DETAILED ACTION
Status of the Claims
Claims 33-37, 39-41, 43 and 44 are pending in the instant application and are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The U.S. effective filing date has been determined to be 05/26/2017, the filing date of the US Provisional Application No. 62/511,889.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 33-37, 39-41, 43 and 44 remain rejected under 35 U.S.C. 103 as being unpatentable over FORD (WO 2017/023165 A1; published 09-FEB-2017) in view of STARIC (US 2013/0338131; published December, 2013); TOELGYESI (US 2012/0164227; published June, 2012); INJAC (US 2011/0262497; published October, 2011); KAKUDA (US 2012/0010221; published January, 2012); WEN (US 2013/0190354; published July, 2012); ROWE (“Handbook of Pharmaceutical Excipients, 6th ed.,”2009, Pharmaceutical Press, pp. 129-133, 185-188 and 317-324); VALAZZA (US 2011/0165240; published 2011); TECKOE (US 2015/0202160; published July, 2015); Srinvastava et al. (“Fluid Bed Technology: Overview and Parameters for Process Selection,” 2010; International Journal of Pharmaceutical Sciences and Drug Research, Vol. 2, No. 4, pp. 236-246); and Thompson et al. 1(“Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance,” 2016, National Lipid Association, Journal of Clinical Lipidology, Vol. 10, pp. 556-567).
Applicants Claims
Applicant claims a process of manufacturing a monolayer tablet comprising Ezetimibe granules and Bempedoic acid granules, the process comprising: (i) granulating a composition comprising Bempedoic acid with a first binder solution to obtain the Bempedoic acid granules; (ii) preparing a second binder solution comprising Ezetimibe and an anionic surfactant, wherein the anionic surfactant is sodium lauryl sulfate; homogenizing the second binder solution to form a uniform dispersion; top spray granulating the uniform dispersion with one or more pharmaceutically acceptable excipients to obtain the Ezetimibe granules; (iii) blending the Ezetimibe granules and Bempedoic acid granules together to obtain a granulated mixture; and (iv) compressing the granulated mixture into the monolayer tablet (instant claim 33).
Determination of the scope
and content of the prior art (MPEP 2141.01)
FORD teaches a pharmaceutical composition and a therapeutic combination comprising a novel cholesteryl ester transfer protein (CETP) inhibitor and an adenosine triphosphate citrate lyase (ACL) inhibitor/ adenosine monophosphate-activated protein kinase (AMPK) activator, which may be used in the treatment of subjects suffering from or having an increased risk for cardiovascular diseases, in particular hyperlipidemia or mixed dyslipidemia (see whole document).
FORD teaches “An intensively studied representative investigational ACL inhibitor / AMPK activator drug compound is the small molecule ETC-1002, or bempedoic acid, previously known as compound "ESP-55016" of Esperion Therapeutics. ETC-1002 is currently under development in the clinic for the treatment of dyslipidemia and coronary artery disease, and other cardiometabolic risk factors. ETC-1002 is in development primarily for patients with hypercholesterolemia and a history of statin intolerance.” [emphasis added](p. 2, last paragraph).
FORD teaches that: “ETC-1002 is analyzed in Phase II clinical trials either as a mono-therapy, or in a combination therapy approach together with ezetimibe in statin-intolerant patients.” (p. 3, lines 3-4). FORD teaches that: “Compound A is preferably used in combination with the ACL inhibitor / AMPK activator ETC- 1002 (also referred to as bempedoic acid) […].” (p. 10, lines 15-20). And “Hence, in one embodiment of the invention, the pharmaceutical composition according to the present invention comprises about 1 to 25 mg Compound A and about 20 to 240 mg, preferably about 60 to 180 mg of the at least one ACL inhibitor / AMPK activator, e.g. ETC-1002, and further comprises about 1 to 30 mg of a cholesterol absorption inhibitor, e.g. ezetimibe, preferably about 10 mg ezetimibe.” [emphasis added](paragraph bridging pp. 13-14)(instant claims 40 & 44, amount of Bempedoic acid and Ezetimibe).
