DETAILED ACTION
Status of the Claims
Claims 22-24 are pending in the instant application and are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The U.S. effective filing date has been determined to be 12/20/2019, the filing date of the instant application.
Claim Rejections - 35 USC § 112(b)
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 22-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a New Matter rejection.
Scope of the Claimed Invention:
Applicant claims a method of treating nonalcoholic steatohepatitis (NASH) in a subject in need thereof comprising changing the isotope ratio of zinc in a subject to greater 64Zn by administering to said subject orally, ingragastrically or by injection a therapeutically effective amount of a composition comprising a 64Zne compound or a salt thereof, wherein the 64Zne compound or salt thereof is at least 95% 64Zne; wherein the composition further comprises one or more diluents and/or one or more excipients; wherein the diluent comprises deuterium-depleted water; wherein said therapeutically effective amount is an amount that results in greater 64Zn in said subject; wherein 64Zne is in a form of salt of zinc aspartate with 2 aspartic acid molecules, wherein the zinc aspartate has the structure
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;wherein the therapeutically effective amount of zinc aspartate is between 21 μg to about 25 μg per gram of said subject. (instant claim 22).
Disclosure of the Instant Application:
The chemical structure of zinc aspartate is disclosed as:
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(instant Specification, p. 24, [00133]).
Discussion:
The claimed chemical structure for zinc aspartate does not find support in the as-filed Application. Applicant has amended the claim to insert a new structure for zinc aspartate which is inconsistent with the disclosure (p. 24, [00133]). The examiner finds no support for the limitation “wherein the therapeutically effective amount of zinc aspartate is between 21 μg to about 25 μg per gram of said subject”. Applicant points to “the Specification at ¶[00159] to ¶[00161]; and ¶[00265] to ¶[00282]” however, the examiner finds no support on these pages for the added limitation “wherein the therapeutically effective amount of zinc aspartate is between 21 μg to about 25 μg per gram of said subject”. The examiner notes that the cited portions appear to be limit the subject to a rat administered intragastrically. Claim 22 is properly rejected for lack of written description for the introduction of new matter. Appropriate correction is required. Claims 23 and 24 inherit the new matter from the parent claim and are therefore rejected for the same.
Claim Rejections - 35 USC § 112(b)
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 22-24 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 22 is rejected as being indefinite because the claim recites “administering to said subject orally, ingragastrically or by injection” (in line 3). It is unclear what exactly administering to said […], ingragastrically” should be considered. The word “ingragastrically” appears to be a typo of intragastrically (as recited in claim 42). Claims 23 and 24 are rejected as inheriting the same. Appropriate clarification is required.
Claim 24 is rejected as being indefinite because the claim recites “intragastrically” which lacks proper antecedent basis in the claim. Appropriate clarification is required.
Claim 22 is further rejected as being indefinite for reciting a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 22 recites the broad recitation “wherein said therapeutically effective amount is an amount that results in greater 64-Zn in said subject” (lines 8-9), and the claim also recites “wherein the therapeutically effective amount of zinc aspartate is between about 21 μg to about 25 μg per gram of said subject.” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Claims 23 and 24 inherit this limitation and are also rejected as being indefinite for the same.
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 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over NOVAK (US 2018/0055879; published 01/03/2018) in view of Himoto et al. ("Associations between Zinc Deficiency and Metabolic Abnormalities in Patients with Chronic Liver Disease," (01/14/2018), MDPI; Nutrients, Vol. 10, No. 88, pp.1-17); Albarede et al. ("Medical applications of Cu, Zn, and S isotope effects," 2016; RSC; Metallomics, Vol. 8, pp. 1056-1070); USPENSKAYA et al. (“Kinetics of Active Pharmaceutical Ingredient Solubility in Water with Different Hydrogen Isotopic Content,” 2018; Indian Journal of Pharmaceutical Sciences, Vol. 80, No. 2, pp. 318-324) and Thoen et al. (Zinc Supplementation Reduces Diet-Induced Obesity And Improves Insulin Sensitivity in Rats,” Applied Physiology, Nutrition and Metabolism, Canadian Science Publishing; 19-OCT-2018; Vol. 44, No. 6, pp. 580-586 - pp. 1-30 as provided); and as evidenced by Povsic et al. (“A Structured Literature Review of the Epidemiology and Disease Burden of Non-Alcoholic Steatohepatitis (NASH),” 07-MAY-2019; SPRINGER; Advances in therapy, Vol. 36, pp. 1574-1594).
