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
The office acknowledges Applicants’ filing of claim amendments dated 3/20/2025. Claims 1-17 has been cancelled and 18-37 has been added new. The pending claims 18-37 are examined based on the merits herein.
Application Priority
This application filed 08/05/2024 is a continuation of 17232527 filed 04/16/2021, now U.S. 12053443 is a continuation of 15971496, filed 05/04/2018, now U.S. 11000491, 15971496 Claims Priority from Provisional Application 62502385, filed 05/05/2017, 15971496 Claims Priority from Provisional Application 62539036, filed 07/31/2017. As to the priority of the claims, it is noted that the support for the claimed subject matter is in the parent application, 15971496, filed 5/4/2018.
Information Disclosure Statement
The information disclosure statement(s) (IDS) filed on 11/27/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the Examiner.
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.
Claims 18-37 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 the compounds of claim 18, its effects in lipid droplet formation in hepatocytes and the inhibitory effects on the expression of SREBP-1 and SREBP-2 in primary human hepatocytes and data with HPN-01 in NASH mice, select compounds in treating nonalcoholic steatohepatitis, does not reasonably provide enablement for the treatment of all nonalcoholic fatty liver diseases with all the compounds as claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to the invention commensurate in scope with these claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated: the test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
(1),(2),(3): The nature of the invention, state of the art and relative skill level:
The examined claims are to a method of treating nonalcoholic fatty liver disease (NAFLD) in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of HPN-01101 to HPN-01133, HPN-01201 to HPN-01224, HPN-01301 to HPN-01322, HPN-01401 to HPN-01430, HPN-01501 to HPN-01534, HPN-01601-01630 etc. (total of 172 compounds), or hydrate or solvate or pharmaceutically acceptable salt thereof.
Non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated liver disease (MASLD), is a spectrum of liver disease. Pathologically, NAFLD is linked to lipid toxicity, oxidative stress, lipid deposits, and endoplasmic reticulum stress. There are limited number of medicinal therapies, including vitamin E and pioglitazone. Various natural substances have also been identified as NAFLD in vivo and in vitro regulators. The frequency, complexity of the pathophysiology, lack of authorized medications, and difficulty in interpretation of NAFLD have made it a major problem (See Abstract). In addition to vitamin E and pioglitazone, several studies examining the mechanisms underlying various forms of medicine in NAFLD have been released in the past few years, with encouraging outcomes. Nevertheless, none have yet appeared in international or national norms (See p 9, para 5) (Sahu P, Chhabra P, Mehendale A M (December 08, 2023) A Comprehensive Review on Non-Alcoholic Fatty Liver Disease. Cureus 15(12): e50159).
Han teaches that NAFLD has a variety of clinical phenotypes and heterogeneity due to the complexity of pathogenesis and clinical conditions of its occurrence, resulting in various clinical prognoses (See Abstract). It is taught that NAFLD is a generic term that encompasses the spectrum of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and NASH-related cirrhosis. NASH is the inflammatory subtype of NAFLD, and it is characterized by steatosis, evidence of hepatocyte injury (ballooning), and inflammation with or without fibrosis. NASH-cirrhosis is the presence of cirrhosis with current or previous histological evidence of steatosis or steatohepatitis (p S6, col. 1, para 2). The reference in detail provides the classification, definition and clinical implications of the NAFLD diseases types and subtypes in Table 2. Further it is taught that NAFLD affects a heterogeneous patient population. (Han,Clin Mol Hepatol. 2022 Dec 28;29 (Suppl):S5–S16.).
Hardy teach that NAFLD represents a spectrum of liver disease that includes simple steatosis (triacylglycerol (TAG) infiltration in > 5 percent of hepatocytes), fatty infiltration plus inflammation, and hepatocellular ballooning degeneration (nonalcoholic steatohepatitis,20 SH), progressing to liver fibrosis and ultimately cirrhosis (Hardy et al., 2016 Annual Reviews of Pathology).
The relative skill of those in the art is high, that of an MD or PhD.
(4) The breadth of the claims:
The scope of the claims are broad in regards to the compounds used in the method.
(5) Predictability of the art:
Despite the advanced training of practitioners in the art, it is still impossible to predict from the specification and the prior art that the compounds of claim 18 would be useful in the treatment of all NAFLD diseases such as liver fibrosis, steatosis etc.