FORD teaches that “The pharmaceutical composition according to the present invention comprises besides Compound A and the at least one ACL inhibitor / AMPK activators also a pharmaceutically acceptable excipient, i.e. a pharmaceutically acceptable ingredient, which is commonly used in the pharmaceutical technology for preparing granulate, solid or liquid oral dosage formulations.” (paragraph bridging pp. 12-13). FORD teaches the further embodiment that includes a statin drug (p. 13, lines 13-19).
FORD teaches that: “The different pharmaceutically active ingredients may be present in said combinations as granulates. Preferably, the pharmaceutical composition is an oral fixed dose combination, such a combination is very convenient for patients and avoids problems with administering the correct amounts of these compounds.” [emphasis added](p. 11, lines 15-18). And that “The oral fixed dose combination or oral free dose combination is preferably formulated as a solid dosage form, such as a tablet or capsule.” (p. 11, lines 24-25).
FORD teaches that: “Examples of categories of excipients include, but are not limited to, binders, disintegrants, lubricants, glidants, fillers and diluents. One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the granulate and/or solid oral dosage form by routine experimentation and without any undue burden. The amount of each excipient used may vary within ranges conventional in the art. The following references which are all hereby incorporated by reference disclose techniques and excipients used to formulate oral dosage forms.” (p. 13, lines 3-9).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of FORD is that FORD does not expressly teach the specific steps of granulation of bempedoic acid or ezetimibe, and particularly for the Ezetimibe granulating by including the API with binder solution which is homogenized and top spray granulating, or the granules included in a monolayer table. FORD does not expressly teach including a granulation solution that includes silicon dioxide and low substituted hydroxypropyl cellulose (HPC-L)(instant claim 41).
Thompson et al. teaches bempedoic acid (ETC-1002) as a monotherapy and as a combination therapy with ezetimibe (EZE) (see whole document). Thompson et al. teaches that the objective of their study was to compare two doses of ETC-1002, alone or combined with EZE 10 mg vs. EZE monotherapy for lowering low-density lipoprotein cholesterol (LDL-C) (abstract: objectives). Thompson et al. teaches that their study included doses of ETC-1002 of 120 mg or 180 mg daily including the combination with 10 mg EZE (p. 559, Figure 1 and accompanying text). Thompson et al. teaches that “ETC-1002 alone or in combination with EZE reduced LDL-C from baseline to 12 weeks more than EZE monotherapy (Table 2). LDL-C reduction was greatest with the combination of ETC-1002 120 mg(43%) or 180 mg (48%) plus EZE [... ]. The combined treatment effect of ETC-1002 plus EZE was approximately equal to the sum of their individual effects on LDL-C.” (p. 559, col. 2, first paragraph).
Thompson et al. teaches that “ETC-1002 120 mg and ETC-1002-180 mg were well tolerated both alone and in combination with EZE 10 mg daily, and safety profiles were similar across all treatment groups.” [emphasis added] (p.565, col. 1, 4'" paragraph) (instant claims 40 & 44 amount of Bempedoic acid + Ezetimibe). Thompson et al. further teaches that “There is a need for alternative oral treatment strategies for hypercholesterolemic patients who cannot sufficiently reduce their LDL-C with available agents, including patients with intolerance of statins.” And that the results of their study indicate that a ETC-1002 alone or in combination with EZE is suggested for such patients (p. 565, col. 2, last paragraph).
STARIC teaches a process for the preparation of a pharmaceutical composition comprising a low soluble pharmaceutically active ingredient (API)(see whole document, title, abstract).
STARIC teaches that their process includes the steps of: “a) providing a suspension comprising API particles and one or more excipients, b) subjecting the suspension provided by step a) to a high energy input treatment, so that essentially no agglomerates are present in the suspension, c) further processing the suspension by high shear granulation, fluid bed granulation, spray drying or lyophilisation.” [emphasis added]([0011]). And further that: “(2) The process according to item (1), wherein the high energy input treatment is selected from rotor-stator mixing, ultrasound treatment, ball milling, and high energy mixing. Furthermore, high pressure homogenizer such as EmulsiFlex C3 at 300-1500 bar can be used.” [emphasis added]([0012]). And further: “(3) The process according to item (1) or (2), wherein after step (c) a further step (d) of formulating the pharmaceutical composition into a dosage form is carried out.” ([0013]).
