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`43060-706 201
`Attorney Docket No.
`First lVarned Inventor Gerold L. Mosher
`Lisinopril Forn1ulations
`Tille
`Electronicaiiv on
`1) 2015
`Commissioner for Patents
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`November 6, 2015
`67024
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`Attorney Docket No. 43060-706.201
`
`UNITED STATES PATENT APPLICATION
`LISINOPRIL FORMULATIONS
`
`Inventors:
`
`Gerold L. Mosher,
`Citizen of the United States of America, Residing at
`12215 Avila Drive
`Kansas City, MO 64145
`David W. Miles,
`Citizen of the United States of America, Residing at
`12309 Wyandotte Street
`Kansas City, MO 64145
`
`Assignee:
`
`Entity:
`
`Silvergate Pharmaceuticals, Inc.
`6251 Greenwood Plaza Blvd., Suite 101
`Greenwood Village, CO 80111
`a Delaware Corporation
`Large business concern
`
`\\Tilson Sonsini Goodrich & Rosati
`
`650 Page Mill Road
`Palo Alto, CA 94304
`(650) 493-9300 (Main)
`(650) 493-6811 (Facsimile)
`Filed Electronically on: November 6, 2015
`
`7933051 l.docx
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`LISINOPRIL FORMULATIONS
`
`BACKGROUND OF THE INVENTION
`[0001] Hypertension, or high blood pressure, is a serious health issue in many countries. According to
`the National Heart Blood and Lung Institute, it is thought that about 1 in 3 adults in the United States
`alone have hypertension. Left unchecked, hypertension is considered a substantial risk factor for
`cardiovascular and other diseases including coronary heart disease, myocardial infarction, congestive
`heart failure, stroke and kidney failure. Hypertension is classified as primary (essential) hypertension or
`secondary hypertension. Primary hypertension has no known cause and may be related to a number of
`environmental, lifestyle and genetic factors such as stress, obesity, smoking, inactivity and sodium intake.
`Secondary hypertension can be caused by drug or surgical interventions or by abnormalities in the renal,
`cardiovascular or endocrine system.
`[0002] A number of antihypertensive drugs are available for treating hypertension. Various therapeutic
`classes of antihypertensive drugs include alpha-adrenergic blockers, beta-adrenergic blockers, calcium-
`channel blockers, hypotensives, mineralcorticoid antagonists, central alpha-agonists, diuretics and rennin-
`angiotensin-aldosterone inhibitors which include angiotensin II receptor antagonists (ARB) and
`angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme (ACE) inhibitors
`inhibit angiotensin-converting enzyme (ACE), a peptydyl dipeptidase that catalyzes angiotension I to
`angiotension II, a potent vasoconstrictor involved in regulating blood pressure.
`[0003] Lisinopril is a drug belonging to the angiotensin-converting enzyme (ACE) inhibitor class of
`medications. Lisinopril IUPAC name is N2-[(1 S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline. Its
`structural formula is as follows:
`
`Lisinopril
`[0004] Lisinopril is currently administered in the form of oral tablets, (e.g., Prinivil®, Zestril®). In
`addition to the treatment of hypertension, lisinopril tablets have been used for the treatment of heart
`failure and acute myocardial infarction.
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`SUMMARY OF THE INVENTION
`[0005] Provided herein are lisinopril oral liquid formulations. In one aspect, the lisinopril oral liquid
`formulation comprises (i) lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) a
`sweetener that is xylitol, (iii) a buffer comprising citric acid (iv) a preservative that is sodium benzoate,
`and (v) water; wherein the pH of the formulation is between about 4 and about 5; and wherein the
`formulation is stable at about 25±5 °C for at least 12 months.
`[0006] In some embodiments, the lisinopril is lisinopril dihydrate. In some embodiments, the formulation
`further comprises a flavoring agent. In some embodiments, the formulation further comprises a second
`sweetener. In some embodiments, the second sweetener is sodium saccharin or sucralose. In some
`embodiments, the pH is about 4.9. In some embodiments, the formulation is stable at about 25±5 °C for at
`least 18 months. In some embodiments, the formulation is stable at about 25±5 °C for at least 24 months.
