sense strand of the dsRNA
agent, or salt thereof (claim 29).
Regarding claim 72, “661” teaches the method of claim 28, wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative (claim 30).
Regarding claim 73, “661” teaches The method of claim 28, wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent linker (claim 31).
Regarding claim 74, “661” teaches the method of claim 31, wherein the ligand is (claim 32).
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Regarding claim 75, the method of claim 32, wherein the dsRNA agent or salt thereof, is conjugated to the ligand as shown in the following schematic (claim 33).
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Regarding claim 81, the method of claim 17, wherein the AGT-associated disorder is selected from the group consisting of high blood
pressure, hypertension, borderline hypertension, primary hypertension, secondary hypertension isolated systolic or diastolic hypertension, pregnancy-associated hypertension, diabetic hypertension, resistant hypertension, refractory hypertension, paroxysmal hypertension, renovascular hypertension, Goldblatt hypertension, hypertension associated diabetic cardiac myopathy, glomerulosclerosis, coarctation
of the aorta, aortic aneurism, ventricular fibrosis, heart failure, myocardial infarction, angina, stroke, renal disease, renal failure, systemic sclerosis, intrauterine growth restriction (IUGR), fetal growth restriction, obesity, liver steatosis/fatty liver, non-alcoholic Steatohepatitis (NASH), non-alcoholic
fatty liver disease (NAFLD); glucose intolerance, type 2 diabetes (non-insulin dependent diabetes), and metabolic syndrome (claim 18).
Regarding claim 87, “661” teaches the method of claim 17, wherein the AGT-associated disorder is hypertension (claim 22).
Regarding claim 91, “661” teaches the method of claim 16, wherein the dsRNA agent, or salt thereof, is present in a pharmaceutical composition (claim 36).
Regarding claim 98, “661” teaches the method of claim 16, wherein the dsRNA agent is in a salt form (claim 35).
Regarding claim 103, “661” teaches the method of claim 33, wherein the X is 0 (claim 34).
“661” does not recite “a fixed dose of about 200 mg to about 400 mg of a double-stranded ribonucleic acid (RNAi) agent” on the instant claims. However, these deficiencies are cured by Foster and Borodovsky.
Foster teaches methods and therapies for treating a subject having a disorder that would benefit from inhibiting or reducing the expression of an AGT gene, e.g., an angiotensinogen-associated disease, such as hypertension (high blood pressure), using iRNA compositions (e.g., paragraph 0009). Foster teaches that the administration may be repeated, for example, on a regular basis, such as weekly, biweekly (i.e., every two weeks) for one month, two months, three months, four months or longer. After an initial treatment regimen, the treatments can
be administered on a less frequent basis. For example, after administration weekly or biweekly for three months, administration can be repeated once per month, for six months or a year or longer (e.g., paragraph 0483). Foster teaches the double-stranded RNAi agent (SEQ ID NO 482, SEQ ID NO 666, comprising modified nucleotides), is administered at a dose of an iRNA of the invention in the range of about 0.001 to about 200.0 milligrams per kilogram body weight of the recipient per day, generally in the range of about 1 to 50 mg per kilogram body weight per day. For example, the dsRNA can be administered at about 0.01 mg/kg, about 0.05 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 3 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, or about 50 mg/kg per single dose (e.g., paragraph 0470). After an initial treatment regimen, the treatments can be administered on a less frequent basis. For example, after administration weekly or biweekly for three months, administration can be repeated once per month, for six months or a year or longer (e.g., paragraph 0636).