STARIC further teaches that: “(11) Process according to any of the preceding items wherein step (a) comprises the step of: a1) providing a solution containing one or more excipients as defined in any of items (8) to (10), a2) suspending the API as defined in item (7) in the solution of step a1), a3) homogenizing the resulting suspension.” [emphasis added]([0022]). And further that: “(13) Process according to any of the preceding items, wherein in step ( c) the suspension resulting from step (b) is spray dried by spraying the suspension onto a carrier, thereby obtaining the pharmaceutical composition, preferably the suspension is sprayed onto the carrier in a fluidized bed process.” ([0024]).
STARIC teaches that: “(17) Process according to any of the preceding items, wherein during step (a), preferably during steps (a) and (b), only one API, preferably ezetimibe, is used.” ([0029]).
STARIC teaches forming tablets ([0034]), including coating the tablets ([0035]), “The coating may comprise components that are conventionally used for coating dosage purposes; preferably, said components are selected from the group consisting of polymers including cellulose derivatives (e.g. hypromellose), povidone, polyvinylalcohol [(PVA)], polyethylene glycol and insoluble compounds including titanium dioxide, pigments, lakes and talc. Preferably, the coating comprises hypromellose, polyethylene glycol, talc and suitable pigments.” ([0036])(instant claims 35-37).
STARIC teaches that: “Surprisingly and distinct from conventional methods, the process according to the present invention allows obtaining improved dissolution performance of poorly soluble API while starting the process with appropriate primary particle sizes thereof, even if the initial particle size of the primary API particle that is used may be very small, […].” (p. 4, col. 1, lines 2-7). And that: “Unexpectedly, the method according to claim 1, i.e. the provision of a suspension comprising poorly soluble API and one or more excipients, and subjecting said suspension to a high energy input treatment, followed by further processing said suspension as indicated herein provides for enhanced pharmaceutical compositions and dosage forms, respectively, e.g. exhibiting satisfying, enhanced dissolution profiles of the API.” ([0053]), and including Ezetimibe ([0058]).
STARIC teaches that: “The pharmaceutical composition prepared in step (c) can then be formulated into a dosage form in a further step (d). Step (d) can e.g. comprise a drying step, a step of mixing the pharmaceutical composition comprising the carrier with the API with further excipients and then formulating the mixture preferably into a solid dosage form, including tablets, capsules (soft or hard capsules), caplets, lozenges, and sachets, preferably the dosage form is a tablet.” ([0095])(instant claim 34).
STARIC teaches the manufacturing procedure including: “Ezetimibe and simvastatin were suspended in a solution of hypromellose in water and a part of lactose and mixed with a propeller mixer to prepare a homogenous suspension. Resulting suspension was sprayed onto microcrystalline cellulose, remaining lactose and croscarmellose sodium in a fluid bed apparatus. The resulting granulate was mixed with magnesium stearate and compressed into tablets.” ([0114])(instant claims 33, 39, 43). STARIC teaches a formulation including Ezetimibe, lactose, microcrystalline cellulose, sodium lauryl sulfate, among others ([0125]) including the manufacturing procedure: “Ezetimibe was suspended in a solution of hypromellose and lactose in water and mixed with a high energy rotor stator mixer (e.g. Ultra Turrax). The resulting suspension was further milled with a ball mill and sprayed onto the remaining part of the lactose. Sodium lauryl sulfate was dissolved in water and sprayed onto circulation powders in a fluid bed apparatus after the ezetimibe suspension. The resulting granulate was mixed with microcrystalline cellulose and magnesium stearate and compressed into tablets.” ([0126])(instant claims 33: “an anionic surfactant” 39, 42: “the anionic surfactant is sodium lauryl sulfate”; 43). STARIC does not expressly teach “preparing a binder solution comprising Ezetimibe and sodium lauryl sulfate,” however this limitation is clearly taught by TOELGYESI.