`In some embodiments, the buffer further comprises sodium citrate.
`[0007] In some embodiments, the amount of lisinopril or a pharmaceutically acceptable salt or solvate
`thereof is about 0.8 to about 1.2 mg/ml. In some embodiments, the amount of xylitol is about 140 to about
`160 mg/ml. In some embodiments, the amount of citric acid in the buffer is about 0.5 to about 1.2 mg/ml.
`In some embodiments, the amount of sodium citrate in the buffer is about 1.2 to about 1. 7 mg/ml. In some
`embodiments, the amount of the sodium benzoate is about 0.5 to about 1.2 mg/ml.
`[0008] In one aspect, the lisinopril oral liquid formulation comprises (i) about 1 mg/ml lisinopril or a
`pharmaceutically acceptable salt or solvate thereof, (ii) about 150 mg/ml of a sweetener that is xylitol,
`(iii) a buffer comprising about 0.86 mg/ml citric acid, (iv) about 0.8 mg/ml of a preservative that is
`sodium benzoate; and (v) water; wherein the pH of the formulation is between about 4 and about 5; and
`wherein the formulation is stable at about 25±5 °C for at least 12 months.
`[0009] In some embodiments, the lisinopril is lisinopril dihydrate. In some embodiments, the formulation
`further comprises a flavoring agent. In some embodiments, the formulation further comprises a second
`sweetener. In some embodiments, the second sweetener is sodium saccharin or sucralose. In some
`embodiments, the pH is about 4.9. In some embodiments, the formulation is stable at about 25±5 °C for at
`least 18 months. In some embodiments, the formulation is stable at about 25±5 °C for at least 24 months.
`In some embodiments, the buffer further comprises sodium citrate. In some embodiments, the buffer
`further comprises about 1.44 mg/ml sodium citrate.
`[0010] In some embodiments, the amount of lisinopril or a pharmaceutically acceptable salt or solvate
`thereof is about 0.5 to about 1 % (w/w of solids). In some embodiments, the amount of xylitol is about 95
`to about 98 % (w/w of solids). In some embodiments, the amount of citric acid in the buffer is about 0.3
`to about 0.7 % (w/w of solids). In some embodiments, the amount of sodium citrate in the buffer is about
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`0.7 to about 1.3 % (w/w of solids). In some embodiments, the amount of sodium benzoate is about 0.4 to
`about 1.2 % (w/w of solids).
`[0011] In another aspect, the lisinopril oral liquid formulation comprises (i) about 0. 7 % (w/w of solids)
`lisinopril or a pharmaceutically acceptable salt or solvate thereof, (ii) about 97.3 % (w/w of solids) of a
`sweetener that is xylitol, (iii) a buffer comprising about 0.01 molar citrate, (iv) about 0.52 % (w/w of
`solids) of a preservative that is sodium benzoate, and (v) water; wherein the pH of the formulation is
`between about 4 and about 5; and wherein the formulation is stable at about 25±5 °C for at least 12
`months.
`[0012] In some embodiments, the lisinopril is lisinopril dihydrate. In some embodiments, the formulation
`further comprises a flavoring agent. In some embodiments, the formulation further comprises a second
`sweetener. In some embodiments, the second sweetener is sodium saccharin or sucralose. In some
`embodiments, the pH is about 4.9. In some embodiments, the formulation is stable at about 25±5 °C for at
`least 18 months. In some embodiments, the formulation is stable at about 25±5 °C for at least 24 months.
`In some embodiments, the buffer comprises citric acid and sodium citrate.
`[0013] In another aspect, the lisinopril oral liquid formulation consists of (i) about 1 mg/ml lisinopril or a
`pharmaceutically acceptable salt or solvate thereof, (ii) about 150 mg/ml of a sweetener that is xylitol,
`(iii) a buffer comprising about 0.86 mg/ml citric acid and about 1.44 mg/ml sodium citrate, (iv) about 0.8
`mg/ml of a preservative that is sodium benzoate, (v) and water; wherein the pH of the formulation is
`between about 4 and about 5 adjusted by sodium hydroxide or hydrochloric acid; and wherein the
`formulation is stable at about 25±5 °C for at least 12 months. In some embodiments, the formulation is
`stable at about 25±5 °C for at least 24 months. In some embodiments, the pH is about 4.9.