Borodovsky teaches iRNA compositions which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a C5 gene (e.g., line 30, page 2). Borodovsky teaches therapeutics and therapeutic methods suitable for treating a subject that would benefit from reduction in C5 expression, e.g., a subject having a complement component C5-associated disease, include angiotensin converting enzyme inhibitors (e.g., lines 20-36, page 153). Borodovsky teaches that the therapeutic methods of the invention include administering a fixed dose of an dsRNA agent of the invention to a subject. The therapeutic methods of the invention include administering a single fixed dose of about 50 mg, 200 mg, 400 mg, 600 mg or 900 mg to the subject. The therapeutic methods of the invention include administering a weekly fixed dose of about 100 mg, 150 mg, 200 mg, 250 mg, or 400 mg to the subject. The therapeutic methods of the invention include administering a monthly fixed dose to the subject. The therapeutic methods of the invention include administering a quarterly fixed dose to the subject (e.g., lines 27-35, page 31). Borodovsky teaches an iRNA agent is administered to a subject as a fixed dose. A "fixed dose" (e.g., a dose in mg) means that one dose of an iRNA agent is used for all subjects regardless of any specific subject-related factors, such as weight. In one particular embodiment, a fixed dose of an iRNA agent of the invention is based on a predetermined weight or age (e.g., line 36, page 98).
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 combine the teachings of “661” -a method for treating a subject having an angiotensinogen-(AGT-)associated disorder, the method comprising administering to the subject a dsRNA agent, wherein the dsRNA agent, comprises a sense strand and an antisense strand forming a double stranded region (SEQ ID NOs 482 and 666) with the teachings of Foster -the suitable dose of an iRNA in the range of about 0.001 to about 200 milligrams per kilogram body weight of the recipient per day, such as every month, once every 3-6 months as to target AGT gene in subjects with an angiotensinogen (AGT)-associated disorder, and with the teachings of Borodovsky -administering a fixed dose of an dsRNA agent to a subject by administering a single fixed dose of about 200 mg to 400 mg; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of developing a method for inhibiting the expression of an AGT gene in an AGT-associated disorder, e.g., high blood pressure by using a pharmaceutical composition comprising of a modified dsRNA agent (SEQ ID NOs 11 and 12) with a fixed dose of about 200 to 400 mg of modified double-stranded RNA every month, once every 3-6 months.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to obtain a pharmaceutical composition of modified dsRNA (antisense/sense strands) to treat AGT-associated disorder human disease e.g., high blood pressure by inhibiting AGT gene expression in subjects using a fix dose of modified dsRNA.
The instant claims are drawn to a variation of the same invention claimed by the reference patent “661”, Foster and Borodovsky. The Examiner considers it prima facie obvious to optimize the amounts of any biologically active agent to achieve their known biological effect, absent unexpectedly superior properties of the claimed invention. Specifically, the only difference between the claimed invention and the patented invention resides in the specific limitation of the dosage regimen: the patented claim recites a weight-normalized dosage, while the instant claim recites a fixed dosage range. A fixed dose (200 mg to about 400 mg or 300 mg) that falls within the operative range derived from the weight-based dose (mg/body weight) of the prior art patent would have been obvious to one of ordinary skill in the art. Selecting an absolute dose range that is clinically relevant and therapeutically effective, based on the teaching of weight-normalized dosing, does not render the claimed method patentably distinct.
For example, in the issued patent “661”, the broad claims encompass treating any type of subject and the broad claims do not specify the amount administered. However, the specification of the issued patent and Foster indicates “the dsRNA can be administered at about 0.01 mg/kg, about 0.05 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 3 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, or about 50 mg/kg per single dose”. Furthermore, the specification teaches the treatment of subjects with siRNA (assuming that the average body weight of the subject, human is about 50 kg, depending of the age and sex). Treating an average weight subject with a dose in the range taught by the issued patent (“0.01 mg/kg to about 50 mg/kg”) was clearly encompassed by the broad claims of the issued patent; thus 4 mg/kg administered to a 50 kg subject would be administering a dose of 200 mg (4 * 50 = 200), treatment with a dose of 6 mg/kg administered to a 50 kg subject would be administering 300 mg (6* 50 = 300 mg), similarly treatment with 8 mg/kg to a 50 kg subject would be administering 400 mg (8* 50 = 400), which is clearly within the range of the claimed range of about 200 to about 400mg required by the instant claims. Furthermore, prior art by the same Applicant (WO 2016/201301 A1) teaches therapeutic methods including administering a fixed dose of an dsRNA agent of the invention to a subject. The therapeutic methods include administering a single fixed dose of about 50 mg, 200 mg, 400 mg, 600 mg or 900 mg to the subject, which is clearly within the range of the claimed range of about 200 to about 400mg required by the instant claims.
