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 .
Priority
The present application, filed November 12, 2024, is a Continuation of U.S. Patent Application Ser. No. 17/261,279 (now U.S. Patent No. 12,161,621), filed January 19, 2021, which is a national phase entry of International Patent Application No. PCT/US2019/042034, filed July 16, 2019, which claims the benefit of U.S. Provisional Patent Application No. 62/698,468, filed July 16, 2018.
Status of the Claims
In the amendment filed February 21, 2025, claims 3, 7, 10, 12, and 18 are canceled, and claims 4, 8, 11, 13-17, 19-21, and 24-25 are amended. Claims 1-2, 4-6, 8-9, 11, 13-17, and 19-25 are currently pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on March 12, 2025 is acknowledged.
Claim Objections
Claim 4 is objected to because of the following informality: claim 4 misspells “a phosphorothioate” as “a phosphothioate” in line 1.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 21-25 are indefinite:
Claims 21-25 are 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 21 is indefinite for reciting, “wherein the conjunctive agent comprises one or more of aldose reductase agents, uric acid lowering agents...” because a person of ordinary skill in the art could not reasonably determine the metes and bounds of this limitation. With respect to the recited “aldose reductase agents,” this is not defined in the specification and does not appear to be a commonly understood term of art. While the specification gives four examples of such “agents” (paragraph [0049]) and all four appear to be known aldose reductase inhibitors (notwithstanding apparent misspellings of two of the compounds), the term is plainly not limited to these agents. It would be unclear whether “aldose reductase agents” means aldose reductase inhibitors, or some broader category. Even if the phrase is understood as aldose reductase inhibitors, in the absence of any threshold of specificity or efficacy, one could not reasonably determine what compounds qualify as aldose reductase inhibitors. Similarly, while the phrase “uric acid lowering agents” describes the type of activity, in the absence of any description of mechanism, activity, or specificity, one could not reasonably determine what constitutes a uric acid lowering agent. For example, water could be considered a “uric acid lowering agent,” as increased hydration has been shown to decrease serum uric acid levels (see, for example, the non-patent publication, Quantity-effect correlation between water intake and serum uric acid in US adults: a cross-sectional study based on NHANES data, Transl. Androl. Urol., 14, pgs. 3930-3944 (2025) by Meng et al.).
Claims 22-25 are indefinite for depending directly or indirectly from claim 21 without curing this indefiniteness.
Notes on claim interpretation:
The preamble of claim 1 recites a method of reducing a craving for alcohol in a subject. This merely states the purpose of the method, while the performance of the method is set out entirely in the claim body, with little-to-no reliance on or reference to the preamble. It is further noted that neither the claim nor the specification gives any guidance on how to objectively measure “craving” not how to determine whether it has been reduced, nor does the claim require any reduction in craving. For these reasons, the preamble is minimally limiting, and only to the extent that the method is directed to subjects who drink alcohol and would potentially benefit from drinking less alcohol.
Furthermore, the phrase “a therapeutically effective amount” is somewhat ambiguous, as to whether it refers to an amount effective to reduce cravings or an amount effective to inhibit KHK. Since KHK inhibition is the only outcome referenced in the claim body, a therapeutically effective amount is understood to refer to an amount effective to inhibit KHK activity.
Similarly, the preambles of claim 8 of “a method of…treating alcoholism in a subject” and “a method of…treating an alcohol-induced liver disease in a subject,” are limiting only to the extent that they constrain the subject populations to subjects suffering from alcoholism and those suffering from an alcohol-induced liver disease, respectively. As above, these preambular recitations are principally mere statements of purpose.
And also similarly, the preambles of claim 17 of “of treating alcohol-induced pancreatitis in a subject” or “preventing alcoholism, an alcohol-induced liver disease, or alcohol-induced pancreatitis in a subject or recurrence of the same,” are limiting only to the extent that they constrain the subject populations to subjects suffering from alcohol induced pancreatitis in the first case, or subjects suffering from or reasonably deemed at risk of developing alcoholism, alcohol-induced liver disease, or alcohol-induced pancreatitis. In at least the case of subjects at risk of developing alcoholism, this is a marginal limitation at best, as nearly anyone could reasonably benefit from a treatment that prevents alcoholism. As above, because these are principally mere statements of purpose, they are limiting only to the modest extent that they constrain subject populations.