`[0014] Also provided herein are methods of treating hypertension comprising administering to a patient
`in need thereof a lisinopril oral liquid formulation described herein. In some embodiments, the
`hype1tension is primary (essential) hypertension. ln some embodiments, the hype1iension is secondary
`hypertension. In some embodiments, the subject with hypertension has blood pressure values greater than
`or equal to 140/90 mmm Hg.
`[0015] Also provided herein are methods of treating prehypertension comprising administering to a
`patient in need thereof a lisinopril oral liquid formulation described herein. In some embodiments, the
`subject with prehype1iension has blood pressure values of about 120-139/80-89 mm Hg.
`[0016] Also provided herein are methods of treating heart failure or acute myocardial infarction
`comprising administering to a patient in need thereof a lisinopril oral liquid formulation described herein.
`!0017] In some embodiments, the subject is an adult. In some embodiments, the subject is elderly. ln
`some embodiments, the subject is a child. Tn some embodiments, the lisinopril oral liquid formulation is
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`administered to the subject in a fasted state. In sorne ernbodiments, the lisinopril oral liquid formulation is
`administered to the subject in a fed state.
`[0018] ln some embodiments, the lisinopril oral liquid fonnulation is further administered in
`combination with an agent selected from the group consisting of diuretics, beta blockers, alpha blockers,
`mixed alpha and beta blockers, calcium channel blockers, angiotensin II receptor antagonists, ACE
`inhibitors, aldosterone antagonists, and alpha-2 agonists.
`[0019] Also provided herein is a process for preparing a stable oral liquid formulation comprising
`lisinopril, xylitol, a buffer, and sodium benzoate, the process which comprises the step of adding about
`0.86 mg/ml anhydrous citric acid, about 1.44 mg/ml anhydrous sodium citrate, about 0.80 mg/ml sodium
`benzoate, about 1.09 mg/ml lisinopril dihydrate, and about 150 mg/ml xylitol to water; adjusting the
`volume to the desired volume by adding more water; and adjusting the pH to 4.9 by adding sodium
`hydroxide or hydrochloric acid.
`
`INCORPORATION BY REFERENCE
`[0020] All publications, patents, and patent applications mentioned in this specification are herein
`incorporated by reference to the same extent as if each individual publication, patent, or patent application
`was specifically and individually indicated to be incorporated by reference.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`[0021] The novel features of the invention are set forth with particularity in the appended claims. A
`better understanding of the features and advantages of the present invention will be obtained by reference
`to the following detailed description that sets forth illustrative embodiments, in which the principles of
`the invention are utilized, and the accompanying drawings of which:
`[0022] FIGURE 1: Degradant formation in lisinopril formulations after 145 hours at 60 °C
`diketopiperazine, D-hydrolysate ).
`[0023] FIGURE 2: Chromatograms showing esterification degradation peaks in formulation 1
`(containing lisinopril, parabens and xylitol) and placebo 1 (containing parabens and xylitol) versus
`formulation 2 (containing lisinopril and paraben but no sugar alcohol) and placebo 2 (containing paraben
`but no sugar alcohol).
`
`DETAILED DESCRIPTION OF THE INVENTION
`[0024] Provided herein are stable lisinopril oral liquid formulations. Also provided herein are stable
`lisinopril powder formulations for reconstitution for oral liquid administration. These lisinopril
`formulations described herein are useful for the treatment of hypertension, prehypertension, heart failure
`as well as acute myocardial infarction. The formulations are advantageous over conventional solid dosage
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`administration of lisinopril ranging from ease of administration, accuracy of dosing, accessibility to
`additional patient populations such as to children and the elderly, and an increased patient compliance to
`medication.
