DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Previously pending claims 5, 9, 13, 16, 18, 21, 26, 30, 31, 33, 36, 38, 40, and 42-48 are cancelled. Upon entry of the instant amendment, filed on 28 January 2025, claims 1-4, 6-8, 10-12, 14, 15, 17, 19, 20, 22-25, 27, 29, 32, 34, 35, 37, 39, and 41 are pending
Priority
This application, filed 7 August 2024, is a National Stage entry from International Application No. PCT/US2023/012935, filed 13 February 2023, which claims priority under 35 U.S.C. 119 or 365 to the benefit of the US Provisional Application Nos. 63/311,905 and 63/312,650, filed on 18 February 2022 and 22 February 2022. The certified copy of the foreign application has been received.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 20 October 2025 has been acknowledged and considered.
Claim Rejections - 35 USC § 112(a)
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.
Claim 41 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, does not reasonably provide enablement for a method of treating, preventing, or ameliorating one or more fatty liver diseases in a subject in need thereof comprising administering to said subject the oral dosage form comprising Compound 1 also defined as VK2809 in the instant Abstract. 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.
MPEP § 2164.01(a) explains how enablement for the claimed invention can be analyzed:
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” . . . These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The Wands factors are analyzed with respect to the claimed invention in turn below.
The breadth of the claim is broad in scope. The claim recites: “A method of preventing, treating, or ameliorating one or more fatty liver diseases in a subject in need thereof comprising administering to said subject in need thereof, the method comprising administering the oral dosage forms of claim 1 to said subject.” This method of treatment extends to all possible fatty liver diseases with a vast population of subjects. The Specification states: “TRβ agonists may be useful as therapeutics for conditions such as hepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), and a variety of fibrotic disease and disorder.” (Spec. ¶[0005]). The claim therefore encompasses a method of treating, preventing, or ameliorating one or more fatty liver diseases in a subject after administration of an oral dosage form of a TRβ agonist.
The nature of the invention generally relates to the pharmaceutical art and more specifically to a method of administering an oral dosage form comprising VK2809 to treat, prevent, or ameliorate one or more fatty liver diseases in a subject. The instant specification states: “Compound l is a low solubility, lipophilic prodrug compound in development for the treatment of chronic liver diseases including non-alcoholic fatty liver disease (NAFLD). The current clinical dosage form is an encapsulated PEG-based formulation that provides adequate exposure but requires cold chain storage due to chemical stability challenges. Provided herein are immediate release tablet formulations that comprise solid amorphous spray dried dispersions (SDD) of Compound 1 that matches or exceeds the exposure provided by the current formulation, with improved stability such that room temperature storage can be utilized.” (Spec. p.6). Thus, the nature of the invention is to administering a specific dosage form of VK2809 to treat a broad group of diseases, and is thus sophisticated.
The state of the art is discussed in an article from the Mayo Clinic, “Lifestyle changes — including diet and weight loss — are the main ways to prevent and manage metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called nonalcoholic fatty liver disease (NAFLD).” (Mayo Foundation for Medical Education and Research. (n.d.). Fatty liver disease (MASLD) diet. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/fatty-liver-disease-masld/in-depth/fatty-liver-disease-masld-diet/art-20588469).
With respect to prevention of a fatty liver disease, like steatohepatitis, a review article discusses the state of the art with agonists of THRβ. “It has been showed that thyroid dysfunctions, particularly hypothyroidism, are associated with insulin resistance and dyslipidemia and with cardiovascular mortality. Furthermore, hypothyroidism has been recently shown as an independent risk factor for NAFLD. For these reasons, THRβ agonists, particularly MGL-3196 and VK-2809, are still under investigation.” VK2809 is currently in clinical trials for treating NAFLD (NCT02927184) and non-alcoholic steatohepatitis (NASH) (NCT04173065). However, prevention of a fatty liver disease through administration of a THRβ agonist is not disclosed. In contrast, administration of IVA337, a pan-PPAR agonist, in animals, showed positive effects on improvement of insulin resistance, prevention of steatohepatitis, decrease of steatosis, etc. (Pennisi et al., Int. J. Environ. Res. Public Health 2019, 16, 4334, pp. 7-9).