The phrase “a therapeutically effective amount” as used in claims 1, 8, and 17 is found to be minimally limiting, to the extent that it excludes negligible amounts of KHK inhibitor that could not plausibly have a significant effect. Paragraph [0023] of the specification states that a therapeutically effective amount refers to a dosage, including duration, necessary to achieve the desired result. Whether the result is inhibition of KHK activity in the subject (claim 1), or the various desired outcomes of claims 8 and 17 such as treating/preventing alcoholism, alcohol-induced liver disease, etc., it would be unclear how one would determine whether the desired result had been achieved. For example, there does not appear to be any disclosed or commonly understood means to determine whether craving had been reduced, nor any threshold that would constitute a statistically significant reduction.
It is noted that in claim 1, the recitation of a therapeutically effective amount is ambiguous as to whether it is an amount effective to reduce craving or an amount effective to inhibit KHK activity in the subject. While it is understood that the latter is believed to result in the former, it does not appear to be demonstrated that any degree of KHK inhibition will produce an observable decrease in craving. Because no means for quantifying craving appear to be disclosed and because inhibition of KHK activity is recited in the claim body, a therapeutically effective amount of claim 1 is understood to be an amount plausibly capable of effectuating some degree of KHK inhibition in the subject.
Claim 19, depending from claim 17, recites wherein the subject has been diagnosed with an alcohol-induced liver disease or alcohol-induced pancreatitis. This is understood as excluding the prevention (including prevention of recurrence) of alcoholism of claim 17, but is also understood as excluding prevention of a first onset (primary prevention) of alcohol-induced liver disease or pancreatitis. Primary prevention cannot be undertaken for a subject who has already been diagnosed with the condition. As such, claim 19 is understood as being directed to prevention of recurrence of alcohol-induced liver disease or pancreatitis in a subject who has previously been diagnosed with the condition, but has recovered (secondary prevention).
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.
Claims 1, 5-6, 8-9, 11, 13-16, and 20-25 are anticipated by Ciccocioppo:
Claims 1, 5-6, 8-9, 11, 13-16, and 20-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by International Patent Application Publication No. WO/2014/008351 to Ciccocioppo (hereinafter, “Ciccocioppo”).
Claim 1 recites a method of reducing a craving for alcohol in a subject. The method comprises a single step of administering a therapeutically effective amount of a ketohexokinase (KHK) inhibitor to the subject to inhibit KHK activity in the subject.
Ciccocioppo teaches methods for treatment or prevention of addictions, including cravings, to addictive substances including alcohol (Ciccocioppo, e.g. abstract; pg. 10 lines 4-7; pg. 14 lines 8-13; and pg. 42 lines 12-15). The method of Ciccocioppo includes a step of administering to the subject an effective amount of an extract of Andrographis paniculata (pg. 8, lines 5-10). The instant specification (pg. 32 line 6 through pg. 7 line 1) describes Andrographis extracts as examples of plant extracts that include KHK inhibitor(s). In addition, U.S. Patent Application Publication No. 2014/0377386 to Rana et al. teaches that Andrographis paniculata extracts include KHK inhibitor(s) (paragraph [0006]). As such, a KHK inhibitor is inherent to the Andrographis paniculata extract of Ciccocioppo.
With respect to claim 5, the instant specification states that a pharmaceutically acceptable carrier includes a diluent (paragraph [0017]) while Ciccocioppo teaches that the Andrographis paniculata extract can be combined with a solvent, i.e. a diluent (Ciccocioppo claim 2). With respect to claim 6, the plant extract of Ciccocioppo is obtained from the Andrographis genus.
Claim 8 recites a method of treating either alcoholism or an alcohol-induced liver disease in a subject, the method having the same single administering step as does claim 1. Ciccocioppo is applied to claim 8 as to claim 1, and expressly teaches a method of treating substance addiction (Ciccocioppo claim 1), and further teaches that in particular embodiments, the subject is addicted to alcohol (pg. 26, lines 7-9). Treating an addiction to alcohol in an alcohol-addicted individual per Ciccocioppo is understood as being equivalent to treating alcoholism and claim 8 is thus anticipated. With respect to claim 9, the Andrographis paniculata extract of Ciccocioppo is a plant-based extract. With respect to claim 11, the instant specification states that a carrier for purposes of the present application includes an excipient, i.e. any non-active ingredient. Ciccocioppo teaches that Andrographis compositions can further include one or more excipients (pg. 46, lines 1-4). Claims 13-16, depending from claim 8, specify certain types of liver disease to be treated, but do not require that alcohol-induced liver disease, as opposed to alcoholism generally, be treated. As such, claims 13-16 are anticipated for the same reason as is claim 8.