`[0025] It is generally known that certain segments of the population have difficulty ingesting and
`swallowing solid oral dosage forms such as tablets and capsules. As many as a quarter of the total
`population has this difficulty. Often, this leads to non-compliance with the recommended medical therapy
`with the solid dosage forms, thereby resulting in rending the therapy ineffective. Further, solid dosage
`forms are not recommended for children or elderly due to increased risk in choking.
`[0026] Furthermore, the dose of lisinopril to be given to children is calculated according to the child's
`weight. When the calculated dose is something other than the amount present in one or more intact solid
`dosage forms, the solid dosage form must be divided to provide the correct dose. This leads to inaccurate
`dosing when solid dosages forms, such as tablets, are compounded to prepare other formulations for
`children.
`[0027] For lisinopril, the current solution to overcoming the use of the tablet form is for a compounding
`pharmacist to pulverize and crush the lisinopril tablet(s) into a powder via mortar and pestle and
`reconstitute the powder in some liquid form. However forming a lisinopril oral liquid in this fashion has
`significant drawbacks including large variability in the actual dosage, incomplete solubilizing of the
`lisinopril tablet in the liquid, rapid instability, inconsistent formulation methods per compounding
`pharmacy, and a number of other potential issues. The crushed tablet liquid formulation may also be
`potentially unsafe due to contamination with residual drugs and other substances from the mortar and
`pestle or other crushing agent.
`[0028] The present embodiments provide a safe and effective oral administration of lisinopril for the
`treatment of hypertension and other disorders. In particular, the embodiments provide stable lisinopril oral
`liquid formulations as well as lisinopril powder formulations for reconstitution for oral liquid
`administration.
`[0029] As used herein, "lisinopril" refers to lisinopril base, its salt, or solvate or derivative or isomer or
`polymorph thereof. Suitable compounds include the free base, the organic and inorganic salts, isomers,
`isomer salts, solvates, polymorphs, complexes etc. U.S. 4,374,829, U.S. 4,472,380, and CA 1,275,350
`disclose exemplary methods in the preparation of lisinopril. In some embodiments, the lisinopril used in
`the formulations described herein is a lisinopril salt. In some instances, the lisinopril used in the
`formulations described herein is a lisinopril hydrate. In some instances, the lisinopril used in the
`formulations described herein is lisinopril monohydrate. In some instances, the lisinopril used in the
`formulations described herein is lisinopril dihydrate.
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`[0030] Other ACE inhibitors are contemplated in the formulations within and include but are not limited
`to quinapril, indolapril, ramipril, perindopril, benazepril, imidapril, zofenopril, trandolapril, fosinopril,
`captopril, and their salts, solvates, derivatives, polymorphs, complexes, thereof.
`
`Lisinopril Oral Liquid Formulations
`[0031] Oral liquids include, but are not limited to, solutions (both aqueous and nonaqueous),
`suspensions, emulsions, syrups, slurries, juices, elixirs, dispersions, and the like. It is envisioned that
`solution/suspensions are also included where certain components described herein are in a solution while
`other components are in a suspension.
`[0032] In one aspect, the lisinopril oral liquid formulation described herein comprise lisinopril, a
`preservative, a sweetening agent, a buffer, and water. In one embodiment, the sweetening agent is xylitol.
`In some embodiments, the sweetening agent is sucralose. In some embodiments, the sweetener is
`saccharin. In another embodiment, the preservative is sodium benzoate. In yet another embodiment, the
`preservative is one or more paraben preservatives. In yet another embodiment, the buffer comprises citric
`acid. In yet another embodiment, the buffer comprises citric acid and sodium citrate. In yet another
`embodiment, the buffer comprises phosphoric acid or salts thereof. In one aspect, the lisinopril oral liquid
`formulation described herein comprises lisinopril, xylitol, sodium citrate, citric acid, sodium benzoate,
`and water. In some embodiments, the lisinopril oral liquid formulation herein further comprises a
`flavoring agent.