Alcoholic liver diseases include alcoholic fatty liver disease, alcoholic hepatitis, cirrhosis, etc., with treatments including abstinence, surgery, and pharmacological therapy (Tae Suk et al., World J Gastroenterol 2014 September 28; 20(36): 12934-12944, p. 12934, Abstract). Therapies for alcoholic hepatitis are shown in Table 1, which include abstinence, ablation of TNF- α, reduction of ischemic damage etc. There are no reports of VK2809 indicated for treating alcoholic fatty liver disease.
The state of the art indicates prevention of fatty liver disease is achieved mainly through lifestyle changes including diet and weight loss. Where drug therapy is utilized for prevention, pan-PPAR agonists have shown prevention of steatohepatitis in animal models, whereas no conclusion has been made with THRβ agonists. Furthermore, one or more fatty liver diseases includes alcoholic fatty liver disease, and no disclosure in the prior art or the instant specification evidences its treatment.
The level of one of ordinary skill may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of the factors may not be present in every case, and one or more of them may predominate. Ent. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the pharmaceutical art and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
The level of predictability in the art is generally unpredictable. The relevant art requires each potential drug candidate to be assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18, 24 (CCPA 1970). The more unpredictable an area is the more specific disclosure is necessary to satisfy the statutory requirement. MPEP § 2164.02(II) explains that a correlation between the claimed invention and the evidence provided in an application, along with a correlation between the evidence and the models recognized in the art, are required:
“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.” In this regard, the issue of “correlation” is also dependent on the state of the prior art. In other words, if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. In re Brane, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995) (reversing a USPTO decision based on finding that in vitro data did not support in vivo applications).
Further, treatments may be effective for some subjects and ineffective for other subjects. Thus, each candidate for pharmaceutical or veterinary medicine must be evaluated on its own even when a nexus to an existing drug or class of drugs has been established.
The amount of direction provided by the inventor includes background information about VK2809 as discussed in factor (B). The specification does not provide any detailed guidance regarding the administration of the oral dosage form claimed in subjects having the genus of one or more fatty liver diseases.
The existence of working examples is not present for a method of treating, preventing, or ameliorating one or more fatty liver diseases in a subject after administration of the oral dosage form.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure is extensive, as it includes in vitro and in vivo screening for each specific disease or disorder encompassed by the claims. As claimed, the indefinite scope of such diseases is essentially unbound.
Enablement Conclusion
In view of the Wands factors discussed above, the disclosure of the instant application does not reasonably enable a person having ordinary skill in the art to use the full scope of the claimed invention. The breadth of the claims is broad in scope; the nature of the invention is sophisticated; the state of the prior art indicates, where drug therapy is utilized for prevention, pan-PPAR agonists have shown prevention of steatohepatitis in animal models, whereas no conclusion has been made with THRβ agonists like VK2809, and one or more fatty liver diseases includes alcoholic fatty liver disease, and no disclosure in the prior art or the instant specification evidences its treatment by VK2809; the level of skill in the art is high; the pharmaceutical art is unpredictable; there is no direction provided by the inventor for a method of treatment by administration of the oral dosage form claimed; and does not demonstrate possession of a method of treating, preventing, or ameliorating one or more fatty liver disease by administration of an oral dosage form to a subject; and the quantify of experimentation needed to practice the claimed invention is extensive. Thus, when the evidence is considered as a whole, undue experimentation would be required to practice the full scope of the claimed invention.
Examiner recommends cancelling claim 41.
Claim Rejections - 35 USC § 112(b)
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.
Claim 39 is 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 39 recites:
“A method of preparing an oral dosage of Claim 1 comprising the steps of:
(a) preparing a pregranulation pre-blend comprising (a) a composition comprising Compound 1 and the one or more polymers; (ii) a ductile filler; (iii) a -brittle filler; (iv) a disintegrant; and (v) a glidant;
(b) blending the pre-blend composition;
(c) further adding lubricant to the pregranulation pre-blend;
(d) slugging the pre granulation pre-blend; and
(e) granulating the pregranulation pre-blend to form granulated material.”
