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 .
Drawings
The drawings were received on 9/18/25. These drawings are acceptable.
Response to Arguments
Applicant’s arguments, see pages 9-13, filed 9/18/25, with respect to 103 rejection over clinical trial NCT02553773 in view of applicant’s response to 36 CFR 1.105 filed on 2/28/25 have been fully considered and are persuasive. The rejection of claims 71, 79-80, 83, 85-86, 88-89 and 91-103 has been withdrawn because of the amendment to claims 71 and 83 to recite the limitation ‘wherein the patient on routine prophylaxis has received a therapeutically effective amount of the double-stranded ribonucleic acid molecules subcutaneously about once every month or about once every two months…from about 10U/kg to no more than 50(45)U/kg per dose’ and the clinical trial does not teach or suggest administering to the patient the double stranded ribonucleic acid subcutaneously once every month or about once every two months.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 71 and 78-103 are rejected under 35 U.S.C. 103 as being unpatentable over Akinc (US 20170159053, published June 8, 2017, cited on an IDS) taken with Griffin et al. (US 10407488, of record).
‘053 teach a method of treating a bleeding event in a subject having hemophilia A or B with inhibitors comprising administering a composition comprising a chemically modified double stranded RNA (dsRNA, siRNA) comprising sequences SEQ ID NO: 13 and 14 (the sequences appear to have the same modifications the dsRNA in claim 71) in an amount of 50 or 80 mg, wherein the sense strand is attached to a ligand. See pages 76-79 and 88-91. The ligand has the same structure as the ligand in instant claim 71. The subjects with hemophilia having inhibitors were also administered a bypassing agent (BPA), e.g., activated prothrombin complex concentrate (aPCC) and/or recombinant activated FVII (rFVlla). Paragraph 791 (as pointed out by applicant’s arguments filed on 9/18/25 instead of paragraph 789) of ‘053 teaches that an amount of recombinant Factor VII (BPA) used by the investigators in a patient who had hemophilia without inhibitors (C1-3) was less than the recommended amount of Factor VII. The dsRNA can be administered once a month, once every five weeks, six weeks, seven weeks, once every 2 months, quarter or as needed (e.g., Paragraphs 37-38, 60, 115, 116, and 139-140 and claim 3).
‘053 does not specifically teach using an effective amount of aPCC to treat a bleeding episode in a subject having Hemophilia A or B with inhibitors, wherein the effective amount of about 10U/kg to no more than about 50U/kg per dose and the patient is on a routine prophylaxis of a therapeutically effective amount of the dsRNA.
However, Griffin et al. teach a method for treating adverse bleeding and/or producing blood coagulation in a subject in need thereof comprising administering an effective amount of rFVIla or aPCC (columns 39-49 and 73-75). “Dosing intervals may span from every 2 hours to every 4 hours to every 8 hours to every 12 hours to every 24 hours to every 48 hours to every 72 hours simultaneously or alternating. (column 30, lines 31-34).” “cute bleeding: “For FVIII- or FIX- or FX-product single dose infusion or parenteral administration at ~1- 300 units per kg body weight until optimal response for acute bleeding.” “Dosing intervals may span from every 2 hours to every 4 hours to every 8 hours to every 12 hours to every 24 hours to every 48 hours to every 72 hours simultaneously or alternating. (column 30, lines 44-47).” To treat acute traumatic coagulopathy about 1-100 U/kg, preferably about 0.1-10 U/kg, more preferably about 0.01-1 U/kg, most preferably about 0.001-0.1 U/kg of aPCC. Column 30, Table 4 discloses dose amounts for FVIla and aPCC that would result in treating a bleeding episode in a patient in need thereof.
