DETAILED ACTION
Claims 1-20 were pending; claim 1 was amended and claims 18-20 were canceled.
Claims 1-17 are pending.
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 11/16/2021 claims Priority from Provisional Application 63/114,494, filed 11/16/2020.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 8/7/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the Information Disclosure Statement is being considered by the Examiner.
Claim Rejections - 35 USC § 103
(New Rejection Required by Amendment)
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 unpatentable over
Kashyap et al. “Niacin for treatment of nonalcoholic fatty liver disease (NAFLD): novel use for an old drug?” Journal of Clinical Lipidology (2019) 13, 873–879 available publicly online October 14, 2019;
Hu et al. “Liver fat reduction with niacin is influenced by DGAT-2 polymorphisms in hypertriglyceridemic patients,” Journal of Lipid Research Volume 53, 2012;
Konerman et al. “Pharmacotherapy for NASH: Current and emerging,” Journal of Hepatology 2018 vol. 68, 362–375;
Tacke F. “Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis,” Expert Opinion on Investigational Drugs, 27:3, 301-311, 2018.
Claim 1 is directed towards a method to reverse or regress fibrosis and/or liver cirrhosis in a subject in need thereof, comprising: administering to a subject having fibrosis and/or liver cirrhosis one or more pharmaceutical doses of a pharmaceutical composition comprising niacin, or of a niacin analog thereof, wherein the pharmaceutical composition comprises 250 mg to 2000 mg of niacin, or niacin equivalent dosing of a niacin analog thereof, wherein the subject is administered a total daily dose of 250 mg to 6000 mg of niacin, or niacin equivalent dosing of a niacin analog thereof, and wherein administration of the one or more pharmaceutical doses of niacin or a niacin analog thereof reverses or regresses fibrosis and/or liver cirrhosis in the subject.
Kashyap explains the role of niacin of fibrosis. See the FIBROSIS section page 874.
“The potential use of niacin as an anti-fibrotic agent has been tested in chronic thioacetamide-induced liver fibrosis in rats and in vitro studies using human liver stellate cells. Arauz et al 13 have shown that niacin markedly reduced liver fibrosis induced by chronic administration of thioacetamide in rats. Niacin prevented the elevation of liver enzymes. Liver histopathology and hydroxyproline levels were significantly lower in the rats treated with thioacetamide plus niacin compared with thioacetamide only. Niacin demonstrated antioxidant properties by restoring the redox equilibrium (lipid peroxidation and glutathione peroxidase levels). Western blot assays showed decreased expression levels of TGF-b and its downstream inductor connective tissue growth factor (CTGF). In addition, niacin prevented hepatic stellate cell activation by blocking the expression of alpha smooth muscle actin. Zymography assays showed that niacin decreased the activity of matrix metalloproteinases 2 and 9. These authors suggest that niacin, through antioxidant properties and reducing TGF-b expression, prevented hepatic fibrosis in this animal model.13
Because hepatic stellate cells are the primary cell types involved in liver fibrosis,4 recent studies conducted in our laboratory investigated the direct effect of niacin on stellate cell fibrosis using primary cultures of human hepatic stellate cells isolated from normal (non-NASH) and from NASH patients with fibrosis (cells were obtained from Samsara Sciences, San Diego, CA).
Treating human primary stellate cells from normal subjects with pharmacologically relevant concentrations of niacin markedly inhibited stellate cell fibrosis (collagen type 1 and Sirus Red staining) induced by TGF-b or oxidative stress mediator hydrogen peroxide (H2O2), major physiological stimulators of liver fibrosis.8 Additional studies assessed regression of pre-existing fibrosis in stellate cells from patients with NASH with fibrosis. Stellate cells from patients had significantly increased fibrosis when compared with stellate cells from normal subjects.8 Treatment of these stellate cells from NASH patients with niacin resulted in a robust and significant regression of fibrosis.8”
Kashyap explains the rationale for niacin in a clinical trial of NASH-NAFLD.
“The preclinical and the clinical trial data summarized previously and elucidation of niacin’s unique mechanism of action on steatosis, inflammation, and fibrosis form a strong rationale for a randomized, placebo-controlled double-blind trial.
Niacin’s effects on the earliest stage of steatosis imply that niacin would be expected to reduce the cascade effect of the subsequent complications of NASH and fibrosis. It is noteworthy that niacin, via oxidative stress reduction, ameliorates inflammation and fibrosis. Fibrosis would be reduced not only by stellate cell collagen production, but also indirectly by mitigation of prior pathophysiological stages (inflammation and steatosis) for fibrosis. Thus 2 separate and unique mechanisms potentially impact the clinical manifestation of liver cirrhosis and its serious consequences.