The “pre-blend composition” is initially introduced in step (b), and it is unclear if the pregranulation pre-blend from step (a) or a different pre-blend composition is the one being blended in step (b) because the terms are not identical. Also, because in steps (c), (d), and (e) refer to steps of modifying the pregranulation pre-blend (and not the pre-blend composition), it is unclear whether those steps occur prior to step (b).
Appropriate correction is required.
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 1-2, 4, 8, 15, 17, 24, 27, 29, 32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2021190624 (“Wu”).
Regarding claims 1-2, 4, 15, 17, 24, 27, 29, 32 Wu teaches a formulation composition comprising Compound I (p. 2, lines 5-12, CAS No. 852948-13-1) (“VK2809”), Copovidone Kollidon VA64 (i.e., pyrrolidinone-vinyl acetate copolymer (p. 7, lines 8-21)), mannitol (34.4%), sodium stearyl fumarate (0.8%), and colloidal silicon dioxide (0.3%) (Example 1, Table 1, Formulation Number E1). The API and excipients were evenly added by manual feeding or weightlessness automatic feeder feeding and adjusted within 30 minutes to control the retention time of the material in a hot melt extruder barrel (p.19, step 4, lines11-20). The formulation composition is taught to be orally administered (p. 15, lines 10-11; pp. 17-18, lines 31-32, line 1).
Regarding claims 8, Wu teaches another formulation composition comprising of VK2809 (5.4%), Copovidone Kollidon VA64, mannitol (32%). sodium stearyl fumurate (0.5%), and colloidal silicon dioxide (0.5%) (Comparative Example 2, Table 4, Formulation Number c2).
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.
Claims 1-4, 6-8, 10-12, 14, 15, 17, 19, 20, 22-25, 27, 29, 32, 34, 35, 37, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Wu in view of WO2020092100 (“Lindemann”) evidenced by Merck Sharp & Dohme Corp. (2021). Welireg (belzutifan) tablets. Full prescribing information (NDA 215383). U.S. Food and Drug Administration. (“’383”).
Wu teaches Compound 1 (VK2809) is a lipophilic insoluble drug and thus provides a soluble and stable formulation of VK2809 for the method of treating steatohepatitis. Examples of the formulation composition include VK2809, Copovidone Kollidon VA64 (i.e., pyrrolidinone-vinyl acetate copolymer (p. 7, lines 8-21)), mannitol (34.4%), sodium stearyl fumarate (0.8%), and colloidal silicon dioxide (0.3%) (Example 1, Table 1, Formulation Number E1). VK2809 and excipients were added by manual feeding or weightlessness automatic feeder feeding and adjusted within 30 minutes to control the retention time of the material in a hot melt extruder barrel (p.19, step 4, lines 11-20). Wu teaches another formulation composition comprising VK2809 (5.4%), Copovidone Kollidon VA64, mannitol (32%). sodium stearyl fumurate (0.5%), and colloidal silicon dioxide (0.5%) (Comparative Example 2, Table 4, Formulation Number c2). The formulation composition is taught to be orally administered (p. 15, lines 10-11; pp. 17-18, lines 31-32, line 1).
Wu does not teach a formulation comprising of a ductile filler, like microcrystalline cellulose, a disintegrant, like crospovidone, or the lubricant magnesium stearate. Wu also, does not teach a spray dried dispersion of VK2809 and one or more polymer.
Lindemann teaches compositions with advantageous physical properties, which may provide benefits in processing, formulation, stability, storage, etc. large-scale production compliant with good manufacturing practice (GMP) guidelines (¶ [0038]). Three tablet formulations are described, one of which is in Table 18. The formulation, in the intragranular portion, consists of 32% of a 25:75 mixture of the compound of Formula (I) (“Belzutifan”): hydroxypropyl methyl cellulose acetate succinate type M (HPMCAS-H), microcrystalline cellulose (Avicel PH101, 25%), α-lactose monohydrate (Flo-Lac 90, 25%), 11% crospovidone (Kollidon CL-F, 11%), 0.5% silicon dioxide (Syloid 244FP (¶ [0167], 0.50%), and magnesium stearate (Mg Stearate 2257, 0.50%). The extragranular portion includes crospovidone and magnesium stearate (p. 77, Table 18). Lindemann also teaches a process for preparing formulations comprising: (1) compressing the intragranular formulation consisting of a 25:75 mixture of Belzutifan: HPMCAS-H, microcrystalline cellulose, α-lactose monohydrate, crospovidone, silicon dioxide, and magnesium stearate, (2) milling the slugs through a 30-mesh screen to prepare granules, (3) extragranular excipients consisting of crospovidone and magnesium stearate were added, (4) and the resulting mixture was compressed into tablets.