`[0033] In some embodiments, lisinopril is present in about 0.8 mg/ml to about 1.2 mg/ml in the oral
`liquid formulation. In other embodiments, lisinopril is present in about 0.8 mg/ml, 0.81 mg/ml, about 0.82
`mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml,
`about 0.88 mg/ml, about 0.89 mg/ml, about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93
`mg/ml, about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml, about 0.98 mg/ml,
`about 0.99 mg/ml, about 1 mg/ml, about 1.01 mg/ml, about 1.02, mg/ml, about 1.03 mg/ml, about 1.04
`mg/ml, about 1.05 mg/ml, about 1.06 mg/ml, about 1.07 mg/ml, about 1.08 mg/ml, about 1.09 mg/ml,
`about 1.1 mg/ml, about 1.11 mg/ml, about 1.12, mg/ml, about 1.13 mg/ml, about 1.14 mg/ml, about 1.15
`mg/ml, about 1.16 mg/ml, about 1.1 7 mg/ml, about 1.18 mg/ml, about 1.19 mg/ml, or about 1.2 mg/ml in
`the liquid oral formulation. In some embodiments, lisinopril is present in about 1 mg/ml in the oral liquid
`formulation.
`[0034] In some embodiments, lisinopril is present in about 0.5% w/w to about 5 % w/w of the solids in
`the oral liquid formulation. In other embodiments, Lisinopril is present in about 0.5 % w/w, about 0.55 %
`w/w, about 0.6 % w/w, about 0.65 % w/w, about 0.7 % w/w, about 0.75 % w/w, about 0.8 % w/w, about
`0.85 % w/w, about 0.9 % w/w, about 0.95 % w/w, about 1 % w/w, about 1.1 % w/w, about 1.2 % w/w,
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`about 1.3 % w/w, about 1.4 % w/w, about 1.5 % w/w, about 1.6 % w/w, about 1. 7 % w/w, about 1.8 %
`w/w, about 1.9 % w/w, about 2 % w/w, about 2.1 % w/w, about 2.2 % w/w, about 2.3 % w/w, about 2.4
`% w/w, about 2.5 % w/w, about 2.6 % w/w, about 2. 7 % w/w, about 2.8 % w/w, about 2.9 % w/w, about
`3 % w/w, about 3.1 % w/w, about 3.2 % w/w, about 3.3 % w/w, about 3.4 % w/w, about 3.5 % w/w,
`about 3.6 % w/w, about 3.7 % w/w, about 3.8 % w/w, about 3.9 % w/w, about 4 % w/w, about 4.1 %
`w/w, about 4.2 % w/w, about 4.3 % w/w, about 4.4 % w/w, about 4.5 % w/w, about 4.6 % w/w, about 4.7
`% w/w, about 4.8 % w/w, about 4.9 % w/w, or about 5 % w/w of the solids in the oral liquid formulation.
`In some embodiments, lisinopril is present in about 0.5 % w/w to about 1 % w/w of the solids in the oral
`liquid formulation. In some embodiments, lisinopril is present in about 0.6 % w/w to about 0.8 % w/w of
`the solids in the oral liquid formulation. In some embodiments, lisinopril is present in about 0.7% w/w of
`the solids in the oral liquid formulation.
`[0035] In some embodiments, lisinopril is present in about 10% w/w to about 25 % w/w of the solids in
`the oral liquid formulation. In other embodiments, lisinopril is present in about 10 % w/w, about 10.5 %
`w/w, about 11 % w/w, about 11.5 % w/w, about 12 % w/w, about 12.5 % w/w, about 13 % w/w, about
`13.5 % w/w, about 14 % w/w, about 14.5 % w/w, about 15 % w/w, about 15.5 % w/w, about 16 % w/w,
`about 16.5 % w/w, about 17 % w/w, about 17.5 % w/w, about 18 % w/w, about 18.5 % w/w, about 19 %
`w/w, about 19.5 % w/w, about 20 % w/w, about 20.5% w/w, about 21% w/w, about 21.5% w/w, about
`22% w/w, about 22.5% w/w, about 23% w/w, about 23.5% w/w, about 24% w/w, about 24.5% w/w, or
`about 25% w/w of the solids in the oral liquid formulation. In some embodiments, lisinopril is present in
`about 14% w/w to about 16% w/w of the solids in the oral liquid formulation. In some embodiments,
`lisinopril is present in about 17% w/w to about 19% w/w of the solids in the oral liquid formulation. In
`some embodiments, lisinopril is present in about 20% w/w to about 22% w/w of the solids in the oral
`liquid formulation.
