DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-9, 14, 60-64, and 68-71 are pending.
Priority
This application is filed 07/19/2024, and claims the benefit of domestic priority as below:
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Information Disclosure Statements
One IDS(s) received on 7/19/2024 have been considered unless marked with a strikethrough.
Claim Objections
Claims 9, and 14 are objected to because of the following informalities:
Claim 9 is objected to because the unit “mm” should be “micrometer”.
Claim 14 is objected to because the phrase “from about 1.0% and 20% (m/v)” should be “from about 1.0% to 20% (m/v)”.
Claim interpretation
Claims are interpreted in accordance with the broadest reasonable interpretation (BRI) standard
consistent with the specification (See MPEP 2111).
With respect to claim 1, the claim recites that “a pharmaceutical composition comprising a hypoxia-inducible factor prolyl hydroxylase inhibitor and an oil”. Because the claim imposes no limitation and uses the term “comprising”, claim 1 is interpreted to encompass any hypoxia-inducible factor prolyl hydroxylase inhibitor and oil, while also allowing the inclusion of other additives.
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.
The rejections under this section are made when the scope of the claimed subject matter is not clear. (See MPEP 2173)
Claims 3, 6, 7, 9, 14, and 71 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 3 recites the limitation "Formula (I)" in the body of claim 3. There is insufficient
antecedent basis for this limitation in the claim. Claim 1 recites “a pharmaceutical composition comprising a hypoxia-inducible factor prolyl hydroxylase inhibitor and an oil” without Formula I. Claim 3 does not add a further limitation to the subject matter of claim 1, because Formula I recited in claim 3 does not fall within the limitations of claim 1.
In addition, regarding claim 3, the phrase "preferably 1" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. It is unclear whether the value “1” is required as part of the claimed invention or merely identifies a preferred embodiment. Because claim 3 recites that both m and n may be “1, 2, or 3, preferably 1”, the scope of the claim is ambiguous as to whether m and n are limited to 1 or also include 2 and 3. See MPEP § 2173.05(d)
Regarding claims 6 and 7, the phrase " comprises or consists of" renders the claim(s) indefinite
because the claim(s) include(s) elements not actually disclosed (those encompassed by "or the like"), thereby rendering the scope of the claim(s) unascertainable. See MPEP § 2173.05(d). "Comprise" is open-ended, allowing unrecited elements, making it broader. "Consist" is closed, strictly excluding any unrecited elements. (see MPEP 2111.03)
Regarding claims 9, 14, and 71, the term "about" renders the claim indefinite because it is
unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The current specification does not define the term “about” or otherwise provide guidance, such as a permissible tolerance, ± range, or measurement error range, by which one of ordinary skill in the art could determine the scope of “about”. Accordingly, the claimed ranges in claims 9, 14, and 71 are unclear. For example, with respect to claim 71, the phrases “about 0.5 mg/L or greater”, "about 1 mg/L or greater", and “from about 0.5 mg/L to about 5 mg/L” do not clearly establish the boundaries of the claimed concentration ranges.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Notwithstanding the indefiniteness rejection set forth above, the 35 USC 102 rejection is not cooperated with other rejections, and applied the prior art to the claims under broadest reasonable interpretation and specification.
Claim(s) 1, 60, 61, 68, and 70 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Conca et al. (US 20160120859 A1, pub’d 05/05/2016).
With claims 1, 60, 61, 68, and 70, Conca teaches [(4-Hydroxy-1-methyl-7-phenoxy
isoquinoline-3-carbonyl)-amino]-acetic acid is a potent inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase inhibitor (paragraph [0003]). Conca further discloses that, for soft capsules, the active ingredient may be dissolved or suspended in suitable liquids such as fatty oils (paragraph [0136]). Thus, Conca disclosed a pharmaceutical composition comprising a HIF-PH inhibitor and an oil, as required by claim 1. Conca continually teaches that 1) administration of the formulation to treat HIF associated conditions including anemia and to stimulate endogenous erythropoietin, as required by claims 60 and 61 (paragraph [0142], [0151], and [0153]), and 2) oral administration and administration to a subject/patient, as required by claim 68 and 70 (paragraph [0135], and claim 60).