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It would have been prima facie obvious to a person of ordinary skill in the art before the time the effective filing date to combine the teaching of ‘053 taken with Griffin et al., namely to arrive at the claimed invention. ‘053 teaches The double stranded nucleic acid in the instant claims and a bypassing agent were administered to six inhibitor patients having hemophilia A or B (paragraph 768 of ‘053). Griffin teaches exemplary regimens for bypassing agents, FVIIa and aPCC (column 30, line 1 to column 32, line 5 and Table 4) that would embrace the concentration of either bypassing agent recited in the instant claims. “[W]here the general conditions of a claim are disclosed in the prior art, is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPO 233, 235 (CCPA 1955}. See MPEP 2144.05.II.A. Since the siRNA therapy would lower antithrombin (AT) and improve thrombin generation to restore hemostasis and prevent bleeding, one of ordinary skill in the art would have been motivated to use aPCC in a lower amount compared to the recommended amount taught by Griffin because the amount needed to treat a bleeding event should be reduced due the siRNA therapy with a reasonable expectation of success (see also page 79 of ‘053). It would have been obvious to one of ordinary skill in the art to try an effective amount of aPCC about 10 U/kg, 30U/kg, and 50U/kg per dose to determine the most cost effective amount to use in the method. A person of ordinary skill in the art would have been motivated to repeat the administering step after no less than 24 hours to increase the exposure of the subject to the aPCC. Administering no more than about 50U/kg/24 hours would have been an obvious dose to try to determine the most cost-effective dose. It would have been obvious to use either 50 or 80 mg of the siRNA since these amounts can be used to successfully treat hemophilia A or B with inhibitors in a subject as taught by ‘053. The dsRNA can be administered once a month, once every five weeks, six weeks, seven weeks, once every 2 months, quarter or as needed (e.g., Paragraphs 37-38, 60, 115, 116, and 139- 140 and claim 3 of ‘053). ‘053 discloses monthly doses of the siRNA for three months (see also Paragraphs 37-38, 60, 115, 116, and 139-140, 773, 785 and claim 3 of ‘053). Since aPCC generates thrombin it would have been obvious to use aPCC in the method to assist in thrombin production in the subject. It would have been obvious to the one of ordinary skill in the art to use the method in any bleeding event (minor, moderate, or severe bleeding episode or non-surgery related, spontaneous, surgery related, or bleeding episode resulting from trauma) since the method can successfully treat or reduce any bleeding episode. Since the siRNA therapy would lower antithrombin and improve thrombin generation to restore hemostasis and prevent bleeding, one of ordinary skill in the art would have been motivated to use rFVlla in a lower amount because the amount needed to treat a bleeding event should be reduced due the siRNA therapy (see page 79 of ‘053). Since rFVlla generates thrombin it would have been obvious to use it in the method to assist in thrombin production in the subject. In addition, rFVIIA is expensive, one of ordinary skill in the art would have been motivated to try to use 10ug/kg/dose or 45 ug/kg/dose to determine the minimal amount (cost-effective dose) that can be used in the method. Also since rFVIla is expensive, it would have been obvious for a person of ordinary skill in the art to repeat administering the rFVIIA no less than about 2 hours.
Therefore, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the time of the effective filing date.
Response to Arguments
Applicant's arguments filed 9/18/25 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). This is the case here since it was acknowledged that Akinc (‘305) does not specifically teach the claimed method (specifically the concentration of aPCC or rFVIIa). However, ‘053 taken with Griffin makes obvious the method steps in the claimed method. Griffin was provided to make obvious the concentration of aPCC or rFVIIa since the general conditions of the instant claims were disclosed in the prior art and to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05.II.A.
Applicant argues that the statement on pages 11-12 in the office action does not disclose factor VIIa from about 10 ug/kg to no more than 45 ug/kg of recombinant factor VIIa per dose because paragraphs 786 and 791 (789) of ‘053 disclose a patient without inhibitors (C1-3) and that recombinant FVIII not factor VIIa (a bypassing agent).
