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
Claims 1, 6, 9-10, 12, 15, 18, 20, 22-24, 30, 32-34, 44, 46-48 and 56 are pending and under examination.
Priority
This application is a 371 of PCT/US2021/057895 filed 11/3/2021, which claims benefit of 63/110,789 filed 11/6/2020. The effective filing date of the current application is November 6, 2020.
Information Disclosure Statement
The information disclosure statements filed on 10/2/2023; 8/13/2024; and 11/4/2024 all comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. All references were considered.
Drawings
As per 37 C.F.R. 1.84(b)(1), photographs, including photocopies of photographs,
are not ordinarily permitted in utility and design patent applications. The Office will
accept photographs in utility and design patent applications, however, if photographs
are the only practicable medium for illustrating the claimed invention. For example, photographs or photomicrographs of: electrophoresis gels, blots (e.g., immunological,
western, Southern, and northern), auto- radiographs, cell cultures (stained and
unstained), histological tissue cross sections (stained and unstained), animals, plants, in
vivo imaging, thin layer chromatography plates, crystalline structures, and, in a design
patent application, ornamental effects, are acceptable. If the subject matter of the
application admits of illustration by a drawing, the examiner may require a drawing in
place of the photograph. The photographs must be of sufficient quality so that all details
in the photographs are reproducible in the printed patent. Figure 1 is a black and white drawing, however the quality of the images do not allow all the details to be visualized.
Claim Objections
Claim 20 is objected to because of the following informalities:
Claim 20 recites “wherein optionally generating an area under the curve of the first and second amounts of the reaction product, generating an area under the curve of the second and third amounts of the HSD17B13 substrate, or generating an area under the curve of the second and third amounts of the HSD17B13 substrate precursor”, which appears to be an incomplete thought.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 6, 9-10, 12, 15, 18, 20, 22-24, 30, 32-34, 44, 46-48 and 56 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a natural phenomenon without significantly more.
The claims are drawn to a method of treatment, and recite active method steps of administering to a subject a first amount of HSD17B13 substrate or substrate precursor; and administering or co-administering a first amount of an HSD17B13 inhibitor to the subject with the administration of the first amount of HSD17B13 substrate or substrate precursor. Thus, the claims are directed to a process (Step 1: YES).
The claims set forth judicial exceptions which are abstract ideas, and are directed towards a natural phenomenon of reacting the enzyme HSD18B13 with its substrate and determining the amount of resulting reaction product. In claim 1, the method comprises determining an amount of a reaction product of HSD17B13 in a sample obtained from the subject; determining an HSD17B13 enzyme activity based on the amount of the reaction product; and determining an amount of HSD17B13 inhibitor to administer to the subject based on the HSD17B13 enzyme activity, which include mathematical concepts and mental steps (Step 2A prong 1: YES). Claim 15 recites determining the amount of the reaction product comprises measuring the labeled reaction product or determining the second amount of the HSD17B13 substrate or substrate precursor comprises measuring the labeled HSD17B13 substrate or substrate precursor, which requires a mental step (Step 2A prong 1: YES). Claim 18 recites determining a second amount or determining a third amount of the HSD17B13 substrate or substrate precursor, which requires a mental step (Step 2A prong: YES). Claim 20 recites comparing a first and second amount of reaction product or a third amount to a second amount of HSD17B13 substrate or a third amount to a second amount of HSD18B13 substrate precursor, which is a mental step (Step 2A prong 1: YES). Claims 22 and 23 recite comparing a first area under the curve of the first and second amounts of the reaction product to a second area under the curve of amounts of the reaction product, HSD17B13 substrate or substrate precursor, which requires a mental step (Step 2A prong 1: YES). Claim 24 recites further comparing the HSD17B13 enzyme activity to a baseline HSD17B13 enzyme activity and determining whether to increase, decrease or not change the second amount of the HSD17B13 inhibitor relative to the first amount of the HSD17B13 inhibitor, which requires mental steps (Step 2A prong 1: YES). Claim 34 recites further comprising normalizing the HSD17B13 enzyme activity to obtain a specific HSD17B13 activity of the subject, which requires a mathematical calculation (Step 2A prong 1: YES). Claim 44 recites identifying the subject as likely to develop the liver disease when the HSD17B13 enzyme activity of the subject is greater than the control, baseline or threshold HSD17B13 enzyme activity, which is a mental step (Step 2A prong 1: YES).