Han teaches that NAFLD is an integrated term for heterogeneous pathological states; therefore, the therapeutic approach should be chosen considering each cause and subtype. In recent years, there have been several attempts to refine NAFLD stages and phenotypes (Introduction, p S5, col. 2, lines 2-6). Further it is taught that NAFLD affects a heterogeneous patient population. Although the primary driver in many patients is metabolic syndrome, a complex and dynamic heterogeneous interaction of different factors are involved. Therefore, the response to therapy differs among patients depending on sex, the presence of genetic variants, coexistence of different comorbidities, and various amounts of alcohol consumption (See Conclusion) (Han,Clin Mol Hepatol. 2022 Dec 28;29 (Suppl):S5–S16.). In summary, treating NAFLD conditions is complex in general, the treatment to all NAFLD diseases is not predictable and the response to the therapy may vary in the heterogenous population.
Moslehi teach the role of SREBPs in liver diseases, in specific nonalcoholic fatty liver disease, the most common liver disease is hepatic steatosis and NASH. NASH could lead to cirrhosis and hepatocarcinoma (p 333, col. 2, para 1). As to the role of SREBPs in hepatitis disease the reference in page 335, col. 1, para 3 teach that McPherson has reported that among HCV patients there was no significant difference in the hepatic expression of SREBP-1c compared with normal subjects. Moreover, a negative relationship was found between SREBP-1c mRNA expression and grade of steatosis (Moslehi et al., J of Clinical and Translational Hepatology, 2018, 6, 332-338).
Kawamura teach the association of SREBP inhibition on NASH (Abstract). In the discussion it is taught that there was unexpected exacerbation of liver injury, fibrosis and carcinogenesis following inhibition of SREBP-mediated lipogenesis in a murine NASH model (see p 14, Discussion, col. 2, para 1, lines 1-3) (J Clin Invest, 2022, 132, 11, p 1-18). Creativebiolabs teach SREBP-2 inhibitors for NASH treatment (page 1) (Creativebiolabs, 2023, p 1-2).
To summarize, SREBP inhibition is taught to be associated with NASH and its inhibitors can be used in the treatment of NASH. However the art teach there is unexpected exacerbation of liver injury, fibrosis and carcinogenesis following inhibition of SREBP-mediated lipogenesis. Hence it is not predictable from the art whether SREBP inhibition would lead to the treatment of fibrosis and other NAFLD associated liver diseases. Applicants data provided is the inhibitory effects of the compounds on the expression of SREBP-1 and SREBP-2 in primary human hepatocytes (Table 6).
Applicants have not provided any data in regards to the administration of any of the compounds used in the method for treating conditions like fatty filtration plus inflammation, liver fibrosis, or cirrhosis. Applicants do not provide evidence or support of the use of all the compounds in the treatment of all NAFLD diseases. e.g. liver fibrosis.
(6) The amount of direction or guidance present and (7) the presence or absence of working examples:
Applicants have provided experimental data for the synthesis of the HPN-01 derivative compounds used in the method. Applicants have demonstrated its effects in lipid droplet formation in hepatocytes and the inhibitory effects on the expression of SREBP-1 and SREBP-2 in primary human hepatocytes (see Table 6). The in vivo data provided is with HPN-01 in NASH mice (Example 27). The specification do not provide any examples or data for administration of any of the compound(s) for the treatment of liver fibrosis, cirrhosis etc.
(7) The quantity of experimentation:
The level of experimentation required to practice the claimed invention would be undue as the instant claim is to a method of treating various NAFLD disorders with hundreds of compounds as claimed. Applicants have demonstrated the HPN-01 derivative compounds as SREBP inhibitors. As stated above there is unpredictability in the treatment of fibrosis, steatosis with SREBP inhibitors as taught by Kawamura and Moslehi. As per Han NAFLD is an integrated term for heterogeneous pathological states, NAFLD affects a heterogeneous patient population and the response to the therapy may vary.
Since the guidance and teaching provided by the specification is limited to specific studies for NASH, and the inhibitory effects of the compounds, treatment of other NAFLD disorders with hundreds of compounds as claimed would require a high level of experimentation even for a person highly skilled in the art. It must also be accepted that in vitro testing has its limitations, at least in part because isolated tissues can never fully represent the complex integrated biological systems operating in vivo. When extrapolating in vitro data to in vivo situations, one should be extremely careful with such things as the therapeutic concentrations of the studied substance in relation to the in vitro substrate concentration and the inhibitory values (IC50 and Ki), possible co-medicated drugs, and the other possible pathways of metabolism, elimination as an unchanged compound, binding to serum protein or the effect of active transport systems in and out of the cell. All these factors may have to be taken into consideration in the extrapolation from in vitro metabolic clearance to in vivo clearance in patients.