TOELGYESI teaches “The present invention relates to a process for manufacturing microcrystalline ezetimibe containing granulate, wherein a) ezetimibe is dissolved; b) the dissolved ezetimibe is precipitated with water, which if necessary contains pharmaceutical excipients, preferably lauryl-sulfate derivatives, and c) granulates are formed from the obtained suspension by spraying the suspension onto pharmaceutical excipients. A further aspect of the present invention is the granulate obtained by the present process and the pharmaceutical composition containing such granulate.” (Abstract, see whole document). TOELGYESI teaches that: “As surface active ingredients, e.g. the following can be used: sodium-lauryl-sulfate” ([0042]). TOELGYESI teaches “Known excipients for pressing into one or more layer tablets can be various tablet excipients, such as fillers, disintegrants, binders, surface active agents, lubricants, antiadhesive agents, glidants, colors, stabilizers e.g. pH controllers, antioxidants, chelators etc.” ([0067]). And further teaches: “Preparation: Ezetimibe is dissolved in 96 m/m%, 30-40° C. ethanol, povidon and sodium-lauryl sulfate are dissolved in water. The two solutions are admixed within 30-60 seconds under intensive mechanical stirring and if necessary the precipitated suspension is filtered on a sieve with 0.4-0.6 mm aperture size. The suspension is continuously stirred until further processing.” ([0081] & [0083])(instant claim 33: “preparing a binder solution comprising Ezetimibe and an anionic surfactant, the anionic surfactant is sodium lauryl sulfate”).
INJAC teaches novel Ezetimibe formulations (see whole document), particularly Ezetimibe combined with at least two types of excipients ([0008]) granulated in admixture ([0009]) “to provide improved ezetimibe formulations with a view of a good balance between free-flowing, cohesive powder and compression characteristics combined with yielding formulations of ezetimibe, and finally pharmaceutical formulations containing the same, enabling good chemical and physical stability of ezetimibe as well as good dissolution properties and acceptable levels of hardness when formulated in single unit dosage forms like tablets.” ([0014]).
INJAC teaches that: “The ezetimibe substance is low water-soluble, low permeable, incompatible with most of the excipients usually used in drug formulation, presents stability problems, and is not inherently compressible. Consequently, there is a need to provide a free-flowing and cohesive ezetimibe composition capable of being formulated into dosage forms, especially when formulated at low strengths such as e.g. 10 mg doses or even only 5 mg doses of ezetimibe per unit dosage form, with an acceptable dissolution profile.” ([0016]). However, “Despite of such constraints, it has been surprisingly found according to the invention that formulations of ezetimibe can be provided in a more robust and economical way and can display a good balance of properties including chemical and physical stability, free-flowing characteristics and compressibility as well as acceptable degrees of hardness and particularly acceptable to good dissolution profiles, when attention is paid, alternatively or optionally in combination, to (i) the existence of ezetimibe in the form of primary particles, which when merely blended, without co-milling, with a suitable hydrophilic excipient in particulate form are allowed, at a satisfactory percentage of primary particle status, to be adsorbed on the surface of particles of the hydrophilic excipient; (ii) a selection of specific types of excipients; and/or (iii) a careful control of how the formulation of ezetimibe is obtained. The aforementioned beneficial effects are more enhanced, if two or all of the afore-mentioned features (i), (ii) and (iii) are observed in combination.” ([0017]).
INJAC teaches the hydrophilic excipients include a saccharide, including mono or di-saccharides, and polysaccharides such as starch and microcrystalline cellulose ([0021]), a binder such as polyvinylpyrrolidone ([0022]). INJAC teaches forming a solid solution including ezetimibe using in “a fluid bed top spray granulation procedure.” [emphasis added]([0030]-[0032]). INJAC particularly teaches that: “The fluid bed granulation process involves suspending particulates in an air stream and spraying a liquid from the top down onto the fluidized bed. Particles in the path of the spray get slightly wetted and become tacky. The tacky particles collide with other particles and adhere to them to form a granule. […] Fluid granulation is commonly used to develop porosity and effective surface area, which consequently gives higher solubility of active principle.” ([0045]).