Applicants Claims
Applicant claims a method of treating nonalcoholic steatohepatitis (NASH) in a subject in need thereof comprising changing the isotope ratio of zinc in a subject to greater 64Zn by administering to said subject orally, ingragastrically or by injection a therapeutically effective amount of a composition comprising a 64Zne compound or a salt thereof, wherein the 64Zne compound or salt thereof is at least 95% 64Zne; wherein the composition further comprises one or more diluents and/or one or more excipients; wherein the diluent comprises deuterium-depleted water; wherein said therapeutically effective amount is an amount that results in greater 64Zn in said subject; wherein 64Zne is in a form of salt of zinc aspartate with 2 aspartic acid molecules, wherein the zinc aspartate has the structure
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;wherein the therapeutically effective amount of zinc aspartate is between 21 μg to about 25 μg per gram of said subject. (instant claim 22).
Determination of the scope
and content of the prior art (MPEP 2141.01)
NOVAK discloses pharmaceutical compositions for improving health, cure abnormalities and degenerative disease, for achieving antiaging effect of therapy and therapeutic effect on mammals by administering compositions of having certain elements with enriched isotopic content (see whole document, particularly the abstract). NOVAK teaches that: “Appropriate dosages of the light isotope-enriched element are set forth below. Preferably the composition of the invention comprises an effective amount of at least one light isotope, wherein "effective amount" refers to that amount that provides a therapeutic effect […]. As stated above, the quantity of light isotope that is effective is proportional to the quantity of the corresponding element that is present in the body. Where the body contains a relatively large quantity of the element, a correspondingly relatively large amount of the element's light isotope will be required to provide an effective dosage amount. On the other hand, where the body contains a relatively small quantity of the element, a correspondingly relatively small amount of the element's light isotope will be required to provide an effective dosage amount. These quantities are reflected in the "guidance amounts" for each element, the recommended amount for daily human consumption, as detailed below.” ([0029]). NOVAK teaches compositions enriched in light isotopes of zinc, particularly 64Zn ([0033]) in a recommended daily dose of 2-11 mg, and further administering in an amount of about ½ to about 20 times the recommended daily dose ([0231] through [0237])(instant claims 23: administering a therapeutically effective amount of a composition comprising 64Zne, “wherein said therapeutically effective amount is an amount that results in greater 64-zn in said subject”). NOVAK disclose the zinc-64 enriched compositions include compositions including 95% and 99% zinc-64 ([0237])(instant claims 22-23, zinc-64 isotope content – “at least 95% 64Zne” and “at least 99% 64Zne”).
NOVAK claims “A therapeutic composition comprising an effective amount of one or more of […] 64-Zn-enriched zinc […].” (claim 1), and further claims “The composition of claim 6, wherein the composition contains between 0.6 mg and 330 mg of 64-Zn.” (claim 7). Where a laboratory mouse weighs about 200 grams (instant Specification, p. 26, [00159], line 1; or approximately the weight of a laboratory rat), a dose of 4.4 mg / 200g = 22 μg per gram of said subject. It would have been prima facie obvious to give a dose within the range claimed by NOVAK to an obese laboratory mouse or a laboratory rat. MPEP §2144.05(I) - In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
NOVAK discloses Examples of administering 64Zne as 64Zne aspartate in "Studies Supporting the Efficacy of a Light Isotope-Enriched Compound and Method Performed in In Vivo Experiments Using a Mouse Model of Breast Cancer (Erlich Ascites Carcinoma)." (Example 7, [00487]).
NOVAK teaches solutions of 64Zne aspartate dissolved in deuterium-depleted water as suitable excipient for administration ([0478])(instant claims 22-23). NOVAK teaches the concentration was about 1.5 mg/mL of 64Zne aspartic acid ([0476])(instant claims 22: deuterium-depleted water carrier).
NOVAK teaches that both oral and intravenous administration of pharmaceutical compositions of their invention are considered efficient ([0043])(instant claims 22 “administering orally and/or by injection”).
Regarding the limitation “comprising changing the isotope ratio of zinc in a subject to greater 64Zn by administering to said subject orally or by injection a therapeutically effective amount of a composition comprising a 64Zne compound or a salt thereof”, the method steps and amounts taught by NOVAK are identical to those now claimed. Therefore the method of NOVAK would have more likely than not inherently resulted in “changing the isotope ratio of zinc in a subject to greater 64Zn by administering to said subject orally or by injection a therapeutically effective amount of a composition comprising a 64Zne” (MPEP §2112).