Lindemann does not teach formulations comprising the compound VK2809.
As evidenced by 383, Belzutifan is insoluble in water or other aqueous buffers (p. 7, Drug Substance).
Wu and Lindemann are analogous art because they are in the same field of preparing formulations to improve stability for storage at room temperature to improve dissolution in vivo and in vitro for insoluble drugs. Therefore, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA), prior to the effective filing date of the claimed invention, to combine the teachings of Wu and Lindemann to arrive at the instantly claimed invention. It would have been prima facie obvious to a PHOSITA to modify the intragranular formulation, comprising of VK2809, pyrrolidinone-vinyl acetate copolymer (polymer), mannitol (brittle filler, 34.4%), sodium stearyl fumarate (lubricant, 0.8%), and colloidal silicon dioxide (glidant, 0.3%), prepared by hot melt extrusion, taught by Wu; to include microcrystalline cellulose (ductile filler), crospovidone (disintegrant), and the lubricant magnesium stearate taught by Lindemann; to improve the stability and improve the dissolution of a formulation comprising VK2809 to treat a fatty liver disease like steatohepatitis. The combined teachings of Wu and Lindemann would have yielded reasonably predictable results because Lindemann discloses that the compositions have advantageous physical properties that provide benefits in stability, bioavailability, and storage, among other important pharmaceutical characteristics (vide supra) (MPEP §2143 (A)). Accordingly, claims 1, 2, 4, 10-11, 15, 17, 19, 20, 24-25, 27, 29, 32, and 41 are prima facie obvious.
Regarding claim 3, Lindemann teaches a spray dried dispersion of compound of Formula (I) and the HPMCAS-H polymer. Specifically, the compound was dissolved in acetone and then charged with the HPMCAS-H polymer, followed by removal of acetone through spray drying (¶ [0299]). It would have been prima facie obvious to substitute the compound of formula (I) taught by Lindemann for VK2809 taught by Wu because both compounds are insoluble in water or buffer (vide supra).
Regarding claims 6-7, Lindemann teaches the composition according to Table 18, consists of Belzutifan and HPMCAS-H in the ratio of 25:75, respectively, but can also be in the range of 15:85 to 35:65. It would have been prima facie obvious to substitute VK2809, as taught by Wu for the Belzutifan in the composition taught by Lindemann because they are both known in the art to be insoluble in water (MPEP §2144.06(II)). The ratios of Belzutifan to the polymer overlap with ranges instantly claimed and would therefore be prima facie obvious to a PHOSITA (MPEP §2144.05(I)).
Regarding claim 8, Wu explicitly teaches Formulation Number A1 comprising 5 mg of VK2809 and 75 mg of Copovidone Plasdone S-630 (i.e., a polyvinyl pyrrolidinone-vinyl acetate copolymer) making up a formulation totaling 280 mg. The combination of VK2809 and Copovidone Plasdone S-630 makes up 5.4% of the oral dosage form and overlaps with the claimed range and is thus prima facie obvious (MPEP §2144.05(I)).
Regarding claim 12, 14, and 19, Lindemann teaches the solid dosage form may comprise a binder, wherein the binder is microcrystalline cellulose in an amount from 20$ to 50% by weight. Lindemann also teaches Flo-Lac 90 (lactose) is present in the formulation shown in Table 18 at 25% by weight. The range of microcrystalline cellulose and the amount of lactose (brittle filler) taught overlaps with ranges instantly claimed and are therefore prima facie obvious (MPEP §2144.05(I)).