KAKUDA teaches a tablet and granulated powder containing 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (see whole document), and particularly teaches that the advantages of their invention include: “The granulated powder of the present invention is a granulated powder containing (1) the compound A or a salt thereof, (2) a low substituted hydroxypropyl cellulose or croscarmellose sodium and (3) a binder, wherein the amount of the compound A or a salt thereof contained therein is 50 to 95% of the mass of the granulated powder.” ([0024]). KAKUDA teaches that: “It is preferred that silicon dioxide is added to the tablet and to the granulated powder of the present invention.” ([0041]), and that: “The amount of the silicon dioxide contained therein is 0.5 to 15%, preferably 2 to 10% or, more preferably 3 to 5% of the mass of the tablet or the granulated powder.” ([0043]). KAKUDA teaches wet granulation including fluidized bed granulation method, and tableting the granules ([0062] through [0065]). KADUKA teaches that: “Examples of the method for adding the binder during the granulation include (1) a method in which a binder dissolved in water is sprayed onto a mixed powder comprising the compound A or a salt thereof, a disintegrating agent, etc. and (2) a method in which water is sprayed onto a mixture of the compound A or a salt thereof, a disintegrating agent and a binder.” ([0066]). And further that: “Examples of addition of silicon dioxide include (1) a method in which powdery silicon dioxide is added to a mixed powder comprising the compound A or a salt thereof, a disintegrating agent, etc. and (2) a method in which silicon dioxide and a binder are dispersed in water and then sprayed onto a mixed powder. The method (2) is a preferred adding method since the compressive molding property and the dissolution property upon making into tablets are improved therein as compared with the method (1).” [emphasis added]([0067])(instant claims 21 and 33, a binder solution comprising colloidal silicon dioxide).
Srinvastava et al. teaches fluid bed technology including process selection among top-spray, bottom-spray, and tangential-spray patterns (see whole document). Srinvastava et al. teaches that: “Top-spraying is the most well known process for wet granulation, and it has been used in various industries for more than 30 years.” (p. 237, col. 1, §Top Spray Fluid Bed Process). And that: “Generally, granules prepared by the top-spray method are porous and have a loose structure. They disperse well in water and have lower bulk densities compared with granules prepared by high-shear granulation.” (p. 237, col. 2, lines 29-32). And further that: “Although the top-spray fluid-bed process is widely used for granulation, its use for coating is limited. Top-spraying is the simplest process and offers the highest capacity and lowest capital cost (Fig. 2).” (p. 239, col. 1, lines 1-4).
Srinvastava et al. further suggest that the process parameters for uncoated granules are most favorable for use of the top spray fluid bed process (p. 245, § CRITERIA FOR PROCESS SELECTION; and particularly Table 1).
KADUKA teaches Example 17 including: “Povidone K 30 ([…]) (430 g) was added to and dissolved in 8,170 g of pure water. Further, 430 g of silicon dioxide ([…]) was added thereto and dispersed therein to give a binder solution.” [emphasis added]([0110]).
WEN teaches pharmaceutical compositions including a DGAT 1 inhibitor for treatment of obesity (see whole document, particularly the title, abstract and [0002]). WEN teaches their formulations include fixed dose combinations for treating a condition or disorder associated with DGAT 1 activity including a metabolic disorder such as obesity and hypercholesterolemia, among others ([0074]-[0076]).
WEN teaches that the compounds of formula I (i.e. a DGATl inhibitor), and in particular the sodium salts ([0002], Formula II) are difficult to formulate due to its physicochemical properties, as the compounds are hygroscopic and sticky in nature and exhibit poor flow characteristics ([0004 ]). WEN teaches that the inclusion of specific excipients enables the preparation of pharmaceutical compositions, in particular in the form of compressed tablets, overcoming the drawbacks identified above ([0009]). And in particular WEN teaches the inclusion of glidants such as colloidal silicon dioxide (e.g. Aerosil® 200) in an amount ranging from 0.05 to 5% ([0044]). WEN further teaches the glidant (Aerosil® 200) is included in the intragranular portion (internal) as well as the extragranular portion (external) ([0090]). Thus, it would have been prima facie obvious to include a glidant such as Aerosil® 200 in the intragranular and extragranular portion of a formulation including a hygroscopic sticky active agent, such as Bempedoic acid (see instant specification, p. 1, [0003])(instant claims 27 & 38).