Applicant’s argument is not found persuasive because while it is acknowledged that rFVIII is not FVIIa and that paragraph 791 of ‘053 does not make obvious the claimed method, the rejection is based on a combination of references. ‘053 was combined with Griffin to make obvious the concentration of aPCC or rFVIIa Griffin teaches doses of the bypassing agent, FVIIa and aPCC that would read on doses recited in the instant claims (column 30, table 4).
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In addition, paragraph 791 of ‘053 shows one patient from the clinical study in ‘053 underwent an elective surgery and that recombinant FVIII (replacement factor) was used at a less amount than typically used for this procedures. Paragraph 792 of ‘053 indicates that the method using the dsRNA can result in a significant reduction in replacement factor. One of ordinary skill in the art would have had a reasonable expectation of success to use a replacement factor at a lower dose and could extrapolate that a bypassing agent could be used at a lower dose with a reasonable expectation of success.
Furthermore, several sections of ‘053 suggest using a bypassing agent (aPCC or FVIIa) with a subject that has inhibitors. For example, see paragraphs 768 and 781.
In response to applicant's arguments against Griffin, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. The rejection is a combination of ‘053 taken with Griffin. ‘053 teaches or suggest administration of the double stranded ribonucleic acid once every month and a bypassing agent recited in the pending claims in a subject having inhibitors. The bypassing agents aPCC or rFVIIa were taught in ‘053. Griffin was provided with ‘053 to teach that it would have been obvious to one of ordinary skill in the art to try the amount of either aPCC or rFVIIa recited in the pending claims. ‘053 makes obvious that the amount of aPCC or FVIIa could be reduced relative to the recommend amount of the bypassing agents as suggested by Griffin.
In response to applicant’s argument that the Examiner has not explained why one of skill in the art would have a reasonable expectation that an aPCC dose that is from about 10 U/kg to no more than 50 U/kg would be adequate to treat a bleeding episode in a patient who has hemophilia A or B with inhibitors and is on routine prophylaxis for hemophilia A or B with the double-stranded ribonucleic acid molecule recited in the pending claims, the argument is not found persuasive because Griffin teaches exemplary regimens for FVIIa and aPCC (column 30, line 1 to column 32, line 5). The double stranded nucleic acid in the pending claims and a bypassing agent were administered to six inhibitor patients having hemophilia A or B (paragraph 768 of ‘053). Any bleed events were successfully managed with standard replacement factor or bypass agent administration (paragraph 771 of ‘053). The data demonstrates that administration of dsRNA to inhibitor patients resulted in AT lowering and thrombin generation increase consistent with non-inhibitor patients and that thrombin generation increases consistently exceeded transiently BPA administration (paragraph 785). The teaching of ‘053 taken with Griffin indicate that one of ordinary skill in the art would have a reasonable expectation of success to treat a bleeding episode using the claimed dose of aPCC.
In response to applicant’s argument that the Examiner has not explained why one of skill would have a reasonable expectation that an rFVIIa dose that is from about 10 ug/kg to no more than 45 ug/kg per dose would be adequate to treat a bleeding episode in a patient who has hemophilia A or B with inhibitors and is on routine prophylaxis for hemophilia A or B with the double-stranded ribonucleic acid molecule recited in the pending claims, the argument is not found persuasive because Griffin teaches exemplary regimens for FVIIa and aPCC (column 30, line 1 to column 32, line 5). The double stranded nucleic acid in the pending claims and a bypassing agent was administered to six inhibitor patients having hemophilia A or B (paragraph 768 of ‘053). Any bleed events were successfully managed with standard replacement factor or bypass agent administration (paragraph 771). The data demonstrates that administration of dsRNA to inhibitor patients resulted in AT lowering and thrombin generation increase consistent with non-inhibitor patients and that thrombin generation increases consistently exceeded transiently BPA administration (paragraph 785). The teaching of ‘053 taken with Griffin indicate that one of ordinary skill in the art would of had a reasonable expectation of success to treat a bleeding episode using the claimed dose of rFVIIa.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
See attached PTO-326 for disposition of claims.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636