Therefore, the issued patent (mg/body weight dose) results in an absolute dose of about 200 mg to about 400 mg for an average subject, the instant claims merely represents an obvious, unpatentable subset of the patented invention and the prior art.
Claims 1-5, 8, 18, 45, 70-75, 80-81, 87, 91, 98-104 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 11 of U.S. Patent No. U.S. Patent No. US 11,015,201 B2 (“201”, May, 2021, cited as reference AI on IDS filed 08/05/2025) in view of Foster et al. ("Foster", US 2017/0189541 A1, July 2017, cited as reference AO on IDS filed 08/05/2025) and Borodovsky et al. (“Borodovsky”, WO 2016/201301 A1).
This rejection is made to address the amendment to the claims in the reply filed 02/18/2026.
Regarding the issued patent claims limited only to compositions comprising the recited oligonucleotides, the instant method claims are considered obvious over these claims in view of the findings of the court in Sun Pharmaceutical Industries, Ltd. v. Eli Lilly & Co., No. 10-1105 (Fed. Cir. July 28, 2010) in which the court indicated that obviousness-type double patenting encompasses any use for a compound where that use is disclosed in the specification of an earlier patent claiming the compound and is later claimed as a method of using that compound. Thus, the invention as a whole was prima facie obvious.
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to the same double-stranded ribonucleic acid agent. The difference is that “201” claims are directed to a double-stranded RNA agent for inhibiting expression of angiotensinogen, whereas the instant claims are directed to a method of using the double-strand RNA in a human subject. However, one of the ordinary skill in the art would recognize that if he/she knew how to make the instantly claimed method of using the double-strand RNA in a human subject (product of “201”), then it is obvious that the instant method of using the double-strand RNA in a human subject was known at the time of the filing.
Regarding claims 1-4, 45, 80, 99-102, “201” teaches a double stranded RNA (dsRNA) agent, or a salt 15 thereof, for inhibiting expression of angiotensinogen (AGT) in a cell, comprising a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises the nucleotide sequence 5'-gsuscaucCfaCfAfAfugagaguaca-3' (SEQ ID N0:482) and the antisense strand comprises the nucleotide sequence 5'-usGfsuac(Tgn)cucauugUfgGfaugacsgsa- 3' (SEQ ID N0:666), wherein a, g, c, and u are 2'-0-methyl (2'-0Me) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2'-fluoro A, G, C and U, respectively; s is a phosphorothioate
linkage; and (Tgn) is a thymidine-glycol nucleic acid (GNA) S-Isomer (Claim 1).
Regarding claim 70, “201” teaches the dsRNA agent, or salt thereof, of claim 1, further comprising a ligand (Claim 2).
Regarding claim 71, “201” teaches the dsRNA agent, or salt thereof, of claim 2, wherein the ligand is conjugated to the 3' end of the sense strand of the dsRNA agent, or salt thereof (Claim 3).
Regarding claim 72, “201” teaches The dsRNA agent, or salt thereof, of claim 2, wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative (Claim 4).
Regarding claim 73, “201” teaches the dsRNA agent, or salt thereof, of claim 2, wherein the ligand is one or more GalNAc derivatives attached
through a monovalent, bivalent, or trivalent branched linker (Claim 5).
Regarding claim 74, “201” teaches the dsRNA agent, or salt thereof, of claim 4, wherein the ligand is (Claim 6).
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Regarding claims 75, 103, “201” teaches the dsRNA agent, or salt thereof, of claim 6, wherein the dsRNA agent, or salt thereof, is conjugated to the ligand as shown in the following schematic and, wherein X is O or S. (Claim 7).
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Regarding claim 91, “201” teaches a pharmaceutical composition for inhibiting expression of a gene encoding AGT comprising the dsRNA agent, or salt thereof, of claim 1 (Claim 11).
“201” does not recite “a fixed dose of about 200 mg to about 400 mg of a double-stranded ribonucleic acid (RNAi) agent” on the instant claims. However, these deficiencies are cured by Foster and Borodovsky.
