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 .
DETAILED ACTION
1. Claims 1-48 are pending in the current application.
Priority
2. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e), 120, 121, 365(c), or 386(c)as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, 18/232,198, 17/119,343, 16/473,474 and PRO 62/440,601 12/30/2016, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The claims are drawn to a method of treatment of all liver diseases. Original claims 35 and 36 in the parent application 18/232,198, listed only non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) as the sole liver disease. The only other disease associated with the liver is on page 17 of the specification, “The compounds of the invention and pharmaceutical compositions thereof may also be used to repair an alcoholic's liver.” There is no description of a method of treating all liver diseases. Additional liver diseases include Wilson's disease, hemochromatosis, alpha-1 antitrypsin deficiency, biliary atresia, primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), cirrhosis, liver cancer, liver failure, Alagille syndrome, hepatic porphyria, and Gilbert syndrome. The genericization of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) to all liver diseases is unsupported. Claims 5, 7, 15, 17, 25, 27, 35, 37, 45, 47 are afforded the filing date of the claims of January 9, 2025. The additional claims are afforded the priority dates of the prior filed applications.
Information Disclosure Statements
3. The information disclosure statement filed January 9, 2025 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because the document 22 under NPL heading is cited without a date. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Objections
4. Claims 1-48 are objected to for failing to comply with 37 C.F.R. 1.75 (h):
(h) The claim or claims must commence on a separate physical sheet or electronic page. Any sheet including a claim or portion of a claim may not contain any other parts of the application or other material.
The claims appear with a section of the specification, a table with some compounds. Claims must appear on a separate sheet, MPEP 608.01(i). Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
5. Claims 1, 3, 5, 7, 11, 13, 15, 17, 21, 23, 25, 27, 31, 33, 35, 37, 41, 43, 45, 47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating Non-alcoholic fatty liver disease (NAFLD) and acute kidney injury, it does not reasonably provide enablement for treating all kidney and liver diseases. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. The claims are drawn to treating all kidney diseases and all liver diseases. While a complete list is not given, some diseases include non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal ischemia/reperfusion injury (IRI), Alpers's Disease, Pearson Syndrome, autosomal dominant polycystic kidney disease, acute kidney injury, alcohol induced liver damage, alcoholic hepatitis, glomerulonephritis, hepatitis C, hepatitis A, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, acute nephritis, recurrent hematuria, persistent hematuria, chronic nephritis, rapidly progressive nephritis, acute renal failure, chronic renal failure, diabetic nephropathy, and Bartter's syndrome. Additional liver diseases include Wilson's disease, hemochromatosis, alpha-1 antitrypsin deficiency, biliary atresia, primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), cirrhosis, liver cancer, liver failure, Alagille syndrome, hepatic porphyria, and Gilbert syndrome.
The sole data in the specification to support the treatment methods is the ACMSD-1 inhibitor assay on page 100 in Example 57. The compounds of the instant claims inhibit the enzyme to varying degrees. From >10,000 nM in Example 31 to up to 2nM in the elected species. According to the specification on page 1:
ACMSD is a critical enzyme for tryptophan metabolism, and regulates NAD+ biosynthesis from tryptophan. ACMSD is a zinc-dependent amidohydrolase that participates in picolinic acid (PA), quinolinic acid (QA) and NAD+ homeostasis. ACMSD stands at a branch point of the NAD+ biosynthetic pathway from tryptophan and determines the final fate of the amino acid, i.e., transformation into PA, complete oxidation through the citric acid cycle, or conversion into NAD+ through QA synthesis. ACMSD has been purified from liver, kidney, and brain human tissues. There are two isoforms ACMSD1 and ACMSD2 derived from a differential splicing of ACMSD gene transcription but only ACMSD1 is endowed with enzymatic activity. ACMSD1 directs ACMS (a-amino-w-carboxymuconic acid semialdehyde) to the acetyl-CoA pathway, and when ACMSD1 is inhibited, ACMS is non-enzymatically converted to quinolinic acid (QA) leading to the formation of NAD+ and an increase in the intracellular level of NAD+. Increased levels of NAD+ have been shown to protect against neuronal degeneration, improve muscle function and oxidative metabolism in mice, and enhance lifespan in worms. Whilst reduced levels of NAD+ have been associated with a range of pathophysiological states including type 2 diabetes (T2D), hyperlipidemia (elevated cholesterol and TAGs), mitochondrial diseases, neutropenia, cancers, and kidney disorders.