Claim(s) 1-7, 60-62, and 68-70 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Hofmann et al. (WO2021198256 A1, pub’d 10/07/2021). Hofmann qualifies as prior art under 35 U.S.C. 102(a)(1) and 102(a)(2). (see MPEP 2152, and 2154.01(a)). Although, the application share some inventors, the inventive entities are not identical, thus, the “name another inventor” requirement of 35 USC 102(a)(2) is satisfied. (see MPEP 2154.01(c)). The present record does not establish that the subject matter disclosed in ‘256 patent is the inventor-originated disclosure of the inventors of the instant application or that the non-overlapping ‘256 patent’s inventors obtained the relevant subject matter from an inventor or joint inventor of the instant application. Accordingly, absent a proper evidences showing the relied upon subject matter originated from the inventor or a joint inventor of the instant application, the exception under 35 U.S.C. 102(b)(1) and 102(b)(2) do not apply.
With respect to claim 1, Hofmann teaches that a liquid drug-containing formulation comprising hypoxia-inducible factor prolyl hydroxylase inhibitor and at least one natural oil of herbal origin (claim 1). Thus, Hofmann discloses a pharmaceutical composition comprising a HIF-PH inhibitor and an oil, as required by claim 1.
With respect to claim 2, Hofmann teaches that the hypoxia-inducible factor prolyl hydroxylase inhibitor is a compound of formula (I) or a salt, stereoisomer, tautomer, or N-oxide thereof (claim 2). Hofmann’s formula (I) corresponds to formula (I) of the instant application.
With respect to claim 3, Hofmann teaches that the compound of Formula I may be in the form of a salt having Formula (II), wherein M is selected from the group consisting of lithium, sodium, potassium, calcium, magnesium, barium, manganese, copper, silver, zinc, iron, ammonium, and substituted ammonium in which one to four of the hydrogen atoms are replaced by C1-C4-alkyl, and preferably M is sodium (claim 3), as required by claim 3.
With respect to claim 4, Hofmann teaches that the HIF-PH inhibitor is in the form of the sodium salt of formula (Ila), and is also known as sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(lH-1,2,3-triazol-1-yl)-1 H-pyrazol-5-olate that is the same as Formula (IIA), which corresponds to Formula (IIA) recited in claim 4 (page 11, lines 3-6).
With respect to claim 5, Hofmann teaches that the HIF-PH inhibitor may comprise a sodium salt, and sodium as a preferred cation for Formula (II) (claim 3).
With respect to claim 6, Hofmann teaches that the compound of Formula (I), which corresponds to molidustat and further discloses the sodium salt of Formula (IIA) (page 10, line 1 - page 11, line 7).
With respect to claim 7, Hofmann discloses molidustat in salt form and discloses sodium as a preferred cation, thereby discoing molidustat sodium (page 10, line 1 - page 11, line 7).
With respect to claims 60 and 61, Hofmann discloses use of the liquid drug containing formulation for treating diseases associated with HIF-PH enzymes, including anemia, chronic kidney disease, renal insufficiency, and in particular anemia associated with chronic kidney disease (page 17, line 34 – page 18, line 4). This disclosure meets the method of treating anemia recited in claim 61 because HIF-PH inhibitors increase endogenous erythropoietin through HIF stabilization; therefore, administration of the disclosed HIF-PH formulation to treat anemia associated with HIF-PH enzyme activity inherently increases erythropoietin as required by claim 60.
With respect to claims 62, and 68-70, Hofmann teaches the liquid drug-containing formulation as defined herein for the control (or management) of secondary, non-regenerative anemia due to chronic kidney disease in animals, preferably in cats and dogs, in particular in cats. (lines 5-8, page 18). Hofmann further teaches the liquid drug-containing formulation as defined herein is administered orally to the animal (lines 26-27, page 18).
Accordingly, Hofmann discloses each and every limitation of claims 1-7, 60-62, and 68-70, either expressly or inherently, and therefore anticipates these claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 1, 8, 9, and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hofmann et al. (WO2021198256 A1, pub’d 10/07/2021), in view of Spence et al. (Increased dissolution rate and bioavailability through comicronization with microcrystalline cellulose, Pharm. Dev. Technol., 10(4), 451-60, pub’d 10/07/2008).
Hofmann teaches a liquid drug containing formulation comprising a HIF-PH inhibitor and an oil, as set forth in the rejection of claims 1-7, 60-62, and 68-70 under 35 USC 102 (a)(1) and (a)(2). Those teaching are incorporated by reference herein. Hofmann further teaches molidustat and molidustat sodium formulation, including liquid formulations containing natural oils of herbal origin, and teaches use of such formulations for treating disease associated with HIF-PH enzyme, including anemia, chronic kidney disease, renal insufficiency, and anemia associated with chronic kidney disease.