This judicial exception is not integrated into a practical application. The additional elements recited are administering a first amount of an HSD17B13 substrate or substrate precursor, and administering or co-administering a first amount of an HSD17B13 inhibitor in claim 1; and measuring labeled reaction product in the sample in claim 15. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the limitations do not impose any meaningful limits on practicing the abstract idea, and rely upon the natural phenomenon of the HSD17B13 enzyme converting its substrate or substrate precursor into a reaction product that is then detected. While the claims recite an active method step of administering a first amount of HSD17B13 substrate and administering or co-administering a first amount of an HSD17B13 inhibitor, these steps are well-understood, routine and conventional activity known in the art before the filing of the current invention.
Stevis et al. (WO 2018/190970 A1, published on October 18, 2018) describes screening methods for identifying modulators of hydroxysteroid (17-BE-TA) dehydrogenase (HSD17B) family member proteins, such as HSD17B13 (abstract). Stevis teaches that inhibitors of HSD17B family member proteins identified through the screening methods may be used to treat liver diseases, disorders or conditions which the HSD17B family member protein plays a role (relevant to a method of treatment) (abstract).
Stevis teaches that HEK293 cells were treated with estradiol or androstanediol, incubated for 2 or 48 hours, and then 40µL of culture medium was transferred from each well into a 96 well plate (description p.24, Example 1 - lines 23-26). Stevis further teaches that the consumption of estradiol and androstanediol was evaluated by LC-MS using a Thermo Q exactive™ HF mass spectrometer with a Waters I class ACQUITY UPLC system (description p.25, lines 3-5).
Stevis teaches NAD(P)H assay can be used for substrate and inhibitor screening using equilin inhibition (description p.27, Example 5). Stevis teaches that 1µM NADP and 3µM estradiol were incubated with 270 nM HSD17B1 in the presence of increasing concentrations of equilin for 40 min at 37 degrees C (description p.27, lines 15-18). Stevis teaches that the capacity of HSD17B1 to convert estrone to estradiol and the capacity of equilin to inhibit HSD17B1 was confirmed in a cell-based assay (description p.27, lines 26-27).
Stevis teaches the substrate for the HSD17B family member protein may comprise any suitable substrate whose conversion to a product is catalyzed by an HSD17B family member protein activity (description p.18, lines 1-4). Stevis further teaches the substrate comprises a bioactive lipid including LTB3, 12-HETE, 15-HETE, 13-HODE, 15-HEDE, linoleic acid, or arachidonic acid (description p.19, lines 18-19; p.20 line 19; Table 1).
The administering to a subject a first amount of HSD17B13 substrate and measuring consumption of the substrate and administering or co-administering a first amount of HSD17B13 inhibitor to the subject with the administration of the first amount of HSD18B13 substrate is well-understood, routine and conventional in the field of identifying modulators of hydroxysteroid dehydrogenase enzymes of the HSD17B family, as taught by Stevis et al.
Thus, claims 1, 6, 9-10, 12, 15, 18, 20, 22-24, 30, 32-34, 44, 46-48 and 56 are rejected under 35 U.S.C. 101.
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.
Claims 1, 6, 9-10, 12, 15, 18, 20, 22-24, 30, 32-34, 44, 46-48 and 56 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 recites “determining an amount of the HSD17B13 inhibitor to administer” in line 11, which lacks antecedent basis because there is no prior recitation of “an HSD17B13 inhibitor” in the claim.
