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 .
Status of Claims
Claims 1, 4-5, 7-9, 11-12, 14-18, 20-24, and 26-27 are pending as of the response and amendments filed on 1/20/26. Claims 2-3, 6, 10, 13, 19, 25, and 28 have been canceled.
Claims 1, 14-18, 20, and 23-24 were previously rejected under 102(a)(1) as being anticipated by Basu. Applicants’ reasons for traversal are summarized and addressed below.
Applicants have argued Basu treated 20 patients with only cirrhosis, not with liver failure, and in particular, Basu excluded patients with acute liver failure from the study. Applicants have further argued Basu concluded that “[t]he relative contribution of NTZ and lactulose to the efficacy are unclear”. Applicants have argued Basu fails to teach the limitations of amended claim 16, which now recites “consisting of administering a compound to the subject, wherein the compound is selected from the group consisting of nitazoxanide (NTZ)…”, as Basu treated patients with lactulose and NTZ.
In view of the amendments to claim 16, the 102(a)(1) rejection over this claim and dependent claims 17-18, and 20-22 over Basu is withdrawn. However, Applicants’ arguments regarding independent claim 1 have are not fully persuasive. While it is acknowledged Basu excluded patients diagnosed with fulminant liver failure from the study, claim 1 is drawn to “treating or preventing” ACLF or ALF comprising administering NTZ to the subject in need thereof. Therefore, claim 1 encompasses treating patients who do not currently have ACLF or ALF but are at risk of developing one of these conditions and Basu teaches administering NTZ to patients with cirrhosis, a population at risk for developing ACLF or ALF. Therefore, as Basu administered NTZ to a patient population who did not currently have ACLF or ALF, but did have cirrhosis, thus inclusive of a patient at risk of developing ACLF or ALF, prevention of these conditions as claimed would have necessarily resulted. See MPEP 2112.02: The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978). For these reasons and those of record, the 102(a)(1) rejection of claims 1, 14-15, and 23-24 over Basu is maintained.
Upon further consideration, the 103 rejection over Basu in view of Arroyo is withdrawn. New rejections under 35 USC 102 and 103, and for provisional nonstatutory double patenting are made; as the new rejections are not based wholly on claim amendments, this action is non-final.
Claims 1, 4-5, 7-9, 11-12, 14-18, 20-24, and 26-27 were examined. Claims 17-18, 21-22, and 26-27 are objected to. Claims 1, 4-5, 7-9, 11-12, 14-16, 20, and 23-24 are rejected.
Claim Rejections-35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 14-15, and 23-24 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Basu et. al., “A pilot study utilizing nitazoxanide for hepatic encephalopathy in chronic liver failure”, 73rd Annual Scientific meeting of the American College of Gastroenterology, vol. 103, abstract 392, publ. Sept. 2008 (of record).
Basu discloses hepatic encephalopathy as a serious sign of liver failure that typically warrants liver transplantation (see abstract). Basu discloses patients with liver cirrhosis and chronic liver failure, including patients with alcoholic cirrhosis, hepatic encephalopathy, and decompensated cirrhosis were administered 500 mg. nitazoxanide twice daily; therapy was well-tolerated and clinically effective for hepatic encephalopathy (see abstract).
Regarding instant claim 1, Basu discloses treatment of a patient in need thereof by administering the same active agent as claimed, nitazoxanide. Therefore, Basu’s method would have necessarily resulted in the same effect as claimed, i.e., acute on chronic liver failure (ACLF), and acute liver failure (ALF) would have been prevented. Additionally, drug induced ALF and acetaminophen induced ALF would have been prevented as recited by instant claims 14-15, for the same reasons.
Regarding instant claims 23-24, as Basu discloses treatment of the same patient population as claimed by administering the same active agent, the effects of treatment would have necessarily been the same and resulted in the same effects as recited in these claims, i.e., further prevention of hepatic encephalopathy, and prevention of brain edema. See MPEP 2112.02: The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978). Basu therefore anticipates the claims.
Claim(s) 16 and 20 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Stankovic-Valentin et. al., WO 2020208208 A1, publ. 10/15/2020, international filing date 4/9/2020 (cited in the IDS).