Furthermore, NOVAK teaches that: “The products of such autocatalytic reactions, such as proteins, play important chemical and structural roles in the body, including immune function. Fully functional products of such reactions require a specific, "correct" chirality at various chiral centers within the product. The inventors further understand that heavy isotopes accumulate in the body beginning at birth such that, over time, the relative abundance of each element's isotopes drifts further and further from the naturally occurring relative abundance, becoming increasingly over-weighted with respect to heavy isotopes. Heavy isotopes can affect auto catalytic reactions by reducing the proportion of products that have the "correct" chirality. […] This causes a reduction in the proportion of products of autocatalytic reactions that are fully functional. In sum, the cumulative divergence of the body's isotope relative abundances from the natural relative abundance causes a decrease in the functionality of various proteins and other molecules in the body, leading to a decline in health with age.” ([0025]). And that: “ Further, the quantity of light isotope that is effective may be proportional to the quantity of the corresponding element that is present in the body. Where the body contains a relatively large quantity of the element, a correspondingly relatively large amount of the element's light isotope will be required to provide an effective dosage amount. On the other hand, where the body contains a relatively small quantity of the element, a correspondingly relatively small amount of the element's light isotope will be required to provide an effective dosage amount.” ([0026]). And further that: “As stated above, the quantity of light isotope that is effective is proportional to the quantity of the corresponding element that is present in the body. Where the body contains a relatively large quantity of the element, a correspondingly relatively large amount of the element's light isotope will be required to provide an effective dosage amount. On the other hand, where the body contains a relatively small quantity of the element, a correspondingly relatively small amount of the element's light isotope will be required to provide an effective dosage amount. These quantities are reflected in the "guidance amounts" for each element, the recommended amount for daily human consumption, as detailed below.” ([0229]). And further that: “In certain embodiments, the preferred dosage of any of the light isotopes is proportional to various authoritative daily ingestion guidances (e.g. recommended dietary allowance (USRDA), adequate intake (AI), recommended dietary intake (RDI)) of the corresponding element. The light isotope dosage is preferably between about ½ and about 30 times the guidance amount of the corresponding element […].” ([0230]).
NOVAK teaches compositions enriched in light isotopes of zinc, particularly 64Zn ([0033]) in a recommended daily dose of 2-11 mg, and further administering in an amount of about ½ to about 20 times the recommended daily dose ([0231] through [0237])(instant claims 23: administering an effective amount of a composition comprising 64Zne). NOVAK disclose the zinc-64 enriched compositions include compositions including 95% and 99% zinc-64 ([0237])(instant claims 22-23, zinc-64 isotope content – “at least 95% 64Zne” and “at least 99% 64Zne”). And clearly suggest the light isotope – zinc 64 – as replacing the heavy isotopes which “can affect auto catalytic reactions by reducing the proportion of products that have the "correct" chirality. […] This causes a reduction in the proportion of products of autocatalytic reactions that are fully functional.” and therefore implicitly teaches “changing the isotope ratio of zinc in a subject to greater 64Zn by administering to said subject orally or by injection a therapeutically effective amount of a composition comprising a 64Zne compound or a salt thereof” and “wherein said therapeutically effective amount is an amount that results in greater 64Zn in said subject” (instant claim 23)(MPEP §2144.01).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of NOVAK is that NOVAK does not expressly teach treating NASH by administering a therapeutically effective amount of a 64Zne compound; or “administered intragastrically” (instant claim 24).
Himoto et al. teaches that "Zinc (Zn) is an essential trace element which has favorable antioxidant, anti-inflammatory and apoptotic effects. The liver mainly plays a crucial role in maintaining systemic Zn homeostasis. Therefore, the occurrence of chronic liver diseases, such as chronic hepatitis, liver cirrhosis, or fatty liver, results in the impairment of Zn metabolism, and subsequently Zn deficiency. [ ... ] Zn supplementation has shown beneficial effects on such metabolic abnormalities in experimental models and actual patients with chronic liver disease." [emphasis added](abstract). Himoto et al. further teaches that: Nonalcoholic fatty liver disease (NAFLD) is currently the most prevalent liver disease worldwide, characterized by the accumulation of triglycerides in the liver, and the absence of excessive alcohol consumption. NAFLD covers a spectrum of liver diseases that range from simple steatosis called nonalcoholic fatty liver (NAFL) through nonalcoholic steatohepatitis (NASH), which is associated with hepatic inflammation and fibrosis in addition to simple steatosis." And that "NASH patients had significantly lower oral intake of Zn than NAFL patients. Zn deficiency in such patients may be due to this lower Zn intake. Zn deficiency results in mitochondrial oxidative stress and subsequently iron over load, insulin resistance, and hepatic steatosis in patients with NASH." [emphasis added](see whole document, particularly p. 3, §2.5).