With respect to claim 8, the claim recites that the pharmaceutical composition of claim 1,
wherein the composition comprises micronized particles comprising the hypoxia-inducible factor prolyl hydroxylase inhibitor.
Hofmann fails to teach the HIF-PH inhibitor particles are micronized.
However, the pharmaceutical suspension art teaches that particle size is a known results effective variable affecting suspension stability, sedimentation, bioavailability, and dose uniformity. Spence teaches that micronization is a known formulation technique used to improve dissolution rate and bioavailability, particular for compounds whose absorption is dissolution rate limited (abstract).
Therefore, in view of the teaching of Spence, it would have been obvious to reduce the particle size of the HIF-PH inhibitor particles, including by micronization, in the oil containing liquid formulation of Hofmann. Selecting the claimed particle size would have been a matter of routine optimizations of a known result effective variable in order to improve suspension uniformity, reduce sedimentation, improve redispersibility, and maintain consistent dosing during oral administration (MPEP 2144.05).
With respect to claim 9, the claim recites that the micronized particles are characterized by a D90 that is about 70 mm or less, about 60 mm or less, about 50 mm or less, about 40 mm or less, or about 30 mm or less.
Hofmann fails to teach the specific micronized particles are characterized by a D90.
However, as discussed above with respect to claim 8, Spence teaches micronization as a known technique for improving dissolution rate and bioavailability. Once micronization of the HIF-PH inhibitor particle in Hofmann’s oil containing oral formulation would have been obvious selecting a D90 within the claimed range would have been a matter of routine optimization of a known result effective variable. The claimed D90 values represent particle size targets that one of ordinary skill in the art would have reasonably evaluated when preparing an oral pharmaceutical suspension or liquid formulation to obtain predictable advantages in dissolution behavior, oral absorption, formulation performance, and dose consistency. Absent evidence that the claimed D90 values are critical or produce an unexpected results, optimizing particle size to achieve the claimed D90 values would been obvious.
With respect to claim 14, the claim recites that the pharmaceutical composition of claim 1, wherein the hypoxia-inducible factor prolyl hydroxylase inhibitor concentration is from about 1.0% and 20% (m/v).
Hofmann teaches the hypoxia-inducible factor prolyl hydroxylase inhibitor in an amount of from 0.1 to 20 wt%, preferably from 0.5 to 10 wt%, based on the total weight of the liquid drug-containing formulation. (page 17, lines 14-16).
Hofmann does not teach the claimed concentration range in % (m/v)
However, example 1 in the specification discloses a molidustat sodium oily suspension containing 2.50 g of molidustat sodium per 100 mL, i.e., 2.5% (m/v) molidustat sodium concentration corresponds to approximately 2.7 wt% based on the total weight of the formulation. Thus, using the formulation weight reflected in example 1 in the specification, the claimed concentration range of about 1.0% to 20 % (m/v) corresponds to approximately 1.08 wt% to 21.5 wt% based on the total weight of the formulation. This converted concentration range overlaps with the concentration ranges of about 1.0% to 20% taught by Hofmann.
Absent evidence that the claimed concentration range is critical or produces an unexpected result, it would have been prima facie obvious to select a concentration within the overlapping range would have been obvious. (see MPEP 2144.05)
Claim(s) 1, 61, 63, 64, and 71 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hofmann et al. (WO2021198256 A1, pub’d 10/07/2021), in view of Flamme et al. (Mimicking Hypoxia to Treat Anemia: HIF-Stabilizer BAY 85-3934 (Molidustat) Stimulates Erythropoietin Production without Hypertensive Effects, PLoS One, 9(11), e111838, pub’d 11/13/2014), and further in view of Bohlius et al. (Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice Guideline Update, J. Clin. Oncol., 37(15), 1336-1351, pub’d 04/10/2019).
Hofmann teaches a liquid drug containing formulation comprising a HIF-PH inhibitor and an oil, and a method for treating anemia of the composition, as set forth in the rejection of claims 1-7, 60-62, and 68-70 under 35 USC 102 (a)(1) and (a)(2). Those teaching are incorporated by reference herein.
With respect to claim 63, the claim recites that the anemia is iron-deficiency anemia, pernicious anemia, aplastic anemia, hemolytic anemia, chemotherapy-induced anemia (CIA), or immune mediated hemolytic anemia (INIHA).