There is no basis in the specification or the scientific literature to correlate the inhibition of ACMSD with the treatment of all liver or kidney diseases. The 2-amino-3-carboxy-muconate-semialdehyde decarboxylase (ACMSD) which acts upon 2-amino-3-carboxy-muconate-semialdehyde to form picolinic acid, is an alternative pathway in the kynurenine catabolic pathway of tryptophan. However like many biochemical pathways, NAD+ synthesis is redundant and there are a number of alternative pathways to make NAD+ that do not involve Tryptophan or ACMSD. “Trp will only be diverted to NAD+ synthesis when the substrate supply far exceeds the enzymatic capacity of ACMSD [89], which helps explain the weak niacin equivalence of 60 mg trp per mg niacin [79]… Being an alternative but weak source for NAD+, it is an interesting question why the Trp pathway to NAD+ is evolutionarily well-retained in humans (cats do not use Trp efficiently to make NAD+ [89]). Studies have shown that the de novo biosynthesis rate of NAD+ from Trp is unchanged by the absence or presence of nicotinamide in the diet, as the urinary excretion of intermediates in the Trp pathway is not altered with 0 or up to 68.6 mg/day nicotinamide [91].” [Yang, Y.; Sauve, A. A. “NAD+ metabolism: bioenergetics, signaling and manipulation for therapy.” Biochim. Biophys. Acta, Proteins Proteomics 2016, 1864, 1787−1800., page 1791]
Assuming that inhibition of the ACMSD meaningfully increased NAD+ biosynthesis in vivo, there is no evidence that increasing NAD+ would be beneficial in all the claimed diseases. While the specification contains no data in regard to disease models. “The high expression levels of ACMSD in the kidney and liver in mammals suggests the therapeutic potential of ACMSD inhibition for diseases of these organs such as NAFLD, non-alcoholic steatohepatitis, AKI and chronic kidney disease, which—despite their high prevalence—represent large unmet medical needs. We demonstrate beneficial effects of two potent and selective ACMSD inhibitors in animal models of NAFLD and AKI.” [Katsyuba “De novo NAD+ synthesis enhances mitochondrial function and improves health” Nature 2018, volume 563, p354–359]. “Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury.” [Katsyuba, abstract]. Beyond these indications, there is little evidence of a therapeutic use for ACMSD inhibitors.
The claims are drawn to treating all forms of cancer in the liver and kidney, however there is no basis for treating these cancers. The specification has no data regarding cancer treatment. The existence of a single compounds to treat all cancer is contrary to our present understanding of pharmacology and medicine. “Thus, we ask a simple, yet fundamental, question: why is it so difficult to cure cancer? Cancer is not a single disease that can be eradicated by a single drug. Cancer occurs for a variety of reasons and no two cancers are identical.” Bae, Cancer Targeted Drug Delivery, Springer: New York, 2013, Page v. A tumor is caused by abnormal tissue growth. That can be growth by cellular proliferation more rapidly than normal, or continued growth after the stimulus that initiated the new growth has ceased, or lack (partial or complete) of structural organization and/or coordination with surrounding tissue. It can be benign or malignant. Different types of tumors affect different organs and have different methods of growth and harm to the body. Thus, it is beyond the skill of oncologists today to get an agent to be effective against all solid tumors. The ideal chemotherapeutic drug would target and destroy only cancer cells without adverse effects or toxicities on normal cells. Unfortunately, no such drug exists; there is a narrow therapeutic index between cell kill of cancer cells and that of normal cells. The major modalities of therapy are surgery and radiotherapy (for local and local-regional disease) and chemotherapy (for systemic sites). Dosage regimen is dependent on several risk factors. “The failure of even cancer-targeted drugs can be explained by assuming that a single tumor can be composed of many different types of cancer cells, necessitating the determination of the diversity within a tumor and the need of different treatments. In other words, a cancerous tumor is not homogeneous. It is possible that cancerous cells continue to mutate, become more aggressive, move around, and resist therapeutic drugs. The implication is that a cancer patient may have multiple subtypes of a cancer. The initial mutation is common to all cancer cells in a tumor, but subsequently cancer diversifies.” Hayat, M.A. AUTOPHAGY CANCER, OTHER PATHOLOGIES, INFLAMMATION, IMMUNITY, INFECTION, AND AGING Volume 5 Academic Press: Sand Diego, 2015, page xxi. “[I]t has become clear both how fundamentally different most cancer is from infectious disease, and also how limited the magic bullet approach is against genetically unstable pathogenic cells. There is a scientific consensus that most cancer results from somatic cellular evolution [7- 11]. This makes cancer fundamentally different from other cellular pathogens. In most cases, it arises from endogenous parasitism by human cells (5) rather than arriving exogenously as a non-human pathogen species. Consequently, cancer cells are genetically heterogeneous but fundamentally human, as opposed to