Himoto et al. concludes that: "This review complied overwhelming evidence that Zn deficiency is common in patients with chronic liver diseases such as chronic hepatitis and NASH, as well as liver cirrhosis. In such patients, Zn deficiency causes various types of metabolic abnormalities, including insulin resistance, hepatic steatosis, iron overload and hepatic encephalopathy. As expected, these metabolic abnormalities may be recovered by Zn supplementation. Further trials will be required to verify the beneficial effects of Zn administration on these metabolic abnormalities especially in NASH patients." [emphasis added](p. 11, §5). Based on the teachings of Himoto et al. it would have been prima facie obvious to treat NASH by zinc supplementation, however, Himoto et al. does not teach administering 64Zne as a zinc supplement in NASH, particularly given that NOVAK clearly teaches their 64Zne compositions are “used for improving health, cure abnormalities and degenerative disease; achieve anti-aging effect of therapy and therapeutic effect on mammals.” (abstract).
Albarede et al. teaches medical applications of Cu, Zn, and S isotope effects (see whole document) and particularly that medical uses of isotopes are well-known but mostly focus on radioactive nuclides, and that "It is also suggestive of nutrition studies in which enriched stable isotopes are added to the diet of volunteers to monitor the transit of a particular element." (p. 1056, col. 1). Albarede et al. further teaches that "Metals such as alkaline-earth Ca and Mg and transition elements such as Cu and Zn, however, are more promising because of their much smaller number of functional roles in biology and also because their turnover rate in the body is relatively short. Copper plays a major role in oxidizing iron and controlling electron fluxes, while Zn is a cofactor of hundreds of important enzymes." [emphasis added](p. 1056, col 2, lines 6-12).
Albarede et al. further teaches that: "In addition to the effects just described for systems at thermodynamic equilibrium, the smaller activation energy of the lighter isotopes allows them to react faster: kinetic effects have been advocated as a cause of biologically mediated isotope fractionation, but they require either nonsteady state conditions ( the system grows) or the existence of competing reaction pathways (Fig. 1). What comes around goes around: the proportion of isotopes present within a system ( cell, organ, body fluid) must vary if they are imported and exported at different rates. After a time exceeding the mean turnover in the system, the input and the output must be balanced." [emphasis added](p. 105 8, col. 2, 3rd paragraph).
Albarede et al. further teaches that "How isotope compositions of Cu and Zn (and Fe) vary among the organs and body fluids of a mammal was essentially unknown until the first investigations by Balter et al. and Moynier et al. of sheep and mouse. For ethical reasons, access to such a variety of human materials is much more restricted. The first major observation was that, in most cases, the isotope compositions of Cu, Zn, and Fe of each organ falls, for a given species, within a narrow range of values (Fig. 4 ). In mice, Zn is isotopically heavy in red blood cells and bone and light in the serum, liver, and brain and is not dependent on the genetic background." [emphasis added](p. 1062, col. 1, lines ).
Regarding the use of a deuterium-depleted water carrier, USPENSKAYA et al. teaches that: “For the first time the quantitative measure of the kinetic isotope effect connected with the isotopic nature of the solvent-water has been assessed. It is shown that irrespective of pharmacological and chemical properties of APIs, the rate of solubility in deuterium-depleted water exceeds the speed of solubility in Mili-Q water by approximately 1.5 times. This feature will allow to increase the pharmacological availability of slightly soluble in water APIs ensuring a better release out of the pharmaceutical form by means of speed acceleration of pharmaceutical substances solubility.” [emphasis added](see whole document, particularly p. 323, paragraph bridging cols. 1-2).