Foster teaches methods and therapies for treating a subject having a disorder that would benefit from inhibiting or reducing the expression of an AGT gene, e.g., an angiotensinogen-associated disease, such as hypertension (high blood pressure), using iRNA compositions (e.g., paragraph 0009). Foster teaches the subject is a human (e.g., paragraph 0125). Foster teaches that the angiotensinogen-associated disease is selected from the group consisting of hypertension,
borderline hypertension, primary hypertension, secondary hypertension, hypertensive emergency, hypertensive urgency, isolated systolic or diastolic hypertension, pregnancy-associated hypertension, diabetic hypertension, resistant hypertension, refractory hypertension, paroxysmal
hypertension, renovascular hypertension, Goldblatt hypertension, ocular hypertension, glaucoma, pulmonary hypertension, portal hypertension, systemic venous hypertension, systolic hypertension, labile hypertension; hypertensive heart disease, hypertensive nephropathy, atherosclerosis,
arteriosclerosis, vasculopathy, diabetic nephropathy, diabetic retinopathy, chronic heart failure, cardiomyopathy, diabetic cardiac myopathy, glomerulosclerosis, coarctation of the aorta, aortic aneurism, ventricular fibrosis, Cushing's syndrome, and other glucocorticoid excess states including chronic steroid therapy, pheochromocytoma, reninoma, secondary aldosteronism and other mineralocorticoid excess states, sleep apnea, thyroid/parathyroid disease, heart failure, myocardial infarction, angina, stroke, diabetes mellitus, renal disease, renal failure, systemic sclerosis, intrauterine growth restriction (IUGR), and fetal growth restriction (e.g., paragraph 0126). Foster teaches that the administration may be repeated, for example, on a regular basis, such as weekly, biweekly (i.e., every two weeks) for one month, two months, three months, four months or longer. After an initial treatment regimen, the treatments can
be administered on a less frequent basis. For example, after administration weekly or biweekly for three months, administration can be repeated once per month, for six months or a year or longer (e.g., paragraph 0483). Foster teaches the double-stranded RNAi agent (SEQ ID NO 482, SEQ ID NO 666, comprising modified nucleotides), is administered at a dose of an iRNA of the invention in the range of about 0.001 to about 200.0 milligrams per kilogram body weight of the recipient per day, generally in the range of about 1 to 50 mg per kilogram body weight per day. For example, the dsRNA can be administered at about 0.01 mg/kg, about 0.05 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 3 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, or about 50 mg/kg per single dose (e.g., paragraph 0470). After an initial treatment regimen, the treatments can be administered on a less frequent basis. For example, after administration weekly or biweekly for three months, administration can be repeated once per month, for six months or a year or longer (e.g., paragraph 0636).
Borodovsky teaches iRNA compositions which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a C5 gene (e.g., line 30, page 2). Borodovsky teaches therapeutics and therapeutic methods suitable for treating a subject that would benefit from reduction in C5 expression, e.g., a subject having a complement component C5-associated disease, include angiotensin converting enzyme inhibitors (e.g., lines 20-36, page 153). Borodovsky teaches that the therapeutic methods of the invention include administering a fixed dose of an dsRNA agent of the invention to a subject. The therapeutic methods of the invention include administering a single fixed dose of about 50 mg, 200 mg, 400 mg, 600 mg or 900 mg to the subject. The therapeutic methods of the invention include administering a weekly fixed dose of about 100 mg, 150 mg, 200 mg, 250 mg, or 400 mg to the subject. The therapeutic methods of the invention include administering a monthly fixed dose to the subject. The therapeutic methods of the invention include administering a quarterly fixed dose to the subject (e.g., lines 27-35, page 31). Borodovsky teaches an iRNA agent is administered to a subject as a fixed dose. A "fixed dose" (e.g., a dose in mg) means that one dose of an iRNA agent is used for all subjects regardless of any specific subject-related factors, such as weight. In one particular embodiment, a fixed dose of an iRNA agent of the invention is based on a predetermined weight or age (e.g., line 36, page 98).