Regrading the use of HPC-L as a binder, ROWE teaches that Low-substituted hydroxypropyl cellulose is widely used in oral solid-dosage forms. It is primarily used as a disintegrant, and as a binder for tablets and granules in wet or dry granulation. […] LH-21 is less fibrous and is used as a binder and disintegrant for tablets through the wet-granulation process.” (p. 322, item 7). Thus, it would have been prima facie obvious to substitute (or use in combination) the povidone binder solution suggested by STARIC, INJAC and/or KADUKA for HPC-L, as suggested by ROWE with the expectation that it would function as binder in the wet granulation processes therein (instant claims 21 and 33, HPC-L in binder solution).
ROWE teaches that “Microcrystalline cellulose is widely used in pharmaceuticals, primarily as a binder/diluent in oral tablet and capsule formulations where it is used in both wet-granulation and direct-compression processes.” (p. 130, item 7). WEN also teaches microcrystalline cellulose and HPC-L as suitable dry binders ([0030]). Thus, it would have been prima facie obvious to utilize microcrystalline cellulose and/or HPC-L as a dry binder with a Bempedoic acid wet granulation process (instant claims 22-23).
Regarding the Bempedoic acid granules being present in an amount of at least 50% and no more than 95%, WEN teaches a sticky active agent included in an amount of about 50% ([0041])(instant claim 32).
VALAZZA teaches Galenical formulations of organic compounds (see whole document) including oral fixed dose combinations in a monolayer tablet ([0016], [0019]), including granulation of the two drugs, “(6) mixing respective granulates; (7) screening the material from step (6); (8) optionally, blending the obtained sieved material from (7) together with further pharmaceutically acceptable additives; (9) compressing the blend from (8) to form a monolayer tablet and (10) optionally, film coating the obtained monolayer tablet.” ([0055])(instant claims 33-35).
TECKOE teaches an immediate release film coating compositions for use on oral dosage forms such as compressed tablets (see whole document), including improved properties ([0005] through [0009]). TECKOE teaches their film coating includes: “The dry film coating composition was prepared by adding all dry ingredients (PVA, talc, sodium lauryl sulfate and titanium dioxide) into a laboratory blender and blending for 5 minutes until a homogenous mixture was produced. Glycerol monocaprylocaprate, the only liquid component, was then gradually added to the dry mixture, and the total mixture was blended for an additional 2 minutes after all liquid was introduced.” [emphasis added]([0039] & claims)(instant claims 35-37).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a granulation process for production of ezetimibe granules and bempedoic acid granules and formulating the two in a monolayer tablet, as suggested by FORD et al., the process of granulating the ezetimibe including homogenization of the API with mixed with a binder solution and said granulation process being a top-spray-granulation because ezetimibe is a low solubility drug (BCS Class II) and the top-spray-granulation process results higher porosity which consequently gives improved dissolution, as suggested by INJAC ([0045]) and Srinvastava et al., the granules including known excipients based on function in conventional amounts (“One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the granulate and/or solid oral dosage form by routine experimentation and without any undue burden. The amount of each excipient used may vary within ranges conventional in the art.”), and specifically to include colloidal silicon dioxide in the binder solution as suggested by KADUKA, as a conventional binder solution, and to include suitable conventionally known binders as suggested by WEN and ROWE; and further to produce a fixed dose formulation by combining granules of the different drugs in a monolayer tablet, as suggested by VALAZZA, in order to produce a fixed dose film coated tablet formulation using the improved tablet film coating taught by TECKOE; and to include a wetting agent/surface active agent such as sodium lauryl sulfate in a Ezetimibe granulation process as suggested by TOELGYESI.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because, as suggested by FORD: “One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the granulate and/or solid oral dosage form by routine experimentation and without any undue burden” (p. 13, lines 3-9). Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 08/27/2025 have been fully considered but they are not persuasive.
Applicant argues that: “Ford does not provide any specific guidance regarding formulation of said compositions, or of the granulates that may comprise said compositions. Moreover, there is no disclosure in Ford of a specific formulation employing the use of two binder solutions as in instant claim 33 nor the specific process of preparing the instantly claimed monolayer tablet.” (p. 6, 1st paragraph).