Claims 6, 9-10, 12, 15, 18, 20, 22-24, 30, 32-34, 44, 46-48 and 56 are rejected for depending from rejected claim 1 but failing to remedy the indefiniteness therein.
Regarding claim 10, 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 10 recites the broad recitation “wherein the first amount of the HSD17B13 substrate or substrate precursor is 10-1000 µg”, and the claim also recites “wherein the first amount of the HSD17B13 substrate or substrate precursor is optionally about 100µg” which is the narrower statement of the range/limitation. The claim is 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.
Claim 34 recites “further comprising normalizing the HSD17B13 enzyme activity to obtain a specific HSD17B13 enzyme activity of the subject, wherein further comprising comparing the HSD17B13 enzyme activity of the subject to a control HSD17B13 enzyme activity measurement, a baseline HSD17B13 enzyme activity measurement, or a threshold HSD17B13 enzyme activity, further comprising identifying the subject as likely to benefit from the treatment with the HSD17B13 inhibitor when the HSD 17B 13 enzyme activity of the subject is greater than the control HSD 17B 13 enzyme activity measurement, baseline HSD 17B 13 enzyme activity measurement, or threshold HSD 17B 13 enzyme activity.” It is unclear what the claim further requires, and whether comparing the HSD17B13 enzyme activity of the subject to a control, baseline or threshold measurement is required or not; and whether identifying a subject as likely to benefit from treatment is required or not.
Claim 44 recites identifying the subject as likely to develop “the liver disease” in line 2, which lacks antecedent basis because there is no prior recitation of “a liver disease” in either claim 44, or claim 1 from which claim 44 depends.
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, 6, 10, 12, 15, 30, 32-34 and 46 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Stevis et al. (WO 2018/190970 A1, published on October 18, 2018).
Regarding claim 1, the term “a subject” does not have a specific definition in the specification, and given its broadest reasonable interpretation, includes any biological entity containing expressed genetic material, including cells, tissue and multicellular organisms.
Stevis teaches screening methods for identifying modulators of hydroxysteroid (17-BE-TA) dehydrogenase (HSD17B) family member proteins, such as HSD17B13 (abstract). Stevis teaches that inhibitors of HSD17B family member proteins identified through the screening methods may be used to treat liver diseases, disorders or conditions which the HSD17B family member protein plays a role (relevant to a method of treatment) (abstract).
Stevis teaches estradiol is a substrate for HSD17B13 in a cell-based assay (Figure 2). Stevis teaches that HEK293 cells were treated with estradiol or androstanediol, incubated for 2 or 48 hours, and then 40µL of culture medium was transferred from each well into a 96 well plate (description p.24, Example 1 - lines 23-26). Stevis further teaches that the consumption of estradiol and androstanediol was evaluated by LC-MS using a Thermo Q exactive™ HF mass spectrometer with a Waters I class ACQUITY UPLC system (description p.25, lines 3-5).
Stevis teaches NAD(P)H assay can be used for substrate and inhibitor screening using equilin inhibition (description p.27, Example 5). Stevis teaches that 1µM NADP and 3µM estradiol were incubated with 270 nM HSD17B1 in the presence of increasing concentrations of equilin for 40 min at 37 degrees C (description p.27, lines 15-18). Stevis teaches that the capacity of HSD17B1 to convert estrone to estradiol and the capacity of equilin to inhibit HSD17B1 was confirmed in a cell-based assay (description p.27, lines 26-27).
Stevis teaches the substrate for the HSD17B family member protein may comprise any suitable substrate whose conversion to a product is catalyzed by an HSD17B family member protein activity (description p.18, lines 1-4). Stevis further teaches the substrate comprises a bioactive lipid including LTB3, 12-HETE, 15-HETE, 13-HODE, 15-HEDE, linoleic acid, or arachidonic acid (description p.19, lines 18-19; p.20 line 19; Table 1).