Regarding claims 22-23, Lindemann teaches Kollidon CL-F (crospovidone) is present in the amount of 11% by weight of the total formulation. Lindemann teaches that a sufficient amount of disintegrant may be used as to not alter the release of the active ingredient. Further, the amount of disintegrant may vary based on the type of formulation and mode of administration and can be present in about 5% to 15% (¶[0166]). The amounts instantly claimed overlap with the range taught by Lindemann and would have been prima facie obvious to a PHOSITA to arrive at the claimed invention through routine optimization as it is taught to be a result-effective variable (MPEP §2144.05(I-II)).
Regarding claim 34, Lindemann teaches a formulation, wherein in the intragranular portion, consists of a 25:75 mixture of Belzutifan: HPMCAS-H, microcrystalline cellulose, α-lactose monohydrate, crospovidone, silicon dioxide, and magnesium stearate. The extragranular portion consists of crospovidone and magnesium stearate (vide supra). It would have been prima facie obvious to substitute the active pharmaceutical ingredient Belzutifan taught by Lindemann for VK2809 taught by Wu to arrive at the invention instantly claimed. A PHOSITA would have had a reasonable expectation of success in making this substitution because both VK2809 and Belzutifan are insoluble in water, and would therefore lead a skilled artisan to incorporate the teachings of Lindemann improve the solubility of VK2809 (MPEP §2143 (A)).
Regarding claims 35 and 37, Wu teaches formulation E1 was subjected to accelerated investigation at 30°C ± 2 °C and 65% ± 5% relative humidity for 2 months wherein only 0.32% of impurities were detected (p. 34, lines 21-26, Table 14). The temperature of 50°C would have been prima facie obvious for a PHOSITA through routine optimization to arrive at the claimed invention (MPEP §2144.05(II)).
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over Wu in view of Lindemann, further in view of US20120046330 (“Alargova”), evidenced by ‘383.
The teachings of Wu and Lindemann and the evidence provided by ‘383 are discussed above, and incorporated by reference herein.
Regarding claim 39, Wu does not explicitly teach a method of preparing an oral dosage formulation comprising the steps of: (1) blending a pre-blend composition, (2) further adding lubricant to the pregranulation pre-blend, (3) slugging the pregranulation pre-blend, and granulating the pregranulation pre-blend to form granulated material. Lindemann does not explicitly teach the steps of blending a pre-blend composition and blending a lubricant prior to slugging.
Alargova teaches methods of preparing a pharmaceutical composition of Compound 1 (“Vanzacaftor”) which has poor solubility in water (¶ [0203]). The manufacturing procedure described is (1) mixing all intragranular ingredients and the ingredients can be lubricated with a suitable lubricant like magnesium stearate, (2) slugging the of the powder admixture and sized ingredients, (3) slugged blends are milled into granules and sifted to obtain desired sizes, (4) granules can be further lubricated with, for example, magnesium stearate and, (5) compression of granular composition on suitable punches into various pharmaceutical formulations (¶ [0211]).
Wu, Lindemann, and Alargova are all analogous art because they are in the same field of preparing formulations of active pharmaceutical ingredients (APIs), which are poorly soluble in water. Therefore, it would have been prima facie obvious to a PHOSITA to combine the teachings of Wu, Lindemann, and Alargova and arrive at the method instantly claimed. It would have been prima facie obvious to prepare a formulation comprising the VK2809 API, as taught by Wu; with the same ingredients of the intragranular blend and the same process of slugging the intragranular blend then milling to form granules as taught by Lindemann; by first mixing all the intragranular ingredients, including a lubricant, prior to slugging as taught by Alargova. The blending of all intragranular ingredients, prior to slugging, is explicitly taught by Alargova, and would have yielded predictable results to a PHOSITA to mix all intragranular ingredients, including the VK2809 API, with a lubricant, prior to slugging and milling the ingredients to form granules for compression (MPEP §2143 (A)).
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.