FORD teaches that: “The different pharmaceutically active ingredients may be present in said combinations as granulates. Preferably, the pharmaceutical composition is an oral fixed dose combination, such a combination is very convenient for patients and avoids problems with administering the correct amounts of these compounds.” [emphasis added](p. 11, lines 15-18). And that “The oral fixed dose combination or oral free dose combination is preferably formulated as a solid dosage form, such as a tablet or capsule.” (p. 11, lines 24-25). And further that: “Examples of categories of excipients include, but are not limited to, binders, disintegrants, lubricants, glidants, fillers and diluents. One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the granulate and/or solid oral dosage form by routine experimentation and without any undue burden. The amount of each excipient used may vary within ranges conventional in the art. The following references which are all hereby incorporated by reference disclose techniques and excipients used to formulate oral dosage forms.” (p. 13, lines 3-9).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant further that: “Staric teaches providing a solution containing one or more excipients selected from hydrophilic excipients and polymers (preferably cellulose derivatives), suspending API in the solution, homogenizing the resulting suspension, and spray drying the suspension onto a carrier, and Ezetimibe is the preferred APL However, Staric fails to teach or suggest suspending Ezetimibe with sodium lauryl sulfate in the binder solution, as required by amended claim 33. To the extent the formulations of Staric include an anionic surfactant, the anionic surfactant appears to be added to the formulations separately and is not dispersed with the Ezetimibe in the binder solution (see Example 7 of Staric).” And further that: “Applicant submits that Staric fails to teach the formulation of a monolayer tablet comprising two APIs, Bempedoic acid and Ezetimibe, and sodium lauryl sulfate.” (p. 7, paragraphs 1-2).
In response the examiner argues that it would have been prima facie obvious to include a wetting agent such as sodium lauryl sulfate in a wet-granulation process (STARIC - “A further advantage of the process according to the present invention is that it allows the use of wet granulation. Wet granulation may be a preferred method in pharmaceutical industry, as it provides for better prospects in terms of ease of processing, especially with respect to the required flow and cohesive properties.” - [0049]). TOELGYESI teaches that: “As surface active ingredients, e.g. the following can be used: sodium-lauryl-sulfate” ([0042]). TOELGYESI teaches “Known excipients for pressing into one or more layer tablets can be various tablet excipients, such as fillers, disintegrants, binders, surface active agents, lubricants, antiadhesive agents, glidants, colors, stabilizers e.g. pH controllers, antioxidants, chelators etc.” ([0067]). And further teaches: “Preparation: Ezetimibe is dissolved in 96 m/m%, 30-40° C. ethanol, povidon and sodium-lauryl sulfate are dissolved in water. The two solutions are admixed within 30-60 seconds under intensive mechanical stirring and if necessary the precipitated suspension is filtered on a sieve with 0.4-0.6 mm aperture size. The suspension is continuously stirred until further processing.” ([0081] & [0083])(instant claim 33: “preparing a binder solution comprising Ezetimibe and an anionic surfactant, the anionic surfactant is sodium lauryl sulfate”). FORD teaching “One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the granulate and/or solid oral dosage form by routine experimentation and without any undue burden.” (p. 13, lines 3-9).