Thoen et al. teaches that: “Rates of obesity have been growing at alarming rates, compromising the health of the world population. Thus, the search for interventions that address the metabolic repercussions of obesity are necessary. Here we evaluated the metabolic and antioxidant effects of zinc and branched chain amino acid (BCAA) supplementation on obese rats. […] In conclusion, zinc supplementation may be a useful strategy for the treatment of the metabolic dysfunction associated with obesity.” (p. 4, Abstract). Thoen et al. teaches that: “Zinc (Zn) is the second most abundant essential trace micronutrient found in the human body. It is found in all human tissues playing catalytic or structural functions. Muscles and bones contribute with about 90% of zinc storage whilst 5% is stored in the liver. As an enzymatic cofactor, zinc participates in the regulation of metabolism of carbohydrates, fats, and proteins. It is also required for the activity of more than 200 metalloenzymes such as the antioxidant enzyme copper zinc superoxide dismutase.” (paragraph bridging pp. 5-6). And further that: “Despite advances in the understanding of the mechanisms involved in the pathophysiology of obesity, treatment of this condition is still undefined. Weight loss strategies are not always effective. Management of obesity involves changes in eating habits, physical activity, or even administration of some drugs and surgical intervention. However, a co-adjuvant treatment is still necessary, as living habits are not easy to change. Zinc and BCAA are used in the treatment of metabolic dysfunction that occurs in cirrhosis, hepatitis, and nonalcoholic steatohepatitis (NASH). Hepatic steatosis caused by obesity is an initial stage of steatohepatitis and hepatic fibrosis, thus, zinc and BCAA treatments may be useful to prevent the evolution of steatohepatitis. Therefore, the aim of the present study was to investigate the effect of zinc or BCAA supplementation on metabolic and oxidative parameters of obese rats that consumed a high fructose/high fat diet (HFD).” (paragraph bridging pp. 6-7).
Thoen et al. teaches that; “Nonalcoholic fatty liver disease (NAFLD) is currently the most prevalent liver disease worldwide, characterized by the accumulation of triglycerides in the liver. It is usually associated with obesity and is not related with excessive alcohol consumption. Lower oral intake of zinc was observed in patients with NAFLD. Zinc deficiency results in mitochondrial oxidative stress and subsequently iron overload, insulin resistance, and hepatic steatosis in patients with NASH.” [emphasis added](p. 15, lines 3-8).
Thoen et al. teaches that: “It has been shown that zinc-deficient diets cause insulin resistance in animal models and there is also evidence of insulin resistance and hepatic steatosis due to zinc deficiency in patients with chronic liver disease. On the other hand, zinc supplementation reverses alcohol-induced hepatic steatosis in mice. Our findings support the hypothesis that zinc supplementation provides beneficial effects on the regulation of insulin sensitivity in obesity.” [emphasis added](p. 13, lines 8-13). And that: “In summary, this study reveals that zinc supplementation is beneficial for the treatment of metabolic dysfunction caused by obesity. […] Despite the finding that zinc supplementation did not reduce diet-induced oxidative stress in our animal model, the enhancement in insulin sensitivity in obese rats receiving zinc supplementation suggests this micronutrient may be an important alternative for the treatment of obesity.” (p. 15, last paragraph).
Regarding instant claim 24, Thoen et al. discloses that: “Animals received
Zn or BCAA supplementation daily from the 15th week until the end of the experiment (at the19th week), and the SD+vehicle and HFD+vehicle groups received water by gavage for the same period. Zinc and BCAA were diluted in water and administered by gavage, at the doses of 6mg/kg and 750mg/kg, respectively.” [emphasis added] (p. 7, last two lines through p. 8, line 3). Administered by gavage is intragastrically administered (instant claim 24).
The prior art further suggests that NASH and obesity are comorbid conditions (often occurring together) as evidenced by Povsic et al. teaching that: “NASH is often inaccurately described as an asymptomatic disease—it presents with nonspecific symptoms, such as tiredness or developing pain in the upper right side of the abdomen, therefore the disease can progress undetected. This makes the exact burden difficult to establish. However, NASH burden is increasing, paralleled by the rise of obesity and NAFLD, with an estimated one-third of NAFLD patients progressing into NASH.” (p. 1575, col. 1, 1st full paragraph, lines 1-10). And more particularly that: “Obesity -- The obesity prevalence in the NASH population was reported in two publications, ranging from 31% to 95% (Table 1).” (p. 1582, col. 1, lines 1-4).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
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 utilize the compositions of NOVAK in the treatment of NASH and obesity because Himoto et al. teaches that Zn deficiency is common in patients with chronic liver diseases such as chronic hepatitis and NASH, and that these metabolic abnormalities may be recovered by Zn supplementation, and Thoen et al. teaching that NAFLD is usually associated with obesity, zinc being an important nutrient in treatment of obesity; and Albarede et al. teaches that in mice Zn is isotopically light in the liver, thus treating a liver disease with the compositions of NOVAK would have been expected to enhance treatment of a fatty liver diseases such as NASH, and further to utilize a deuterium-depleted water carrier as suggested by NOVAK, and taught by USPENSKAYA et al., as improving “a better release out of the pharmaceutical form by means of speed acceleration of the pharmaceutical substance solubility.” Additionally, it is clear that the patient populations of Obesity and NASH overlap due to the high prevalence the comorbidity of these two conditions, as evidenced by Povsic et al., therefore, in treating NASH the with a 64Zne compound, as suggested by the cited combination of references, in comorbid cases (NASH + Obesity) obesity would have also been treated as well.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because administering a zinc compound enriched in Zn-64 stable isotope would have been substantially the same, and Albarede et al. teaches that Zn is isotopically light is the liver thus providing a reasonable expectation that a zinc compound enriched in Zn-64 stable isotope would accumulate in the liver. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 01/12/2026 have been fully considered but they are not persuasive.