(i) Claim 41 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 54-59, and 86-89 of copending Application No. 17/311,014 (“’014”) in view of Wu and Lindemann, evidenced by ‘383.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 54-55 of ’014 recite a method of treating non-alcoholic fatty liver disease in a subject comprising administering to the subject a pharmaceutical composition comprising a compound (VK2809) and a pharmaceutically acceptable excipient in combination with one or more second pharmaceutical agents wherein the second pharmaceutical agent is semaglutide, and not elafibranor.
The claims of ‘014 do not explicitly teach an oral dosage form composition comprising VK2809.
Wu teaches VK2809 is a lipophilic insoluble drug and thus provides a soluble and stable formulation of VK2809 for the method of treating steatohepatitis. Examples of the formulation composition taught consist of VK2809, Copovidone Kollidon VA64 (i.e., pyrrolidinone-vinyl acetate copolymer (p. 7, lines 8-21)), mannitol (34.4%), sodium stearyl fumarate (0.8%), and colloidal silicon dioxide (0.3%) (Example 1, Table 1, Formulation Number E1). The API and excipients were evenly added by manual feeding or weightlessness automatic feeder feeding and adjusted within 30 minutes to control the retention time of the material in a hot melt extruder barrel (p.19, step 4, lines 11-20). Wu teaches another formulation composition comprising of VK2809 (5.4%), Copovidone Kollidon VA64, mannitol (32%). sodium stearyl fumurate (0.5%), and colloidal silicon dioxide (0.5%) (Comparative Example 2, Table 4, Formulation Number c2).
Wu does not teach a formulation comprising of a ductile filler, like microcrystalline cellulose, a disintegrant, like crospovidone, or the lubricant magnesium stearate. Wu also, does not teach a spray dried dispersion of VK2809 and one or more polymer.
Lindemann teaches compositions with advantageous physical properties, like improved bioavailability, which may provide benefits in processing, formulation, stability, storage, etc. in large-scale production compliant with good manufacturing practice (GMP) guidelines (¶ [0038]). Three tablet formulations described, one of which is described in Table 18. The formulation, in the intragranular portion, consists of 32% of a 25:75 mixture of the compound of Formula (I) (“Belzutifan”): hydroxypropyl methyl cellulose acetate succinate type M (HPMCAS-H), microcrystalline cellulose (Avicel PH101, 25%), α-lactose monohydrate (Flo-Lac 90, 25%), 11% crospovidone (Kollidon CL-F, 11%), 0.5% silicon dioxide (Syloid 244FP (¶ [0167], 0.50%), and magnesium stearate (Mg Stearate 2257, 0.50%). The extragranular portion consists of crospovidone and magnesium stearate (p. 77, Table 18). Lindemann also teaches a process for preparing formulations comprising: (1) compressing the intragranular formulation consisting of a 25:75 mixture of Belzutifan: HPMCAS-H, microcrystalline cellulose, α-lactose monohydrate, crospovidone, silicon dioxide, and magnesium stearate, (2) milling the slugs through a 30-mesh screen to prepare granules, (3) extragranular excipients consisting of crospovidone and magnesium stearate were added, (4) and the resulting mixture was compressed into tablets.
Lindemann does not teach formulations comprising the compound VK2809.
As evidenced by 383, Belzutifan is insoluble in water or other aqueous buffers (p. 7, Drug Substance).
It would have been prima facie obvious to a PHOSITA to combine the teachings of ‘014, Wu and Lindermann to arrive at the method instantly claimed. The combined teachings would have led a PHOSITA to (1) administer VK2809 in a pharmaceutical composition, including excipients, to treat a subject with non-alcoholic fatty liver disease, as taught by ‘014, (2) in an oral dosage form with an intragranular formulation, comprising VK2809, an insoluble drug, pyrrolidinone-vinyl acetate copolymer (polymer), mannitol (brittle filler, 34.4%), sodium stearyl fumarate (lubricant, 0.8%), and colloidal silicon dioxide (glidant, 0.3%), prepared by hot melt extrusion, as taught by Wu, and include in the oral dosage form (3) microcrystalline cellulose (ductile filler), crospovidone (disintegrant), and the lubricant magnesium stearate taught by Lindemann. The combined teachings of ‘014, Wu, Lindemann would have yielded reasonably predictable results because a PHOSITA would have been motivated to prepare the formulation instantly claimed to use as a method of treatment to increase bioavailability, and storage, among other important pharmaceutical characteristics as taught by Lindemann (vide supra) (MPEP §2143 (A)).