Applicant argues that: “Toelgyesi teaches a method of manufacturing microcrystalline ezetimibe that employs ezetimibe as a granulate, and Toelgyesi's process for preparing the ezetimibe granules uses an aliphatic alcohol. However, Applicant submits that similar to Staric, Toelgyesi fails to teach a method of preparing a monolayer tablet comprising Bempedoic acid and Ezetimibe.” (p. 7, 3rd paragraph). Applicant argues that: “Injac teaches Ezetimibe formulations with desirable dissolution properties. The formulation processes described in Injac involve blending Ezetimibe with hydrophilic excipients, thereby allowing the hydrophilic excipients to adsorb onto the surface of the Ezetimibe particles, followed by fluid bed granulation to produce Ezetimibe granules. The processes described in Injac do not utilize a binder solution to suspend the Ezetimibe, much less a binder solution comprising sodium lauryl sulfate, as required by amended claim 33.” (p. 7, 4th paragraph). Applicant argues that: “The Office alleges that Thompson teaches the use of ETC-1002 (Bempedoic acid) as a monotherapy and as a combination therapy with Ezetimibe. Nonetheless, Thompson fails to disclose any method of preparing a monolayer tablet that comprises Bempedoic acid and Ezetimibe.” (p. 7, last paragraph). Applicant argues that: “Kakuda teaches the formulation of a completely different API, 6-flouro-3-hydroxy-2-pyrazinecarboximide. However, Kakuda is completely silent on a formulation method for preparing a monolayer tablet comprising Ezetimibe and Bempedoic acid.” (p. 8, 1st paragraph). Applicant agues that: “Wen, Rowe, Valazza, Teckoe, and Srinvastava each fail to teach formulations of Ezetimibe, granulated or otherwise, much less processes for granulating Ezetimibe that include dispersion of Ezetimibe in a binder solution with sodium lauryl sulfate, as required by amended claim 33.” (p. 8, 2nd paragraph).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant further argues that: “combining Ford with Staric, Toelgyesi, Injac, Kakuda, Wen, Rowe, Valazza, Teckoe, and/or Thompson does not lead to the instantly claimed process, which requires homogenization of Ezetimibe in a binder solution comprising sodium lauryl sulfate to directly form a uniform dispersion.” (p. 8, 3rd paragraph). And that: “Moreover, Applicant submits that the modifications to the combined teachings of the cited references necessary to arrive at the presently claimed invention would have been nonobvious to a person of ordinary skill in the art. As described in paragraph [00217] of the instant application, including sodium lauryl sulfate in the binder solution was critical for achieving optimal contact between the Ezetimibe and the surfactant and improving dissolution. Applicant notes that various techniques that were well-known in the art to improve dissolution failed to achieve optimal Ezetimibe dissolution in the Bempedoic acid/Ezetimibe monolayer tablets of the instant application, as described in the instant application, and that the specific steps involving incorporation of sodium lauryl sulfate, which the cited references fail to teach or suggest, were critical for achieving optimal dissolution.” (p. 8, 4th paragraph).
In response the examiner maintains that it would have been prima facie obvious to include a wetting agent such as sodium lauryl sulfate in a wet-granulation process (STARIC - “A further advantage of the process according to the present invention is that it allows the use of wet granulation. Wet granulation may be a preferred method in pharmaceutical industry, as it provides for better prospects in terms of ease of processing, especially with respect to the required flow and cohesive properties.” - [0049]). TOELGYESI teaches that: “As surface active ingredients, e.g. the following can be used: sodium-lauryl-sulfate” ([0042]). TOELGYESI teaches “Known excipients for pressing into one or more layer tablets can be various tablet excipients, such as fillers, disintegrants, binders, surface active agents, lubricants, antiadhesive agents, glidants, colors, stabilizers e.g. pH controllers, antioxidants, chelators etc.” ([0067]). And further teaches: “Preparation: Ezetimibe is dissolved in 96 m/m%, 30-40° C. ethanol, povidon and sodium-lauryl sulfate are dissolved in water. The two solutions are admixed within 30-60 seconds under intensive mechanical stirring and if necessary the precipitated suspension is filtered on a sieve with 0.4-0.6 mm aperture size. The suspension is continuously stirred until further processing.” ([0081] & [0083])(instant claim 33: “preparing a binder solution comprising Ezetimibe and an anionic surfactant, the anionic surfactant is sodium lauryl sulfate”). FORD teaching “One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the granulate and/or solid oral dosage form by routine experimentation and without any undue burden.” (p. 13, lines 3-9).
Conclusion
Claims 33-37, 39-41, 43 and 44 are pending and have been examined on the merits. Claims 33-37, 39-41, 43 and 44 are rejected under 35 U.S.C. 103. No claims allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IVAN A GREENE whose telephone number is (571)270-5868. The examiner can normally be reached on M-F, 8-5 PM PST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David J. Blanchard can be reached at (571) 272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
1 Cited on IDS dated 12/27/2019, NPL citation No. C145.