Because niacin’s mechanism of action is different from the many drugs in development for NASH-NAFLD, combination of niacin-based therapy could be very synergistic and more potent than either drug alone.”
Kashyap’s summary and conclusion:
“In preclinical research, niacin inhibits and reverses hepatic steatosis, inflammation, and prevents fibrosis by reduction of oxidative stress, and inhibition of DGAT2 and other possible mechanisms. An uncontrolled clinical trial in 39 hypertriglyceridemic patients with steatosis showed a statistically significant reduction of liver fat by 47% and reductions in liver enzymes and CRP from the baseline when treated with Niacin ER for 6 months. Because niacin acts on the 3 major stages of NASH-NAFLD, combination with a drug in development for NASH is likely to result in a broader and more intense efficacy than either drug alone. By acting on the earliest stage of NAFLD, niacin mitigates the cascade effect on the later stages of the disease. Niacin uniquely offers the potential of not only treating NASH but also concurrent dyslipidemia, which very often occur together.
Randomized placebo-controlled double-blind parallel trials to assess the safety and efficacy of niacin in patients with NASH are warranted.”
Kashyap is clearly teaching using niacin for the treatment of fibrosis of the liver associated with NASH to regress the fibrosis. The dosing of the drug is not specifically discussed in the context of the treatment. To this end Hu is brought in to show how niacin is used in patients with dyslipidemia, and how the drug is dosed in trials for studying the efficacy of the drug, niacin.
Hu examined the effect of extended-release niacin on liver fat content in Chinese patients with dyslipidemia and whether the common diacylglycerol acyltransferase-2 ( DGAT2 ) polymorphisms influenced this effect. Hu provides background of niacin.
“Nicotinic acid or niacin, one of the naturally occurring B vitamins (vitamin B3), effectively reduces plasma TG levels. This effect was initially thought to be attributable to its antilipolytic effect in adipose tissue, thereby reducing FFA release from adipocytes and decreasing FFA flux to the liver ( 5, 6 ). However, although niacin initially reduces plasma FFA concentrations, this reduction is actually followed by a rebound within 1 to 9 h postdose, depending on the formulation used, and long-term treatment with niacin is associated with increases in plasma FFA, glucose, and insulin resistance ( 7, 8 ). These observations suggest that the reduction of the FFA delivery to the liver may not be the main mechanism explaining the consistent and maintained plasma TG-lowering effect of niacin.”
Hu discusses the dosing protocol for niacin. Patients were treated with ER niacin (Niaspan®, Abbott Laboratories) once daily at bedtime in increasing doses of 375 mg, 500 mg, and 750 mg (each for 1 week); 1,000 mg and 1,500 mg (each for 4 weeks); and 2,000 mg (for 12 weeks). All participants were advised to continue with their usual diet and other aspects of lifestyle during the study.
A person of ordinary skill in the art would understand that niacin is an active pharmaceutical compound with known activity in humans, and it is known as a safe and effective compound. One would be motivated to use niacin in NASH and in liver fibrosis associated with NASH as taught by Kashyap. Then one would need to look into the previous studies of running trials with niacin, and find the dosing protocol of Hu as a starting point. Therefore one would arrive at using niacin in NASH/fibrosis and doing once daily at bedtime in increasing doses of 375 mg, 500 mg, and 750 mg (each for 1 week); 1,000 mg and 1,500 mg (each for 4 weeks); and 2,000 mg (for 12 weeks), as a potential and obvious starting point. Therefore claim 1 is prima facie obvious based on the rationale provided.
Instant claim 1 requires “wherein the one or more pharmaceutical doses of a pharmaceutical composition comprising niacin are administered sequentially or concurrently with belapectin, cenicriviroc, or lanifibrinor.”
To address the combination therapy Konerman and Tacke references are brought in.
Konerman teaches the “Pharmacotherapy for NASH.” Discussing treatments both current (2018) and emerging. While Konerman is not all-encompassing with the state of the art with regards to all treatments known, the reference does provide an interesting motivation to combine therapies. Stating, “Presently the majority of NASH clinical trials are being conducted with single agent therapies. However, based on the complex pathophysiology and presumed multiple redundant pathways, it is likely that combining therapies that engage different targets may provide a synergistic histopathologic benefit.”
Tacke teaches, “Cenicriviroc (CVC) for the treatment of non-alcoholic steatohepatitis and liver fibrosis.” In section 6, The efficacy and safety of using CVC in patients with NASH and hepatic fibrosis has been tested in a multicenter phase 2b clinical trial, the CENTAUR trial (NCT02217475), over a period of 2 years, of which the primary and secondary end point analyses after 1 year have been published. Tavke notes, “The improvement of fibrosis was seen across all stages of fibrosis, with significant benefit in the pooled data for stage 2 and 3 fibrosis.”