`Sweetener in the Lisinopril Oral Liquid Formulations
`[0036] Sweeteners or sweetening agents include any compounds that provide a sweet taste. This includes
`natural and synthetic sugars, natural and artificial sweeteners, natural extracts and any material that
`initiates a sweet sensation in a subject. In some embodiments, a solid/powder sweetener is used in the oral
`liquid formulation described herein. In other embodiments, a liquid sweetener is used in the oral liquid
`formulation described herein.
`[0037] Sugars illustratively include glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitol,
`isomaltulose, Isomalt ™ (hydrogenated isomaltulose ), lactitol, sorbitol, erythritol, trehalose, maltodextrin,
`polydextrose, and the like. Other sweeteners illustratively include glycerin, inulin, erythritol, maltol,
`acesulfame and salts thereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodium cyclamate,
`saccharin and salts thereof, e.g., saccharin sodium or saccharin calcium, neohesperidin dihydrochalcone,
`
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`stevioside, thaumatin, and the like. Sweeteners can be used in the form of crude or refined products such
`as hydrogenated starch hydrolysates, maltitol syrup, high fructose com syrup, etc., and as branded
`products, e.g., Sweet Am™ liquid (Product Code 918.003-propylene glycol, ethyl alcohol, and
`proprietary artificial flavor combination, Flavors of North America) and Sweet Am™ powder (Product
`Code 918.005--maltodextrin, sorbitol, and fructose combination and Product Code 918.010--water,
`propylene glycol, sorbitol, fructose, and proprietary natural and artificial flavor combination, Flavors of
`North America), ProSweet™ (1-10% proprietary plant/vegetable extract and 90-99% dextrose
`combination, Viriginia Dare), Maltisweet™ (maltitol solution, Ingredion), Sorbo TM (sorbitol and
`sorbitol/xylitol solution, SPI Polyols), Invertose™ (high fructose com syrup, Ingredion), Rebalance M60
`and X60 (sucralose and maltodextrin, Tate and Lyle), and Ora-Sweet® sugar-free flavored syrup
`(Paddock Laboratories, Inc.). Sweeteners can be used singly or in combinations of two or more. Suitable
`concentrations of different sweeteners can be selected based on published information, manufacturers'
`data sheets and by routine testing.
`[0038] In some embodiments, the lisinopril oral liquid formulation described herein comprises a
`sweetening agent. In some embodiments, the sweetening agent is sucralose. In some embodiments, the
`sweetening agent is xylitol. In some embodiments, the sweetener is saccharin.
`[0039] In some embodiments, the sweetening agent is xylitol. In some embodiments, xylitol is present in
`about 140 mg/ml to about 160 mg/ml in the oral liquid formulation. In other embodiments, xylitol is
`present in about 140 mg/ml, about 141 mg/ml, about, 142 mg/ml, about 143 mg/ml, about 144 mg/ml,
`about 145 mg/ml, about 146 mg/ml, about 147 mg/ml, about 148 mg/ml, about 149 mg/ml, about 150
`mg/ml, about 151 mg/ml, about 152 mg/ml, about 153 mg/ml, about 154 mg/ml, about 155 mg/ml, about
`156 mg/ml, about 157 mg/ml, about 158 mg/ml, about 159 mg/ml, or about 160 mg/ml in the oral liquid
`formulation. In some embodiments, xylitol is present in about 150 mg/ml in the oral liquid formulation.