The scope of enablement varies inversely with the degree of unpredictability of the factors involved, and physiological activity is generally considered to be unpredictable factor. A person of ordinary skill in the art from the specification or from the prior art cannot predict that the in vitro data provided for SREBP inhibition would lead to the treatment of liver fibrosis, steatosis etc. In view of the breadth of the claims, the chemical nature of the invention, the unpredictability of pharmaceutical arts, and with the data provided, one having ordinary skill in the art would have to undergo an undue amount of experimentation to practice the claimed invention.
Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states that "a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable".
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 18 and 19 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.
Claims 18 and 19 recite the limitation of ‘and’ in the middle of the claim(s). For example see in line 7 of claim 18, see line 5 of claim 19. It is not clear whether a compound is selected from each section (after ‘and’) or just one compound?. In other words is it combination of compounds that is being administered or just one compound from the list of compounds claimed? Clarification is required.
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 18-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of US 12053443 (‘443).
The instant method claims are directed to a method of treating nonalcoholic fatty liver disease in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group (total of 172 compounds), including compounds, HPN-01113, HPN-01115, HPN-01216, HPN-01218, HPN-01605. The dependent claims are limited to specific NAFLD diseases, e.g. non-alcoholic steatohepatitis, specific dosage, administration regimen and pharmaceutical composition ingredients.
‘443 reference claims are to a method of treating nonalcoholic steatohepatitis in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of: methyl (E)-3-(6-amino-4′-(amino-(methylene)sulfinyl)-5-carbamoyl- [1,1′-biphenyl]-3-yl) acrylate (HPN-01114), (E)-2-amino-5-(3-((4-chlorophenyl)amino)-3- oxoprop-1-en-1-yl)-4′-sulfamoyl-[1,1-biphenyl]-3-carboxamide (HPN-01130), (E)-2-amino-5- (3-((4-fluorophenethyl)amino)-3-oxoprop-1-en-1-yl)-4′-sulfamoyl-[1,1′-biphenyl]-3-carboxamide (HPN-01132), 3-(6-amino-5-carbamoyl-4′-sulfamoyl-[1,1′-biphenyl]-3-yl)prop-2-yn-1-yl 2-methoxybenzoate (HPN-01217), and 4′-amino-4-bromo-N-cyclopropyl-4″-sulfamoyl-[1,1′:3′,1″-terphenyl]-5′-carboxamide (HPN-01606), or hydrate, solvate, or pharmaceutically acceptable salt thereof. The dependent claims are limited to specific dosage, administration regimen and pharmaceutical composition ingredients.
From the reference claims a skilled artisan would have found it obvious to use select compounds of the instant claims, (E)-3-(6- amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)acrylic acid (HPN-01113), ethyl (E)-3-(6- amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)acrylate (HPN-01115) in a method of treating nonalcoholic steatohepatitis in a subject because these compounds are homologs of (E)-3-(6-amino-4′-(amino-(methylene)sulfinyl)-5-carbamoyl- [1,1′-biphenyl]-3-yl) acrylate (HPN-01114, reference claim compound). The difference is the ‘methyl’ group missing in HPN-01113 and an ethyl group is substituted for methyl group in HPN-01115. Structural similarity is the touchstone of the nonobviousness inquiry for patents claiming a novel chemical compound. Eisai Co. v. Dr. Reddy's Laboratories, 533 F.3d1353,1356-57 (Fed. Cir. 2008). "Structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. For example, a prior art compound may suggest its homologs because homologs often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved properties." In re Deue134 USPQ2d 1210 at 1214. Furthermore MPEP 2144.09 (11) states: "Compounds which are [...] homologs (...) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977)." “Compounds which are… homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Further the compound, 3-(6-amino-5-carbamoyl-4′-sulfamoyl-[1,1′-biphenyl]-3-yl)prop-2-yn-1-yl 2-methoxybenzoate (HPN-01217) in the reference claim is structurally similar to instantly used compounds, 3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn- l-yl 3-methoxybenzoate (HPN-01216), 3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-l-yl 4- methoxybenzoate (HPN-01218) compounds as they differ only in the positions of the methoxy group. Obvious variations include positional isomers, homologues, bioisosteres, and hydrogen for methyl substitution at various positions off the core structure. Regarding homologs, MPEP 2144.09.11 states, “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195USPQ 426 (CCPA 1977). Thus claims 18-37 would have been obvious over the reference claims.
Conclusion
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/Umamaheswari Ramachandran/Primary Examiner, Art Unit 1627
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