Regarding claim 6, Stevis teaches that HEK293 cells were treated with estradiol or androstanediol, incubated for 2 or 48 hours, and then 40µL of culture medium was transferred from each well into a 96 well plate (description p.24, Example 1 - lines 23-26).
Regarding claim 10, Stevis teaches adding 1µM or estradiol or androstanediol to 24 well plates containing 1 x 105 cells in 500µL of culture medium/well. Estradiol has a molecular weight of 272.4 g/mol; thus there was 0.13 µg of estradiol added to the cells. Stevis further teaches adding 3µM of estradiol in 20µL reaction volume (description p.27. line 15-18), adding 13.3µM estradiol with increasing amounts of HSD17B1 (description p.27, line 9) and 75µM of estradiol (description p.26, line 10).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the amount of estradiol substrate added to the reaction to arrive at the desired substrate concentration. One of ordinary skill in the art would have been motivated to vary the amount of substrate based on the reaction kinetics, because Stevis teaches varying the amount of enzyme while maintaining the substrate amount steady. One of ordinary skill in the art would have found it beneficial to maintain a fixed amount of enzyme and vary the amount of estradiol substrate added to obtain additional reaction data.
Regarding claims 12 and 15, Stevis teaches contacting the HSD17B family member protein with a test compound and a radio-labeled substrate for the HSD17B family member protein (description p.8, lines 16-18). Stevis teaches that as an alternative to a radio-label, the substrate label may comprise a fluorescent label, and detection may be of the fluorescence instead of the scintillation (description p.9, lines 8-10). Stevis further teaches that the assay measures the labeled substrate consumed and not consumed by the cells (description p.9, lines 17-19).
Regarding claims 30 and 32, Stevis teaches that the amount of reaction product decreased at least about 25% with the administration of equilin as an HSC17B13 inhibitor (description p.6, lines 17-19; Figure 7C).
Regarding claim 33, Stevis teaches that inhibition of HSD17B13 may have a therapeutic effect in human beings, for example, as a treatment for liver diseases, disorders or conditions such as one or more of alcoholic liver disease, non-alcoholic liver disease, cirrhosis, and nonalcoholic steatohepatitis (NASH) (description p.6,lines 25-29). Stevis further teaches that activity against the substrates for each HSD17B family member were normalized to Percent of Control (POC), with the control, estradiol, set as 100% (description p.37, lines 1-3).
Regarding claim 34, Stevis teaches the consumption of estradiol and androstanediol was evaluated by LC-MS, and the retention time and peak area of all compounds were determined using Xcalibur software (description p.25, lines 3-4 and 8-9). Stevis further teaches that the concentration of each compound was calculated from calibration curves, which were constructed by plotting the peak area of each compound versus corresponding concentration (description p.25, lines 9-11; Figure 2).
Regarding claim 46, Stevis teaches an HSD17B13 inhibitor of equilin, which is a small molecule (description p.13, lines 25-26).
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 9 and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Stevis et al. (WO 2018/190970 A1, published on October 18, 2018) as applied to claim 1 above, and further in view of Abul-Husn et al. (WO 2018/136758, published on July 16, 2018).
The teachings of Stevis et al. are discussed above.
Regarding claim 9, Stevis does not teach that the administration of the first amount of the HSD17B13 substrate is intravenous or oral.
However, Abul-Husn teaches administration (of a therapeutic) can be by any suitable route including for example, parenteral, intravenous, oral (description p.155, [00394], [0396]). Abul-Husn teaches the formulation depends on the route of administration chosen (description p.155, [00394]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the formulation of the HSD17B13 substrate taught by Stevis to administer a formulation suitable for intravenous or oral administration taught by Abul-Husn, because Abul-Husn teaches that administration can be intravenous or oral, and the formulation depends on the route of administration chosen. One of ordinary skill in the art would reasonably expect that administering a first amount of HSD17B13 substrate by either intravenous or oral routes would predictably result in the delivery of the substrate to the subject.