infectious cellular diseases that are homogenous and fundamentally non-human. Despite this consensus, the tendencies to think of cancer as a non-self entity, rather than as self cells behaving abnormally, and to think of cancer as a fixed entity rather than a dynamic process, continue to mislead in important ways (12). These conceptual errors encourage efforts to identify molecular targets that will characterize cancer cells in multiple patients with the same 'type' of cancer. This idea was very productive for infectious disease medicine, but has been markedly less so for cancer medicine.” Carlo C. Maley and Mel Greaves Frontiers in Cancer Research Springer: 2016, pages 18-19. Finding a new cancer chemotherapeutic is very challenging. Typically the pre-clinical approach involves cell line screening followed by xenograft models. Damia “Contemporary pre-clinical development of anticancer agents –What are the optimal preclinical models?” EUROPEAN JOURNAL OF CANCER 2009, 45, 2768-2781. Damia outlines a strategy to identify cancer drugs in The Fig. 1 “Preclinical development steps in the evaluation of new compounds” on page 2769. The National Cancer Institute Screening program NCI60 seems to be the most widely used model for an initial screen. Sharma “Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents” Nature Reviews Cancer April 2010, Volume 10, 241-253, also discusses various models for pre-clinical cancer screens. Table 3 “Cell line platforms for assessing anticancer therapeutics” summarizes some approaches. The NCI screening program is also listed here. Ocana, A. “Preclinical development of molecular targeted agents for cancer” Nat. Rev. Clin. Oncol. 2011, 8, 200–209 also discusses such approaches and describes the situation this way: “Preclinical testing of novel drugs usually involves a panel of cancer cell lines, such as those used by the US National Cancer Institute (NCI‑60). Only drugs with some activity against specific cell lines are then evaluated in tumor xenograft models (Figure 2).” Pg. 200 “While these techniques evaluate the preclinical activity of compounds, they do not provide information about molecular mechanisms or tumor selectivity, and have rarely guided subsequent clinical development.” Ocana Pg. 201 “Although the identification of new anti-tumour agents is mainly based on in vitro methodologies, the in vivo models are absolutely required to assess the pharmacological activity of a potential new drug in animal models in which the drug undergoes distribution in both neoplastic and normal tissues, is metabolised and eliminated.” “The preclinical experimental models that are currently used for the identification and selection of novel anticancer drugs, which were overviewed in the present paper, are far from being satisfactory in mimicking the complex biological features of human tumours.” (Damia Page 2778) A retrospective National Cancer Institute Study examined 39 known cancer drugs using transplantable human tumor cell lines and compared them to phase II clinical outcomes (Johnson, et. al. “Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials.” British Journal of Cancer 2001, 84, 1424–1431) The data was not predictive of activity against the same human tumors. Breast cancer cell line data (like AU565) was not predictive, see Figure 1 pg. 1427 far left column. Neither was it predictive of tumors of different tissues, i.e. breast cancer cell line data did not lead to predictive outcomes of lung cancer, skin cancer, colon cancer, etc., see Figure 1 columns second thru sixth to the right of the far left column. “[T]he failure rate in anticancer drug development is higher than for other diseases; only about 5% of agents identified as potential anticancer compounds demonstrate sufficient clinical activity in phase III trials to eventually be licensed.” (Ocana pg. 200). There is no evidence that ACMSD in upregulated in all human cancers and was found only to be overexpressed in 3 of 28 cancers screened. “Other than KAT1 (CCBL1) being up-regulated in the 9/28 cancers listed by Perez-Castro et al. [73], other KP enzymes subsequent to FAMID are up-regulated in fewer cancers as follows: KYNU (5), KMO and QPRT (4 each), ACMSD (3) and 3-HAAO (1).” [Badawy “Tryptophan metabolism and disposition in cancer biology and immunotherapy” Bioscience Reports (2022), 42, 1-22.] There is evidence that ACMSD downregulation promotes cancer growth. “This review provides a new perspective on KP dysregulation in defeating antitumor immune responses, specifically bringing light to the lower segment of the KP, particularly QUIN-induced neurotoxicity and downregulation of the enzyme a-amino-b-carboxymuconate-e-semialdehyde decarboxylase (ACMSD) as a potential mechanism of tumor progression.” [Adams “The Kynurenine Pathway in Brain Tumor Pathogenesis” Cancer Res (2012) 72 (22): 5649–5657, abstract]. “We herein have reviewed evidence implicating a novel mechanism, in which the cooperation of ACMSD downregulation, IDO-1 overexpression, and TDO-2 expression, together contribute to tumor cell persistence and pathogenesis through directing KP metabolism towards the neurotoxic metabolite, QUIN, and limiting neuroprotection.” [Adams, Conclusion, page 5655, col. 1.] This suggests that a compound having the action of inhibiting ACMSD would promote tumor growth.