A person of ordinary skill in the art would understand that niacin is an active pharmaceutical compound with known activity in humans, and it is known as a safe and effective compound for fibrosis. A person of ordinary skill in the art would also understand that Cenicriviroc is an active pharmaceutical compound with known activity in humans, and it is known as a safe and effective compound for fibrosis. One would be motivated to use both niacin and Cenicriviroc in NASH and in liver fibrosis associated with NASH as taught by the art. One would be motivated to use a combination treatment, as the art suggests attacking the disease with multiple modalities would be potentially synergistic and beneficial.
Instant claim 2 is directed towards the method of claim 1, wherein the fibrosis is associated with elevated or overaccumulation of collagen in cells or tissue.
This limitation is obvious 2 ways, one the teaching of Kashyap, the other on inherency. Kashyap states, page 878, “[f]ibrosis would be reduced not only by stellate cell collagen production, but also indirectly by mitigation of prior pathophysiological stages (inflammation and steatosis) for fibrosis,” when discussing NASH as the disease to be treated, and therefore rendering obvious the instant claim limitation. Secondly, this is the inherent activity/property of NASH having elevated or overaccumulation of collagen in cells or tissue.
So in this case, NASH has the property of elevated or overaccumulation of collagen in cells or tissue.
Instant claim 3 requires the method of claim 2, wherein administration of one or more pharmaceutical doses of niacin or of a niacin analog to the subject reduces collagen levels in fibrotic tissue. This is the activity of niacin in the human with fibrosis at a given dose, an inherent property. Since the dosing of the same drug in the obvious patient population, the result of doing so will achieve the result. This wherein clause, while clearly an inherent property, also is simple the recitation of the intended result of performing the process. See MPEP 2111.04. “However, the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).” Therefore the reduction of collogen by niacin is obvious.
Instant claim 4 requires the method of claim 1, wherein administration of one or more pharmaceutical doses of niacin or of a niacin analog stabilizes or normalizes the expression levels of matrix metalloproteinases (MMPs) and/or tissue inhibitors of metalloproteinases (TIMPs). This limitation is again a recitation of the intended result of performing the process step. Niacin has this effect inherently, and the recitation does not lend to patentability.
Instant claim 5 requires the method of claim 1, wherein the fibrosis affects one or more tissues or organs. Instant claim 6 wherein the one or more tissues or organs are selected from liver, bone marrow, lung, kidney, gastrointestinal tract, skin, eye, endomyocardium, musculoskeletal system, and myocardium. Instant claim 7, wherein the one or more tissues or organs is the liver. Instant claim 8, wherein the subject has a disease, disorder, or condition selected from the group consisting of a cystic fibrosis, idiopathic pulmonary fibrosis, post COVID-19 fibrosis, radiation-induced lung injury, liver fibrosis, liver cirrhosis, glial scars, arterial stiffness, arthrofibrosis, Crohn's disease, Dupuytren's contracture, keloids, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic system fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma/systemic sclerosis, adhesive capsulitis, interstitial fibrosis, replacement fibrosis, inflammatory bowel disease, renal fibrosis in patients with tubulointerstitial fibrosis, glomerulosclerosis, lung fibrosis, and chronic kidney disease.
Kashyap teaches NASH effects the liver with fibrosis, meeting these claim limitations.
Instant claim 13 is to the method of claim 1, wherein the pharmaceutical composition is formulated for oral, transdermal or parenteral delivery.
Kashyap teaches oral admin.
Instant claim 14 requires the method of claim 13, wherein the pharmaceutical composition is formulated as an extended-release or time-release formulation for oral delivery.
Hu teaches patients were treated with ER niacin (Niaspan®, Abbott Laboratories), an extended-release form of niacin.
Zhang et al. “Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets,” World J Gastroenterol 2016 December 28; 22(48): 10512-10522.
In regards to claims 9-11. Instant claim 9 requires the method of claim 1, wherein the subject has grade 1, grade 2, grade 3, or grade 4 liver fibrosis. Instant claim 10, the method of claim 1, wherein the subject has liver cirrhosis. Instant claim 11, the method of claim 1, wherein the subject has liver fibrosis resulting from a biliary obstruction, iron overload, autoimmune hepatitis, Wilson's disease, a viral hepatitis B infection, or a viral hepatitis C infection.