Applicant argues that: “As consistently asserted throughout prosecution, the cited references whether considered individually or in combination-fail to disclose or suggest the presently claimed invention. Critically, none of the cited references teaches or suggests administering a therapeutically effective amount of zinc aspartate for the treatment of nonalcoholic steatohepatitis (NASH), as now explicitly recited.” And that: “As amended, independent claim 22-and claims depending therefrom recites a specific therapeutic dosage range of zinc aspartate of about 21 μg to about 25 μg per gram of a subject. This dosage is not arbitrary but is instead directly supported by experimental data in the Specification demonstrating a successful therapeutic outcome in an animal model. See, e.g., paragraphs [00159]-[00161] and [00265]-[00282]. This experimentally validated dosage range constitutes a critical and distinguishing feature of the claimed invention.” (p. 4, last two paragraphs, p. 5, 1st paragraph). And further that: “None of the cited references discloses, teaches, or suggests this specific dosage range. Nor do the references provide any guidance or reasonable expectation of success that would lead a person of ordinary skill in the art to select zinc aspartate in this narrowly defined range to achieve a therapeutic effect in treating NASH.” (p. 5, 2nd paragraph). And further that: “Importantly, the claimed dosage range is not the result of routine optimization but rather reflects a specific and unexpected therapeutic window identified through Applicant's experimentation. The absence of any teaching, suggestion, or motivation in the prior art to arrive at this particular dosage range combined with the demonstrated therapeutic efficacy-renders the claims non obvious.” (p. 5, 3rd paragraph).
In response the examiner argues that NOVAK clearly claims “A therapeutic composition comprising an effective amount of one or more of […] 64-Zn-enriched zinc […].” (claim 1), and further claims “The composition of claim 6, wherein the composition contains between 0.6 mg and 330 mg of 64-Zn.” (claim 7). Where a laboratory mouse weighs about 200 grams (instant Specification, p. 26, [00159], line 1; or approximately the weight of a laboratory rat), a dose of 4.4 mg / 200g = 22 μg per gram of said subject. It would have been prima facie obvious to give a dose within the range claimed by NOVAK to an obese mouse or a rat in a laboratory. MPEP §2144.05(I) - In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
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 utilize the compositions of NOVAK in the treatment of NASH and obesity because Himoto et al. teaches that Zn deficiency is common in patients with chronic liver diseases such as chronic hepatitis and NASH, and that these metabolic abnormalities may be recovered by Zn supplementation, and Thoen et al. teaching that NAFLD is usually associated with obesity, zinc being an important nutrient in treatment of obesity. MPEP 2143.02(II) makes clear that: “Obviousness does not require absolute predictability, but at least some degree of predictability is required.” In the instant case it would have required no more than an ordinary level of skill to administer (orally or by gavage) to a laboratory mouse/rat, the composition(s) of NOVAK within the full scope of the claimed subject matter including the instantly claimed range, with a reasonable expectation of treating NASH per the teachings of Himoto et al. and Thoen et al., as discussed above.
MPEP§2144.05(III)(A) - Applicants can rebut a prima facie case of obviousness by showing the criticality of the range. "The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. . . . In such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range." And MPEP 716.02(d)(II) - To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. The examiner sees no such showing of criticality of the claimed range.
Conclusion
Claims 22-24 are pending and have been examined on the merits. Claims 22-24 are rejected under 35 U.S.C. 112(a); claims 22-24 rejected under 35 U.S.C. 112(b); and claims 22-24 are rejected under 35 U.S.C. 103. No claims allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IVAN A GREENE whose telephone number is (571)270-5868. The examiner can normally be reached M-F, 8-5 PM PST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David Blanchard can be reached on (571) 272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
Prosecution Insights