Regarding claim 56, Stevis does not teach wherein the sample comprises a blood sample, plasma sample or serum sample. Stevis does not teach wherein the subject is a mammal.
However, Abul-Husn teaches compositions related to HSD17B13 variants, and therapeutic and prophylactic methods for treating a subject having or at risk of developing chronic liver disease (abstract). Abul-Husn teaches a biological sample refers to a sample of biological material within or obtainable from a subject, from which a nucleic acid or protein is recoverable (description p.38, [00120]). Abul-Husn further teaches that a subject can be any organism, including for example a human, a non-human mammal, a rodent, a mouse or a rat (description p.38, [00120]). Abul-Husn further teaches a biological sample can comprise a sample of bodily fluid such as blood, plasma and serum. Abul-Husn teaches treating a subject who is not a carrier of the HSD17B13 rs72613567 variant and has or is susceptible to developing a chronic liver disease (description p.146, [00384]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have replaced the cell sample of Stevis with a blood sample, plasma sample, or serum sample from a human taught by Abul-Husn, because Abul-Husn teaches treating a subject having or at risk of developing chronic liver disease. One of ordinary skill would have found it beneficial to use a blood sample, plasma sample or serum sample from a human subject to determine whether a subject was at risk for developing chronic liver disease using the method of Stevis.
Claims 18, 20-24 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Stevis et al. (WO 2018/190970 A1, published on October 18, 2018) as applied to claim 1 above, and further in view of Charatcharoenwitthaya et al. (“The Spontaneous Course of Liver Enzymes and Its Correlation in Nonalcoholic Fatty Liver Disease”, Digestive Diseases and Sciences, 2012, Vol.57, pp.1925-1931) and Sotaniemi et al. (“Measurement of Hepatic Drug-Metabolizing Enzyme Activity in Man”, European Journal of Clinical Pharmacology, 1980, Vol. 17, pp.267-274).
The teachings of Stevis et al. are discussed above.
Regarding claims 18, 20 and 44, Stevis does not teach determining a second amount of the reaction product of the HSD17B13 substrate, or wherein the second sample is obtained from the subject at a second time after administering the first amount of the HSD17B13 substrate to the subject.
However, Charatcharoenwitthaya teaches the course of liver enzymes and their clinical correlations in nonalcoholic fatty liver disease (NAFLD) (abstract). Charatcharoenwitthaya teaches measuring liver enzymes every 3 months in untreated patients and patients with NAFLD (abstract). Patients had serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, direct bilirubin, alkaline phosphatase, γ-glutamyltransferase, albumin, and prothrombin time, and they were measured every 3 months during the 2-year period (p.1926, 2nd column top paragraph). Charatcharoenwitthaya teaches defining normal ALT values, and based on these normal values, different patterns of liver enzymes were identified; liver enzyme changes at 1 and 2 years were calculated by subtracting baseline values from the values of year 1 and 2 (p.1926, 2nd column top paragraph).
Sotaniemi teaches measuring hepatic drug-metabolizing enzyme activity in man (title). Sotaniemi teaches plasma samples were taken by venipuncture before and after 1, 3, 6, 9, 12, 24, 28 and 72 hours (p.268, 1st column – Protocols). Sotaniemi teaches the plasma clearance was obtained by dividing the dose by the area under the curve plasma concentration-time curve, calculated by the trapezoid rule (p.268, 1st column last paragraph – 2nd column top paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have measured a second amount of reaction product of the HSD17B13 substrate at a second time taught by Charatcharoenwitthaya and Sotaniemi in the method of Stevis, because Sotaniemi teaches collecting plasma samples at multiple timepoints and plotting a plasma concentration-time curve, and Charatcharoenwitthaya teaches calculating liver enzyme changes by subtracting baseline values from the values of year 1 and 2. One of ordinary skill in the art would have found it beneficial to collect more than one sample of reaction product after administering the first amount of the HSD17B13 substrate to the subject to monitor changes between baseline and the amount of substrate precursor at different times to determine if the disease was improving, stable or getting worse.