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 combine the teachings of “661” -a method for treating a subject having an angiotensinogen-(AGT-)associated disorder, the method comprising administering to the subject a dsRNA agent, wherein the dsRNA agent, comprises a sense strand and an antisense strand forming a double stranded region (SEQ ID NOs 482 and 666) with the teachings of Foster -the suitable dose of an iRNA in the range of about 0.001 to about 200 milligrams per kilogram body weight of the recipient per day, such as every month, once every 3-6 months as to target AGT gene in subjects with an angiotensinogen (AGT)-associated disorder, and with the teachings of Borodovsky -administering a fixed dose of an dsRNA agent to a subject by administering a single fixed dose of about 200 mg to 400 mg; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of developing a method for inhibiting the expression of an AGT gene in an AGT-associated disorder, e.g., high blood pressure by using a pharmaceutical composition comprising of a modified dsRNA agent (SEQ ID NOs 11 and 12) with a fixed dose of about 200 to 400 mg of modified double-stranded RNA every month, once every 3-6 months.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to obtain a pharmaceutical composition of modified dsRNA (antisense/sense strands) to treat AGT-associated disorder human disease e.g., high blood pressure by inhibiting AGT gene expression in subjects using a fix dose of modified dsRNA.
The instant claims are drawn to a variation of the same invention claimed by the reference patent “201”, Foster and Borodovsky. The Examiner considers it prima facie obvious to optimize the amounts of any biologically active agent to achieve their known biological effect, absent unexpectedly superior properties of the claimed invention. Specifically, the only difference between the claimed invention and the patented invention resides in the specific limitation of the dosage regimen: the patented claim recites a weight-normalized dosage, while the instant claim recites a fixed dosage range. A fixed dose (200 mg to about 400 mg or 300 mg) that falls within the operative range derived from the weight-based dose (mg/body weight) of the prior art patent would have been obvious to one of ordinary skill in the art. Selecting an absolute dose range that is clinically relevant and therapeutically effective, based on the teaching of weight-normalized dosing, does not render the claimed method patentably distinct.
For example, in the issued patent “201”, the broad claims encompass treating any type of subject and the broad claims do not specify the amount administered. However, the specification of the issued patent and Foster indicates “the dsRNA can be administered at about 0.01 mg/kg, about 0.05 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 3 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, or about 50 mg/kg per single dose”. Furthermore, the specification teaches the treatment of subjects with siRNA (assuming that the average body weight of the subject, human is about 50 kg, depending of the age and sex). Treating an average weight subject with a dose in the range taught by the issued patent (“0.01 mg/kg to about 50 mg/kg”) was clearly encompassed by the broad claims of the issued patent; thus 4 mg/kg administered to a 50 kg subject would be administering a dose of 200 mg (4 * 50 = 200), treatment with a dose of 6 mg/kg administered to a 50 kg subject would be administering 300 mg (6* 50 = 300 mg), similarly treatment with 8 mg/kg to a 50 kg subject would be administering 400 mg (8* 50 = 400), which is clearly within the range of the claimed range of about 200 to about 400mg required by the instant claims. Furthermore, prior art by the same Applicant (WO 2016/201301 A1) teaches therapeutic methods including administering a fixed dose of an dsRNA agent of the invention to a subject. The therapeutic methods include administering a single fixed dose of about 50 mg, 200 mg, 400 mg, 600 mg or 900 mg to the subject, which is clearly within the range of the claimed range of about 200 to about 400mg required by the instant claims.
Therefore, the issued patent (mg/body weight dose) results in an absolute dose of about 200 mg to about 400 mg for an average subject, the instant claims merely represents an obvious, unpatentable subset of the patented invention and the prior art.