The claims are also drawn to treating viral infections of the liver like hepatitis, but no antiviral effect has been shown. Based upon the foregoing the claims have taken a specific pharmacological action and claimed a broad list of diseases and with no clear nexus to the treatment of disease. As discussed in MPEP 2164.02:
CORRELATION: IN VITRO /IN VIVO
The issue of “correlation” is related to the issue of the presence or absence of working examples. “Correlation” as used herein refers to the relationship between in vitro or in vivo animal model assays and a disclosed or a claimed method of use. An in vitro or in vivo animal model example in the specification, in effect, constitutes a “working example” if that example “correlates” with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute “working examples.”
Based upon the relevant evidence as a whole, there is no reasonable correlation between the disclosed in vitro utility and the full scope of the in vivo activity and the methods claimed here.
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.
6. Claim(s) 5, 7, 15, 17, 25, 27, 35, 37, 45, 47 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Takahashi US 2019/0367457 A1. Takahashi teaches the compounds of the instant claims for treating specific liver diseases in a method step on page 7 at paragraph [0079] “The present invention provides a method of treat ing a subject with a disease which can be ameliorated by inhibition of ACMSD , by administering to the subject an effective amount of one or more disclosed compounds , or a pharmaceutically acceptable salt thereof , or the corresponding pharmaceutical composition” and “Non - alcoholic fatty liver dis ease ( NAFLD ) , Nonalcoholic steatohepatitis ( NASH)” [page 6 paragraph [0087]] are said to be such diseases. An additional disease associated with the liver is on page 17, “The compounds of the invention and pharmaceutical compositions thereof may also be used to repair an alcoholic's liver.” The compound of claim 5, 7, is the compound of example 1. The compound of claim 15, 17 is the compound example 23. The compound of claim 25, 27 is the compound example 25. The compound of claims 35, 37 is the compound example 41. The compound of claims 4,5 47 is the compound of example 52.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
7. Claims 9-10, 19-20, 29-30, 39-40, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,780,812. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘812 patent are drawn to the same compounds and compositions. The ‘812 patent claims while somewhat broader embrace the species of the instant claims in particular with the subgenus of claim 12, 15, where R2 is thienyl, phenyl or CF3 (haloalkyl) and R1 is H or Cl. The compound in claim 39 is the compound of patent example 52, the compound of claim 29 is the compound patent example 41, the compound of claim 19 is the compound patent example 25, and the compound of claim 9 is the compound patent example 23.
8. Claims 1-8, 11-18, 21-28, 31-38, 40-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-36 of U.S. Patent No. 12,378,200. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘200 patent are drawn to the same methods. The ‘200 patent claims while somewhat broader embrace the species of the instant claims in particular with the subgenus of claim 2-3, 6-12, 15, 20-21, 24, 29-30, 33 where R2 is thienyl, phenyl or CF3 (haloalkyl) and R1 is H or Cl. The compound in claim 39 is the compound of patent example 52, the compound of claim 29 is the compound patent example 41, the compound of claim 19 is the compound patent example 25, compound of claim 9 is the compound patent example 23 and the compound in claims 1-8 is the compound of patent example 1. The instant claims are drawn to treating any liver disease or kidney disease in the broadest sense, while the patent claims are drawn to non-alcoholic fatty liver disease and AKI.
Conclusion
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/ Primary Examiner, Art Unit 1621
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