Regarding claims 22 and 23, the claims are directed towards the optional alternative limitation of “optionally generating an area under the curve of the first and second amounts of the reaction product; generating an area under the curve of the second and third amounts of the HSD17B13 substrate, or generating an area under the curve of the second and third amounts of the HSD17B13 substrate precursor” recited in claim 20, which is not a required limitation of the method. The limitations of claims 22 and 23 are being interpreted as required only if an area under the curve is generated; however if an area under the curve is not generated, then the claim limitations are not required.
Stevis teaches a method comprising a) contacting a first HSD17B13 protein with a test compound (i.e. inhibitor), a substrate for HSD17B13, NAD+, a pre-reduced form of luciferin, an enzyme that reduces the pre-reduced form of luciferin to produce luciferin, and luciferase (b) contacting a second HSD17B13 protein with a control, a substrate for HSD17B13, NAD+, a pre-reduced form of luciferin, an enzyme that reduces the pre-reduced form of luciferin to produce luciferin, and luciferase, (c) detecting the emission wavelength of luciferin produced by the luciferase according to step (a) and according to step (b) (description p.38, lines 11-17).
Stevis does not teach comparing a first area under the curve of the first and second amounts of the reaction product to a second area under the curve of amounts of the reaction product.
Charatcharoenwitthaya is silent on calculating area under the curve.
Sotaniemi teaches measuring hepatic drug-metabolizing enzyme activity in man (title). Sotaniemi teaches plasma samples were taken by venipuncture before and after 1, 3, 6, 9, 12, 24, 28 and 72 hours (p.268, 1st column – Protocols). Sotaniemi teaches the plasma clearance was obtained by dividing the dose by the area under the curve plasma concentration-time curve, calculated by the trapezoid rule (p.268, 1st column last paragraph – 2nd column top paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have generated a first and second area under the curve of the first and second amounts of the reaction product where a second amount of inhibitor was or was not administered, because Stevis teaches collecting data when an HSD17B13 inhibitor is co-administered and when an HSD17B13 inhibitor is not co-administered. One of ordinary skill in the art would have found it beneficial to generate different area under the curve plots from data taken at a first time and a second time because Sotaniemi teaches creating area under the curves, and Charatcharoenwitthaya teaches comparing enzyme activity values to baseline to determine disease progression.
Regarding claim 24, Stevis, Charatcharoenwitthaya and Sotaniemi are silent on determining based on the comparison whether to increase, decrease or not change the second amount of HSD17B13 inhibitor relative to the first amount of HSD17B13 inhibitor. However, this step is a routine data gathering activity taught by each of Stevis, Charatcharoenwitthaya and Sotaniemi.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have compared the HSD17B13 enzyme activity to a baseline HSD17B13 enzyme activity obtained without co-administering the HSD17B13 enzyme activity obtained without co-administering the HSD17B13 inhibitor to the subject, because Stevis teaches determining luciferin signals when HSD17B13 inhibitor is co-administered and not co-administered with HSD17B13 substrate. One of ordinary skill in the art would reasonably expect that increased HSD17B13 activity relative to baseline would predictably result in the need to increase the second amount of inhibitor; decreased HSD17B13 activity relative to baseline would result in the need to decrease the second amount of inhibitor; and no change in HSD17B13 activity relative to baseline would require no change in HSD17B13 inhibitor administered; because one of ordinary skill in the art would recognize that increased enzyme activity indicated disease as taught by Sotaniemi and Charatcharoenwitthaya.