Response to Amendments and Arguments on the Grounds of Non-Statutory Double Patenting
The applicant response asserts “In particular, the claims of the '661 Patent are generally directed to methods of inhibiting expression of an angiotensinogen (AGT) gene in a cell, and for treating a subject having an
angiotensinogen-(AGT-)associated disorder, by administering to the subject a double stranded RNAi agent comprising specific nucleotide sequences. However, the claims of the '661 Patent do not teach or suggest administering a fixed dose of the specifically claimed double stranded RNAi agent, or a salt thereof, to a subject, let alone the specific fixed dose of about 200 mg to about 400 mg, as required by the present claims”. The secondary reference relied on by the Examiner, Foster, does not make up for the deficiencies in the claims of the '661 Patent. Foster teaches the identification of numerous double stranded RN Ai agents targeting
numerous regions of the AGT mRNA. However, none of these include the specifically modified sense strand and antisense strand nucleotide sequences required by the claims. Moreover, Foster teaches methods for inhibiting the expression of AGT which include administering weight-based doses to a subject (see, e.g., page 9, paragraph [0129], pages 49-51, paragraphs [0470]-[0482]). Applicant notes that, as well known in the art at the time of the invention, a weight-based dose is not the same as a fixed dose. In particular, a weight-based dose (e.g., a dose in mg/kg) is a dose of the double stranded RN Ai agent that will change depending on the subject's weight, while a fixed dose (e.g., a dose in mg) is a dose of a double stranded RNAi agent that is used for all subjects regardless of the subject's weight. Foster does not teach or suggest any methods which include administering a fixed dose to a subject, let alone the specific fixed doses required by the claims. Applicant submits that there is no teaching or suggestion in the claims of the '661 patent, and Foster, that would provide one of ordinary skill in the art with a reasonable expectation of success that administration of a fixed dose of a specific double stranded RNAi agent to every subject, regardless of their weight, would effectively, potently and durably inhibit AGT protein levels. There is also no teaching or suggestion in the claims of the '661 Patent, and Foster, that would motivate one of ordinary skill in the art to select the specific fixed doses (i.e., about 200 mg to about 400 mg) required by the claims with a reasonable expectation of success”.
The instant claims are drawn to a variation of the same invention claimed by the reference patent “661”, and Foster. The Examiner considers it prima facie obvious to optimize the amounts of any biologically active agent to achieve their known biological effect, absent unexpectedly superior properties of the claimed invention. Specifically, the only difference between the claimed invention and the patented invention resides in the specific limitation of the dosage regimen: the patented claim recites a weight-normalized dosage, while the instant claim recites a fixed dosage range. A fixed dose (200 mg to about 400 mg or 300 mg) that falls within the operative range derived from the weight-based dose (mg/body weight) of the prior art patent would have been obvious to one of ordinary skill in the art. Selecting an absolute dose range that is clinically relevant and therapeutically effective, based on the teaching of weight-normalized dosing, does not render the claimed method patentably distinct.
For example, in the issued patent “661”, the broad claims encompass treating any type of subject and the broad claims do not specify the amount administered. However, the specification of the issued patent and Foster indicates “the dsRNA can be administered at about 0.01 mg/kg, about 0.05 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 3 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, or about 50 mg/kg per single dose”. Furthermore, the specification teaches the treatment of subjects with siRNA (assuming that the average body weight of the subject, human is about 50 kg, depending of the age and sex). Treating an average weight subject with a dose in the range taught by the issued patent (“0.01 mg/kg to about 50 mg/kg”) was clearly encompassed by the broad claims of the issued patent; thus 4 mg/kg administered to a 50 kg subject would be administering a dose of 200 mg (4 * 50 = 200), treatment with a dose of 6 mg/kg administered to a 50 kg subject would be administering 300 mg (6* 50 = 300 mg), similarly treatment with 8 mg/kg to a 50 kg subject would be administering 400 mg (8* 50 = 400), which is clearly within the range of the claimed range of about 200 to about 400mg required by the instant claims. Furthermore, prior art by the same Applicant (WO 2016/201301 A1) teaches therapeutic methods including administering a fixed dose of an dsRNA agent of the invention to a subject. The therapeutic methods include administering a single fixed dose of about 50 mg, 200 mg, 400 mg, 600 mg or 900 mg to the subject, which is clearly within the range of the claimed range of about 200 to about 400 mg required by the instant claims.
Conclusion
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/JULIO WASHINGTON GOMEZ RODRIGUEZ/ Examiner, Art Unit 1637
/Jennifer Dunston/ Supervisory Patent Examiner, Art Unit 1637
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