With respect to claims 20-21 and 25, Ciccocioppo teaches that the Andrographis paniculata extract can be administered with an additional therapeutic agent (paragraph spanning the bottom of pg. 24 to the top of pg. 25), and that the additional therapeutic agent can be naltrexone (pg. 31, lines 5-7). With respect to claim 22-24, these claims specify, when the co-administered conjunctive agent of claim 20 is a xanthine oxidase inhibitor or aldose reductase agent, certain specific types of xanthine oxidase inhibitor or aldose reductase agent that are acceptable. None of these claims requires that the conjunctive agent be a xanthine oxidase inhibitor or aldose reductase agent however, nor precludes the conjunctive agent from being naltrexone. As such, claims 22-24 are anticipated for the same reason as is claim 20.
Claims 1-2, and 8-9 are anticipated by Joshi:
Claims 1-2, and 8-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by the non-patent publication, Protective effect of quercetin on alcohol abstinence-induced anxiety and convulsions, J. Med. Food, 8, pgs. 392-396 (2005) to Joshi et al. (hereinafter, “Joshi”).
Joshi teaches that administration of quercetin diminishes withdrawal symptoms, including anxiety, in mice after chronic administration of alcohol (Abstract). Joshi notes that withdrawal is associated with craving (pg. 394, right column, third paragraph) and that quercetin administration may help with alcohol dependence, i.e. alcoholism (pg. 396, left column, first paragraph). As such, Joshi teaches administration of quercetin as a method of reducing craving for alcohol in a subject or as a method of treating alcohol dependence (alcoholism) in a subject.
Quercetin is a fructokinase inhibitor, as seen for example in the non-patent publication, Effects of Quercetin on Expression of Genes of Carbohydrate and Lipid Metabolism Enzymes in the Liver of Rats Receiving High-Fructose Ration, Bull. Exp. Biol. Med, 167, pgs. 263-266 (2019) by Mzhel’skaya et al. (hereinafter, “Mzhel’skaya”). The present specification indicates that a KHK inhibitor includes an inhibitor that selectively inhibits expression of KHK (paragraph [0025]). Mzhel’skaya shows that administration of quercetin decreases expression of Khk (Abstract). Thus Mzhel’skaya, while not relied upon as prior art, indicates that the quercetin administration of Joshi constitutes administration of a KHK inhibitor and therefore that Joshi inherently teaches the elements of claims 1 and 8.
With respect to claims 2 and 9, the instant specification states that an interfering molecule is a molecule that has a direct or indirect influence on gene expression (paragraph [0027]). As noted, the quercetin administered in Joshi decreases Khk expression, and is therefore an interfering molecule.
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.
Claim 17 is unpatentable over Molina:
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over the non-patent publication, Quercetin, a Flavonoid Antioxidant, Prevents and Protects against Ethanol-Induced Oxidative Stress in Mouse Liver, Biol. Pharm. Bull., 26, pgs. 1398-1402 (2003) to Molina et al. (hereinafter, “Molina”).
Claim 17 recites a method of treating alcohol-induced pancreatitis in a subject, or preventing alcoholism, an alcohol-induced liver disease, or alcohol-induced pancreatitis in a subject or recurrence of the same. The method comprises the same administration step as do claims 1 and 8.
Molina teaches a study of the protective effects of quercetin against the oxidative effects of alcohol on the liver (Abstract), based on a hypothesis that increasing the diet antioxidant concentration (quercetin intake) may make it possible to prevent the incidence of alcoholic diseases (alcohol-induced liver disease) – pg. 1398, right column, first full paragraph – and notes previous studies indicating that co-administration of quercetin with ethanol reduced ethanol-induced hepatic steatosis (pg. 1398, left column, second paragraph). On the basis of its findings, showing attenuation of alcohol-induced liver damage by quercetin pretreatment, Molina concludes that pre-treatment of quercetin may protect against ethanol-induced oxidative stress by directly quenching lipid peroxides and indirectly by enhancing the production of the endogenous antioxidant glutathione (Abstract).
Quercetin is a fructokinase inhibitor, as discussed above with respect to Mzhel’skaya. Molina thus expressly provides and discusses evidence that administration of quercetin (per Mzhel’skaya, a KHK inhibitor) may be effective to prevent an alcohol-induced liver disease, at minimum rendering obvious a method to prevent alcohol-induced liver disease (e.g. primary prevention) in a subject reasonably believed to be at risk of developing such disease.