Claim 47 is rejected under 35 U.S.C. 103 as being unpatentable over Stevis et al. (WO 2018/190970 A1, published on October 18, 2018) as applied to claim 1 above, and further in view of Bey et al. (“Design, synthesis and biological evaluation of bis(hydroxyphenyl) azoles as potent and selective non-steroidal inhibitors of 17b-hydroxysteroid dehydrogenase type 1 (17b-HSD1) for the treatment of estrogen-dependent diseases”, Bioorganic & Medicinal Chemistry, 2008, Vol. 16, Issue 12, pp.6423-6435).
The teachings of Stevis et al. are discussed above.
Regarding claim 47, Stevis teaches identifying test compounds as inhibitors of HSD17B13 when the emission wavelength of luciferin produced according to step a) is lower than the wavelength of luciferin produced according to step b) (description p.37 line 17 – p.38 line 2).
Stevis is silent on whether the HSD17B13 inhibitor comprises an estradiol mimetic.
However, Bey teaches the design, synthesis and biological evaluation of bis(hydroxyphenyl) azoles (title). Bey teaches that 17β-HSD1 converts estrone (E1) to 17β-estradiol (E2) (p.6424 Chart 1). Bey teaches designing steroidomimetics that were non-steroidal structures that mimic the steroidal substrate structure that would bind in the substrate-binding site (p.6424, 2nd column 2.2. Design of steroidomimetics). Bey teaches that rather than strong reduction of systemic estrogen action which is a rather radical approach, a softer therapy approach for the treatment of breast cancer could be the inhibition of the enzyme catalyzing the last step of E2 biosynthesis: 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) (p.6423, column 1, 2nd paragraph – column 2, top paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have replaced the inhibitor of Stevis with an estradiol mimetic taught by Bey, because Bey teaches that steroidomimetics that were non-steroidal structures could be potential inhibitors, which could be used as a softer approach for the treatment of breast cancer. One of ordinary skill in the art would have found it beneficial to design a treatment that did not strongly reduce systemic estrogen action, and instead targeted the enzyme involved in the last step of E2 biosynthesis.
Claim 48 is rejected under 35 U.S.C. 103 as being unpatentable over Stevis et al. (WO 2018/190970 A1, published on October 18, 2018) as applied to claim 1 above, and further in view of Marchais-Oberwinkler et al. (“17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: Protein structures, functions, and recent progress in inhibitor development”, Journal of Steroid Biochemistry and Molecular Biology, 2011, Vol. 125, Issues 1-2, pp.66-82).
The teachings of Stevis et al. are discussed above.
Regarding claim 48, Stevis does not teach wherein the HSD17B13 inhibitor is
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175
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.
However, Marchais-Oberwinkler teaches compound 17 is a non-steroidal inhibitor of HSD17B1 enzyme, represented by
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229
299
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Greyscale
, which is identical to the fifth structure pictured in the claim, as reproduced above (p.75, Fig. 10, compound 17). Marchais-Oberwinkler teaches that it was found that the exchange of the middle ring can turn an inactive compound into a highly active and selective inhibitor of 17β-HSD1 (p.76, 1st column – 3.1.2.6. Bis(hydroxyphenyl) substituted arenes.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have replaced the HSD17B13 inhibitor taught by Stevis with the bis(hydroxyphenyl) substituted arene having the structure pictured above taught by Marchais-Oberwinkler. Each of Stevis and Marchais-Oberwinkler teach inhibitor molecules for 17β-hydroxysteroid dehydrogenase enzymes. One of ordinary skill in the art would reasonably expect that replacing equilin taught by Stevis with a bis(hydroxyphenyl) substituted arene would predictably result in the inhibition of HSD17B13 enzyme, because it would have amounted to a simple substitution of one known inhibitor for another, and it was known in the art at the time of invention that bis(hydroxyphenyl) substituted arenes could be a highly active and selective inhibitor of 17β-HSD enzymes.
Conclusion
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/DEEPA MISHRA/Examiner, Art Unit 1657