`[0040] In some embodiments, xylitol is present in about 80 % w/w to about 99 % w/w of the solids in the
`oral liquid formulation. In other embodiments, xylitol is present in about 80 % w/w, about 81 % w/w,
`about 82 % w/w, about 83 % w/w, about 84 % w/w, about 85 % w/w, about 86 % w/w, about 87 % w/w,
`about 88 % w/w, about 89 % w/w, about 90 % w/w, about 91 % w/w, about 92 % w/w, about 93% w/w,
`about 94 % w/w, about 95 % w/w, about 96 % w/w, about 97 % w/w, about 98 % w/w, about 99 % w/w
`of the solids in the oral liquid formulation. In some embodiments, xylitol is present in about 96 % w/w to
`about 98 % w/w of the solids in the oral liquid formulation. In some embodiments, xylitol is present in
`about 97 % w/w of the solids in the oral liquid formulation.
`[0041] In some embodiments, the sweetening agent is sucralose. In some embodiments, sucralose is
`present in about 0.5 mg/ml to about 3 mg/ml in the oral liquid formulation. In other embodiments,
`sucralose is present in about 0.5 mg/ml, about 0.6 mg/ml, about 0.7 mg/ml, about 0.8 mg/ml, about 0.9
`
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`mg/ml, about 1 mg/ml, about 1.1 mg/ml, about, 1.2 mg/ml, about 1.3 mg/ml, about 1.4 mg/ml, about 1.5
`mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8 mg/ml, about 1.9 mg/ml, about 2 mg/ml, about 2.1
`mg/ml, about 2.2 mg/ml, about 2.3 mg/ml, about 2.4 mg/ml, about 2.5 mg/ml, about 2.6 mg/ml, about 2. 7
`mg/ml, about 2.8 mg/ml, about 2.9 mg/ml, or about 3 mg/ml in the oral liquid formulation. In some
`embodiments, sucralose is present in about 2 mg/ml in the oral liquid formulation. In some embodiments,
`sucralose is present in about 0. 7 mg/mL in the oral liquid formulation.
`[0042] In some embodiments, sucralose is present in about 10 % w/w to about 40 % w/w of the solids in
`the oral liquid formulation. In other embodiments, sucralose is present in about 10 % w/w, about 10.5 %
`w/w, about 11 % w/w, about 11.5 % w/w, about 12 % w/w, about 12.5 % w/w, about 13 % w/w, about
`13.5 % w/w, about 14 % w/w, about 14.5 % w/w, about 15 % w/w, about 15.5 % w/w, about 16 % w/w,
`about 16.5 % w/w, about 17 % w/w, about 17.5 % w/w, about 18% w/w, about 18.5 % w/w, about 19 %
`w/w, about 19.5 % w/w, about 20 % w/w, about 20.5 % w/w, about 21 % w/w, about 21.5 % w/w, about
`22 % w/w, about 22.5 % w/w, about 23 % w/w, about 23.5 % w/w, about 24 % w/w, about 24.5 % w/w,
`about 25 % w/w, about 25.5 % w/w, about 26 % w/w, about 26.5 % w/w, about 27 % w/w, about 27.5 %
`w/w, about 28 % w/w, about 28.5 % w/w, about 29 % w/w, about 29.5 % w/w, about 30 % w/w, about
`30.5 % w/w, about 31 % w/w, about 31.5 % w/w, about 32 % w/w, about 32.5 % w/w, about 33 % w/w,
`about 33.5 % w/w, about 34 % w/w, about 34.5 % w/w, about 35 % w/w, about 35.5 % w/w, about 36 %
`w/w, about 36.5 % w/w, about 37 % w/w, about 37.5 % w/w, about 38 % w/w, about 38.5 % w/w, about
`39 % w/w, about 39.5 % w/w, or about 40 % w/w of the solids in the oral liquid formulation. In some
`embodiments, sucralose is present in about 34 % w/w to about 35 % w/w of the solids in the oral liquid
`formulation. In some embodiments, sucralose is present in about 28 % w/w to about 30 % w/w of the
`solids in the oral liquid formulation. In some embodiments, sucralose is present in about 12% w/w to
`about 15% w/w of the solids in the oral liquid formulation.
`[0043] In some embodiments, the sweetening agent is saccharin. In some embodiments, saccharin is
`present in about 1 mg/ml to about 3 mg/ml in the oral liquid formulation. In other embodiments, saccharin
`is present in about 1 mg/ml, about 1.1 mg/ml, about, 1.2 mg/ml, about