Stankovic-Valentin discloses treatment of a subject in need of treatment for cirrhosis by administering a therapeutically effective amount of nitazoxanide (NTZ), tizoxanide (TZ), or tizoxanide glucuronide (TZG) (title & abstract; p. 9, lines 15-20; p. 12, line 23-p. 13, line 2). No additional agent is disclosed to be required for treatment. Stankovic-Valentin therefore discloses administering NTZ, TZ, or TZG to the same patient population as claimed, a subject having cirrhosis. Prevention of extrahepatic organ failure, including kidney failure as recited by instant claim 20 would have necessarily resulted. See MPEP 2112.02(II): The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978). Stankovic-Valentine anticipates the claims.
Claim Rejections-35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 4-5, 7, 9, 11-12 and 14-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pranesh et. al., US 20200397807 A1, publ. 12/24/2020, filing date 6/17/2020.
Pranesh teaches nicotinamide riboside (NR) compounds alone or in combination with a mitochondrial uncoupler for the treatment of mitochondrial diseases and metabolic disorders (title & abstract; para [0002], [0009]). Pranesh exemplifies nitazoxanide (NTZ) and tizoxanide as mitochondrial uncouplers, wherein NTZ is taught to possess high oral bioavailability and CNS penetration without causing significant adverse events (para [0549], [0560], [0564], [0566]). Pranesh teaches mitochondrial uncouplers such as NTZ reduce liver inflammation and fibrosis (para [0583]). Pranesh teaches administering the mitochondrial uncoupler and NR compound to treat hepatotoxicity and complications thereof, including ALF and ACLF; Pranesh teaches drug-induced liver injury to cause about 50% of ALF cases (para [0562]). Drug-induced liver injury includes cases caused by acetaminophen (para [0562]). Pranesh teaches an embodiment wherein the subject being treated has acutely decompensated liver disease (para [0683], see #150), as well as prevention of liver decompensation (para [0255]); liver disease includes cirrhosis (para [0239], [0243]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have treated liver failure selected from ACLF or ALF comprising administering to a subject in need thereof NTZ or TZ in view of Pranesh. As discussed above, Pranesh teaches treatment of metabolic and mitochondrial disorders and diseases by administering an NR compound in combination with a mitochondrial uncoupler, with NTZ and TZ both exemplified as mitochondrial uncouplers. Pranesh further teaches diseases to be treated to include cirrhosis, ACLF, and ALF, including drug-induced ALF. As such, one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the method of the instant claims in view of the teachings of Pranesh.
Regarding instant claims 9 and 11, Pranesh teaches liver disorders associated with systemic inflammatory response (SIRS) including ACLF (para [0514], [0585]); additionally, ACLF is taught to arise as a complication of hepatotoxicity or acetaminophen induced liver injury (para [0562]). Therefore, one of ordinary skill in the art upon reviewing Pranesh would have arrived at the claimed method of treating a subject in need of treatment for ACLF, wherein the subject has at least one ACLF precipitating event, such as SIRS or hepatotoxicity.
As Pranesh teaches treatment of acutely decompensated liver disease as well as prevention of liver decompensation, it would have been prima facie obvious to one of ordinary skill in the art to have applied the teachings of Pranesh to prevent progression from compensated to decompensated cirrhosis in a subject having ACLF as recited by instant claim 4, and to have treated a subject having ACLF and compensated cirrhosis as recited by instant claim 5. Moreover, in view of Pranesh one of ordinary skill in the art would have been motivated to have arrived at prevention of liver decompensation in a subject having ACLF by administering NTZ or TZ to a subject in need, as recited by instant claim 12, and to have reversed decompensated cirrhosis in a subject having ACLF as recited by instant claim 7.
Since Pranesh teaches the method to apply to treatment of ALF, including drug induced ALF, with acetaminophen included as one cause of drug induced ALF, it would have been prima facie obvious to have arrived at the claimed method of administering NTZ or TZ to treat drug-induced ALF as recited by instant claim 14, including acetaminophen-induced ALF as recited by instant claim 15.
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pranesh et. al., US 20200397807 A1 as applied to claims 1, 4-5, 7, 9, 11-12 and 14-15, in view of Arroyo et. al., Journal of Hepatology, vol. 62(suppl. 1), pp. S131-S143, publ. 2015 (of record).
The disclosure of Pranesh as discussed previously is incorporated herein. However, Pranesh doesn’t explicitly teach treatment of stage 2 or 3 ACLF.