Combination teachings of Hoffmann and Flamme fail to teach the anemia is iron-deficiency anemia, pernicious anemia, aplastic anemia, hemolytic anemia, chemotherapy-induced anemia (CIA), or immune mediated hemolytic anemia (INIHA).
However, Hofmann teaches treating anemia, including anemia associated with chronic kidney disease, using a liquid molidustat containing HIF-PH inhibitor formulation (page 17, line 34 – page 18, line 4). Flamme also teaches that molidustat stimulates endogenous erythropoietin production after oral administration (discussion). Thus, Hofmann and Flamme collectively teach using orally administered molidustat containing HIF-PH inhibitor formulations to stimulate erythropoietin and treat anemia.
Bohlius teaches the management of cancer associated anemia with erythropoiesis stimulating agents and supports that stimulation of erythropoiesis is a recognized therapeutic approach for chemotherapy associated anemia (abstract and introduction).
One of ordinary skill in the art would have recognized chemotherapy induced anemia as an anemia condition for which erythropoiesis stimulation is therapeutically relevant. Accordingly, at least with respect to chemotherapy induced anemia within the scope of claim 63, it would have been obvious to apply Hoffmann’s molidustat oil formation to treat such anemia in view of Flamme and Bohlius. The motivation would have been to use a known orally activity HIF-PH inhibitor formulation to stimulated endogenous erythropoietin and thereby promote erythropoiesis in an anemia condition where erythropoiesis stimulating therapy was recognized in the art, and it would have been treatment of chemotherapy induced anemia through the known erythropoietin stimulating mechanism of molidustat.
With respect to claim 64, the claim recites that the pharmaceutical composition is administered
once daily.
Hofmann fails to teach the once daily administration.
However, Hofmann identifies the need for daily and long term medication in veterinary medicine and explains that daily administration is difficult in cats and dogs when oral products have undesired flavor (page 2, lines 2-15). Hofmann further teaches improving voluntary acceptance of oral drug intake addresses that problem (page 2, lines 2-15).
Flamme teaches once-daily oral dosing of BAY 85-3934, as corresponding to Formula (I), and reports erythropoietin related pharmacodynamic effect (introduction, and Materials and Methods section).
It would have been obvious to use the molidustat oil formulation once daily where daily long term treatment of anemia associated with CKD is desired, because Hofmann identifies daily long term medication as the formulation problem and teaches oil based formulations to improve acceptance and compliance (Materials and Methods section). In view of Hofmann’s teaching that daily long term medication in cats presents a compliance problem, and Flamme’s teaching that molidustat can be administered orally once daily to stimulate erythropoietin, it would have been obvious to administer Hofmann molidustat oil formulation once daily when daily long term treatment of anemia is desired, to improve an orally acceptable formulation suitable for daily long term anemia therapy while maintaining the known erythropoietin stimulating activity of molidustat.
With respect to claim 71, the claim recites that the composition is administered at sufficient dose to provide a maximum plasma concentration (Cmax) of the hypoxia-inducible factor prolyl hydroxy lase inhibitor of about 0.5 mg/L or greater, about 1 mg/L or greater, 1.5 mg/1 or greater, 2 mg/L or greater, 2.5 mg/L or greater, 3 mg/Lor greater, or from about 0.5 mg/L to about 5 mg/L.
Hofmann fails to teach the maximum plasma concentration (Cmax) of the hypoxia-inducible factor prolyl hydroxy lase inhibitor.
However, the claimed Cmax values are pharmacokinetic results obtained by selecting dose and formulation condition for a known orally administered active. Flamme reports rapid absorption of orally administered Bay 85-3934 and discusses plasma Cmax, Half-life, oral bioavailability, EPO mRNA expression, and plasma EPO after oral administration (Induction of EPO and erythropoiesis in male Wistar rats section).
It would have been obvious to optimize the dose of the Hofmann’s molidustat formulation to obtain therapeutically effective plasma exposure, including a Cmax within the claimed range, because plasma exposure is a routine result effective variable in oral drug development. Absent evidence that the claimed Cmax is critical or produces an unexpected results, selecting a dose to achieve the recited Cmax values would have been routine pharmacokinetic optimization.
Conclusion
Claims 9, and 14 are objected to.
Claims 1-9, 14, 60-64, and 68-71 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEONG JONG KIM whose telephone number is (571)272-6918. The examiner can normally be reached 7:00am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at 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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/SEONG JONG KIM/ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621
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