(ii) Claim 41 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 40-43, 47, 49-51, 53-73 of copending Application No. 16/333,513 (“’513”) in view of Wu and Lindemann, evidenced by ‘383.
This is a provisional nonstatutory double patenting rejection.
Claims 40-43, 47, 49-51, 53-73 of ’513 recite a method of treating non-alcoholic fatty liver disease in a subject comprising administering to the subject a dose of a compound every other day to the subject, wherein said compound is VK2809 and pharmaceutically acceptable salts and prodrugs thereof.
The claims of ‘513 do not teach an oral dosage form comprising VK2809.
The teachings of Wu and Lindemann, and the evidence provided by ‘383 are discussed above, and incorporated by reference herein.
It would have been prima facie obvious to a PHOSITA to combine the teachings of ‘513, Wu and Lindermann to arrive at the method instantly claimed. The combined teachings would have led a PHOSITA to (1) administer VK2809 to treat a subject with non-alcoholic fatty liver disease, as taught by ‘513, (2) in an oral dosage form with an intragranular formulation, comprising VK2809, an insoluble drug, pyrrolidinone-vinyl acetate copolymer (polymer), mannitol (brittle filler, 34.4%), sodium stearyl fumarate (lubricant, 0.8%), and colloidal silicon dioxide (glidant, 0.3%), prepared by hot melt extrusion, as taught by Wu, and include in the oral dosage form (3) microcrystalline cellulose (ductile filler), crospovidone (disintegrant), and the lubricant magnesium stearate taught by Lindemann. The combined teachings of ‘014, Wu, Lindemann would have yielded reasonably predictable results because a PHOSITA would have been motivated to prepare the formulation instantly claimed to use as a method of treatment to increase bioavailability, and storage, among other important pharmaceutical characteristics as taught by Lindemann (vide supra) (MPEP §2143 (A)).
(iii) Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21, and 86-89 US Patent No. 11,707,472 (“’472”) in view of Wu and Lindemann evidenced by ‘383.
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-4, 6-8, 10-12, 14, 15, 17, 19, 20, 22-25, 27, 29, 32, 34, 35, 37, and 41 are obvious over claims 1-21 of ‘472 in view of Wu and Lindemann.
Claims 2, 6, and 7 of ‘472 teach a method of therapeutically treating a subject with one or more conditions selected from non-alcoholic steatohepatitis, alcoholic fatty liver disease, etc., comprising administering to said subject in need thereof at least compound VK2809.
The claims of ‘472 do not teach an oral dosage form comprising VK2809.
The teachings of Wu and Lindemann, and the evidence provided by ‘383 are discussed above, and incorporated by reference herein.
It would have been prima facie obvious to a PHOSITA to combine the teachings of ‘472, Wu and Lindermann to arrive at the method instantly claimed. The combined teachings would have led a PHOSITA to (1) administer VK2809 to treat a subject with alcoholic fatty liver disease, as taught by ‘472, (2) in an oral dosage form with an intragranular formulation, comprising VK2809, an insoluble drug, pyrrolidinone-vinyl acetate copolymer (polymer), mannitol (brittle filler, 34.4%), sodium stearyl fumarate (lubricant, 0.8%), and colloidal silicon dioxide (glidant, 0.3%), prepared by hot melt extrusion, as taught by Wu, and include in the oral dosage form (3) microcrystalline cellulose (ductile filler), crospovidone (disintegrant), and the lubricant magnesium stearate taught by Lindemann. The combined teachings of ‘472, Wu, Lindemann would have yielded reasonably predictable results because a PHOSITA would have been motivated to prepare the formulation instantly claimed to use as a method of treatment to increase bioavailability, and storage, among other important pharmaceutical characteristics as taught by Lindemann (vide supra) (MPEP §2143 (A)).
Conclusion
No claims are allowed.
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/SAHIL CHANDER AGGARWAL/Examiner, Art Unit 1623
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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