Arroyo teaches acute on chronic liver failure (ACLF) as a syndrome characterized by acute decompensation of cirrhosis and organ/system failure involving the liver, kidney, brain, coagulation, circulation, and/or respiration, and hepatic encephalopathy, which is associated with poor survival (see summary & introduction paras). Arroyo teaches ACLF is frequently seen in alcoholic and untreated hepatitis B associated cirrhosis and develops as a result of systemic inflammation, occurring at any time during the course of the disease, including with compensated cirrhosis (see summary para). Arroyo teaches ACLF is categorized as grades ranging from 1 to 3; grade 1 has the lowest mortality rate, grade 2 is characterized by 2 different organ failures and has a mortality rate of 32% in a 28-day period, while grade 3 is characterized by 3-6 different organ failures and has a mortality rate of 73% in a 28-day period (p. S132, Key points 1). Arroyo teaches precipitating events of ACLF include alcoholism and/or hepatitis C infection, renal failure, liver failure, coagulation, cerebral, circulatory, and/or respiratory failure (p. S132, right col., last para-p. S133, left col., para under Fig. 1). Kidney dysfunction is also found among ACLF patients (p. S134, Table 1).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have applied the method of treatment as taught by Pranesh to a subject having grade 2 or 3 ACLF, further in view of Arroyo. As discussed previously, Pranesh teaches treatment of mitochondrial and inflammatory diseases such as ACLF and ALF by administering an NR compound in combination with a mitochondrial uncoupler such as NTZ or TZ. As grades 2 and 3 ACLF are taught by Arroyo to be associated with higher mortality rates, one of ordinary skill in the art would have been motivated to have applied Pranesh’s method of treatment to a subject in either of these categories of ACLF, recognizing the urgent need for such treatment.
Claim Rejections-Nonstatutory 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, 4-5, 7-9, 11-12, and 14-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 and 13 of copending Application No. 18289511 in view of Arroyo et. al., Journal of Hepatology, vol. 62(suppl. 1), pp. S131-S143, publ. 2015. The instant claims are drawn to treating a subject in need of treatment for ALF or ACLF by administering a compound selected from NTZ, TZ, or TZG, while the copending claims are drawn to a method of treating sepsis by administering a compound selected from NTZ, TZ, or TZG. Although the instant claims don’t recite treating sepsis and the copending claims don’t recite treating a subject having ALF or ACLF, these patient populations overlap. Arroyo teaches acute on chronic liver failure (ACLF) as a syndrome characterized by acute decompensation of cirrhosis and organ/system failure involving the liver, kidney, brain, coagulation, circulation, and/or respiration, and hepatic encephalopathy, which is associated with poor survival (see summary & introduction paras). Arroyo teaches ACLF is frequently seen in alcoholic and untreated hepatitis B associated cirrhosis and develops as a result of systemic inflammation, occurring at any time during the course of the disease, including with compensated cirrhosis (see summary para). Arroyo teaches ACLF is categorized as grades ranging from 1 to 3; grade 1 has the lowest mortality rate, grade 2 is characterized by 2 different organ failures and has a mortality rate of 32% in a 28-day period, while grade 3 is characterized by 3-6 different organ failures and has a mortality rate of 73% in a 28-day period (p. S132, Key points 1). Arroyo teaches precipitating events of ACLF include alcoholism and/or hepatitis C infection, bacterial infection, renal failure, liver failure, coagulation, cerebral, circulatory, and/or respiratory failure (p. S132, right col., last para-p. S133, left col., para under Fig. 1; p. S134, table 1). Kidney dysfunction is also found among ACLF patients (p. S134, Table 1). Sepsis can develop in the patient population as a result of bacterial infection (p. S135, right col., first 2 para).
As such, it would have been prima facie obvious to one of ordinary skill in the art to have applied the instantly claimed method of treatment to a patient suffering from sepsis due to bacterial infection as recited in the copending claims, as Arroyo teaches patients with ACLF to be at risk for developing sepsis as a result of bacterial infection, with bacterial infection included as a precipitating event for ACLF. The instant and copending claims are therefore not patentably distinct, as patients with ACLF at risk for developing sepsis as a result of bacterial infection as taught by Arroyo.
This is a provisional nonstatutory double patenting rejection.
Claim Objections
Claims 17-18, 21-22, and 26-27 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Correspondence
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SARAH . PIHONAK
Primary Examiner
Art Unit 1627
/SARAH PIHONAK/ Primary Examiner, Art Unit 1627
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