The previously discussed art shows that one would look to use niacin in the treatment of NASH to “regress” fibrosis, and one would use a known safe and effective dose of niacin and optimize from that starting point. The art didn’t discuss the “grade” of fibrosis or if treating liver fibrosis caused by other methods, as required by claim 11 would be obvious.
Kashyap teaches that the mechanism of clearing/regressing fibrosis in the liver from niacin occurs by inhibiting collogen and MMPs. Kashyap, “Niacin’s effects on the earliest stage of steatosis imply that niacin would be expected to reduce the cascade effect of the subsequent complications of NASH and fibrosis. It is noteworthy that niacin, via oxidative stress reduction, ameliorates inflammation and fibrosis. Fibrosis would be reduced not only by stellate cell collagen production, but also indirectly by mitigation of prior pathophysiological stages (inflammation and steatosis) for fibrosis. Thus 2 separate and unique mechanisms potentially impact the clinical manifestation of liver cirrhosis and its serious consequences.”
Zhang teaches:
“Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells (HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.”
Zhang notes that fibrosis occurs from injury. The type of injury varies but the mechanism for injury and fibrosis plays out through the HSC. This is the same target for niacin as shown by Kashyap. As such the cause of injury leading to fibrosis seems to be irrelevant. The injury leading to liver fibrosis resulting from a biliary obstruction, iron overload, autoimmune hepatitis, Wilson's disease, a viral hepatitis B infection, or a viral hepatitis C infection all have the same inflammation and injury to the HSC, which is the target of niacin.
As such it is obvious to try and treat any liver fibrosis regardless of originating injury, as the mechanism of treatment overlaps with all the diseases mentioned in the instant claims. Therefore these narrower embodiments do not lend to the patentability of the claims, and they are obvious based on the nexus of injury.
Stamford, Chapter 5, “High-Affinity Niacin Receptor GPR109A Agonists,” Annual Reports in Medicinal Chemistry, Volume 45, 2010.
In regards to instant claim 12 requiring the method of claim 1, wherein the niacin analog is selected from nicotinamide, 6- hydroxy nicotinamide, N-methyl-nicotinamide, acifran, acipimox, niceritrol, ARI-3037MO, and nicotinamide riboside chloride.
The previously discussed art shows that one would look to use niacin in the treatment of NASH to “regress” fibrosis, and one would use a known safe and effective dose of niacin and optimize from that starting point. Hu teaches patients were treated with ER niacin (Niaspan®, Abbott Laboratories), an extended-release form of niacin. The art didn’t discuss combination treatment.
Stamford teaches using niacin and its analogs including acipimox for having similar medicianla chemistry properties and activities. Thereby motivating one to try and use analogs og niacin for the treatment of diseases treated with niacin.
One would be motivated to use the analogs of niacin to increase patient compliance with treatment by helping to mitigate a known side effects of niacin and to improve efficacy. As such the claim 12 is obvious.
Rocca et al. US 2008/0050429 A1 published 2/28/2008.
In regards to instant claims 15-17. Instant claim 15 requires the method of claim 14, wherein the pharmaceutical composition is formulated as a film-coated extended-release tablet. Instant claim 16 requires the method of claim 15, wherein the film-coated extended-release tablet comprises hypromellose, povidone, stearic acid, polyethylene glycol, and/or coloring reagents. Instant claim 17 requires the method of claim 13, wherein the pharmaceutical composition is formulated as a tablet and comprises croscarmellose sodium, hydrogenated vegetable oil, magnesium stearate and/or microcrystalline cellulose.
The previously discussed art shows that one would look to use niacin in the treatment of NASH to “regress” fibrosis, and one would use a known safe and effective dose of niacin and optimize from that starting point. Hu teaches patients were treated with ER niacin (Niaspan®, Abbott Laboratories), an extended-release form of niacin. The art didn’t discuss the specific formulation of the tablet or the coating.
Rocca is brought in to show how niacin can be formulated in many conventional ways to achieve options for the prescribing doctor, that all achieve similar efficacious results. Rocca teaches an invention relates to an extended-release matrix formulation capable of being directly compressed into tablets comprising niacin, a release-retarding agent, and other excipients. The resulting tablets of the invention demonstrate favorable release characteristics and a reduction in the severity, duration and incidences of cutaneous flushing commonly associated with niacin treatment. Rocca shows niacin tablets coated with OPADRY, which contains HMPC (Hypromellose).
It would be obvious to use one know equivalent for another, thereby substituting the formulation of Rocca for the Niaspan formulation and arrive at similar results as the active compound is still niacin.
Conclusion
No claims allowed.
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.
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/MICHAEL J SCHMITT/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629