Claim 19 is unpatentable over Molina, in view of Westover:
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Molina, in view of the non-patent publication, Should risky treatments be reserved for secondary prevention? Theoretical considerations regarding risk–benefit tradeoffs, J Clin Epidemiol, 65, pgs. 877-886 (2012) to Westover et al. (hereinafter, “Westover”).
With respect to claim 19, Molina does not expressly teach administration of quercetin is useful for prevention of recurrence of alcohol-induced liver disease (secondary prevention), but it would have been obvious to apply the findings of Molina regarding primary prevention of alcohol-induced liver disease to secondary prevention of the same, because it was well-known in pharmacological arts that measures for primary prevention of a disease are commonly useful for secondary prevention of the same disease. See, for example, Westover.
Westover discusses decision-theoretic models that illustrate conditions of risk and benefit under which a treatment is predicted to be more beneficial in primary than in secondary prevention (Abstract), defining primary prevention as treating asymptomatic patients to reduce the chances of a disease event, and secondary prevention as treating patients who have already suffered at least one disease event to reduce the chances of additional events. Thus, as alluded to above, primary prevention refers to preventing a first occurrence of a disease condition (e.g. alcohol-induced liver disease) and secondary prevention refers to preventing a recurrence of the disease. Westover thus compares scenarios where the same treatment is used for primary prevention and for secondary prevention of the same disease, implicitly based on the concept that treatments which are effective for primary prevention can also be effective for secondary prevention. It thus would have been obvious to apply the primary prevention treatment of Molina to secondary prevention protocols, per Westover.
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 X-Y are rejected for nonstatutory double patenting over Z:
Claims 1-2, 4-6, 8-9, 11, 13-17, and 19-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 12,161,621 (hereinafter, “the ’621 patent”), in view of the non-patent publication, Craving as a DSM-5 Symptom of Alcohol Use Disorder in Non-Treatment Seekers, Alcohol and Alcoholism, 53, pgs. 235-244 (2018) by Hartwell et al (hereinafter, “Hartwell”); A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation, Nat. Cell Biol., 18, pgs. 561-571 (2016) by Li et al (hereinafter, “Li”); as well as Ciccocioppo, Joshi, Molina, and Westover. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims recite methods of treating alcoholism that have substantially the same method step as the subject methods of treating alcohol craving, alcoholism.
Claim 1 of the ’621 patent recites a method of treating alcohol addiction in a subject determined to have alcohol addiction. The method comprises a step of administering a therapeutically effective amount of a ketohexokinase (KHK) inhibitor to the subject to inhibit KHK activity in the subject, wherein the KHK inhibitor is a small molecule KHK inhibitor that inhibits KHK activity; wherein administering is via an oral route; and wherein the therapeutically effective amount is at a dose of 0.001 mg/kg to about 100 mg/kg. Claim 2 of the ’621 patent recites a method of treating alcoholism, with the same method step. These claims substantially overlap with the method of treating alcoholism of instant claim 8, differing essentially only in the specified dosage, and instant claim 8 is thus an obvious variation of claims 1 and 2 of the ’621 patent.
Claim 17 is an obvious variation of claims 1 and 2 of the ’621 patent in view of Molina for the reasons discussed above with respect to the rejection of claim 17 under 35 USC § 103. With respect to instant claim 1, it would have been obvious to apply the method of claims 1 and 2 of the ’621 patent to reduction of craving for alcohol, because alcohol craving was well-known in the art as a common characteristic of alcoholism/alcohol addiction. See, for example, Hartwell, which notes that the DSM-5 has added alcohol craving as a criterion of alcoholism (Abstract). Given that alcohol craving is regarded in the art as a criterion or common characteristic of alcoholism, it would have been obvious to apply the methods of treating alcoholism of claims 1 and 2 of the ’621 patent to the reduction of alcohol cravings.
With respect to claims 2, 5-6, 8-9, 11, 13-17, and 19-25, Ciccocioppo, Joshi, Molina, and Westover are applied as described above. With respect to claim 4, it would have been obvious to use an shRNA as the KHK inhibitor of claim 1 or 2 of the ’621 patent, because properly designed shRNA was well-known in the art to be effective at diminishing KHK expression. See, for example, Li. Li teaches KHK shRNA to knock down KHK expression in hepatocellular carcinoma cell lines (Hep3B and Huh-7), with shRNA details in Supplementary Table 3. It would have been obvious to use an effective KHK expression suppressor like the shRNA of Li as the KHK inhibitor of claim 1 or 2 of the ’621 patent.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER K SHOWALTER whose telephone number is (571)270-0610. The examiner can normally be reached M-F 9:00 am to 5:00 pm, eastern time.
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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