AU2007200901B2 - Use of derivatives of valproic acid and 2-valproenic acid amides for the treatment of mania in bipolar disorder - Google Patents

Use of derivatives of valproic acid and 2-valproenic acid amides for the treatment of mania in bipolar disorder Download PDF

Info

Publication number
AU2007200901B2
AU2007200901B2 AU2007200901A AU2007200901A AU2007200901B2 AU 2007200901 B2 AU2007200901 B2 AU 2007200901B2 AU 2007200901 A AU2007200901 A AU 2007200901A AU 2007200901 A AU2007200901 A AU 2007200901A AU 2007200901 B2 AU2007200901 B2 AU 2007200901B2
Authority
AU
Australia
Prior art keywords
group
compound
bipolar disorder
mania
alkyl group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU2007200901A
Other versions
AU2007200901A1 (en
Inventor
Meir Bialer
Mitchell Shirvan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yissum Research Development Co of Hebrew University of Jerusalem
Original Assignee
Yissum Research Development Co of Hebrew University of Jerusalem
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yissum Research Development Co of Hebrew University of Jerusalem filed Critical Yissum Research Development Co of Hebrew University of Jerusalem
Priority to AU2007200901A priority Critical patent/AU2007200901B2/en
Publication of AU2007200901A1 publication Critical patent/AU2007200901A1/en
Application granted granted Critical
Publication of AU2007200901B2 publication Critical patent/AU2007200901B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Landscapes

  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

P/00/0 Regulation 3.2 AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT (ORIGINAL) Name of Applicant(s): Yissum Research Development Company of the Hebrew University of Jerusalem, 36 Jabotinsky Street; Jerusalem 91042, Israel Actual Inventor(s): Mitchell Shirvan Meir Bialer Address for Service: DAVIES COLLISON CAVE, Patent & Trademark Attorneys, of I Nicholson Street, Melbourne, 3000, Victoria, Australia Ph: 03 9254 2777 Fax: 03 9254 2770 Attorney Code: DM Invention Title: "Use of derivatives of valproic acid and 2-valproenic acid amides for the treatment of mania in bipolar disorder" The following statement is a full description of this invention, including the best method of performing it known to us:- P \OPER\TDO\1,i I h14 dI pgs do.- 1/03/2001 - I USE OF DERIVATIVES OF VALPROIC ACID AND 2-VALPROENIC ACID AMIDES FOR THE TREATMENT OF MANIA IN BIPOLAR DISORDER This application is a divisional application of Australian Application No. 2001280699 the 5 specification and drawings of which as originally filed are incorporated herein in their entirety by reference. This invention is a continuation-in-part and claims the benefit of U. S. Provisional Application No. 60/220,102, filed July 21,2000, the contents of which are hereby 10 incorporated by reference into this application. Throughout this application, various references are referenced by short citations within parenthesis. Full citations for these references may be found at the end of the specification, immediately preceding the claims. These references, in their entireties, are hereby 15 incorporated by reference to more fully describe the state of the art to which this invention pertains. Field of the Invention 20 Disclosed is a method for the treatment of mania in bipolar disorder using derivatives of valproic acid and 2- valproenic acid amides. Background of the Invention 25 Affective disorders refer mainly to changes in mood rather than thought disturbances (Rang, H. P., M. M. Dale and J. M. Ritter). Depression is the most common manifestation, although it also includes mania. In many respects the symptoms of mania are opposite to those of depression. Whereas the symptoms of depression include a feeling of misery, apathy, and low self-esteem, those of mania include excessive exuberance, enthusiasm and 30 self-confidence.
-2 There are two basic types of depressive syndrome: bipolar and unipolar (Rang, H.P., M.M. Dale and J.M. Ritter). Patients with a history of both depression and mania are considered to have a bipolar disorder (BPD). Those 5 patients which suffer from depression are considered to be unipolar. Bipolar disorder is further subdivided into different segments. In bipolar I patients have at least one manic episode with or without depression. In bipolar II patients have at least one hypomanic episode with 10 depression. Patients with BPD have the highest rate of suicide among patients with psychiatric illnesses. Anti-depresants are the standard treatment for unipolar depression, but are not effective for mania. To treat 15 mania in bipolar depression lithium (Li+) has classically been used, and more recently the anti-epileptic drug (AED) valproate has been demonstrated to be effective (Bowden et al.; Calabrese, J.R. et al.) Other AEDs, such as carbamazepine, are also considered to be useful for mania. 20 However phenobarbital, although clearly an effective AED, is not useful as a drug to treat mania (Belmaker, R.H. and Y. Yaroslavsky), or affective disorders. Today, many patients with mania are not controlled by current treatments (Calabresse, J.R. et al.) . Therefore, there is 25 a need for new treatments. In order to discover new drugs in this area, rodent models relevant to the manic phase are used. One commonly used model is the amphetamine-induced hyperactivity model (Lyon, 30 M.). This model focuses on an induced increase in the activity level of the animal (hyperactivity) as a parallel -3 to the hyperactivity of the manic patient. The reversal of the induced hyperactivity in rodents, by pretreatment with a drug indicates the possible efficacy of this drug in the treatment of human mania. The most consistent finding 5 with Li* (the standard drug for mania) in untreated animals, is the reduction in rearing (Johnson, F.N.). Rearing is followed in the models by observing the vertical activity of the animals. 10 Bialer et al. describe a series of derivatives of valproic acid amides and 2 -valproenic acid for the effective treatment of epilepsy and other neurological disorders (U.S. Patent No. 5,585,358).
VV %.1 UZ111 fxp i I PCT/USO1/23116 -4 Summary of the Invention It has been surprisingly observed that the valproic acid amide of Bialer et al. (U.S. Patent No. 5,585,358), 5 Compound 1 below, decreases amphetamine-induced hyperactivity. The subject invention provides a method for the treatment of mania in bipolar disorder using derivatives of valproic acid amides and 2-valproenic acid amides. 10 The subject invention provides a method of treating mania in bipolar disorders in a subject. The invention comprises the administration of a therapeutically effective amount of a derivative of a valproic acid amide or a 2-valproenic 15 acid aide having one of the following structures: O R, 0 20 I N (CH 2 )n NR 2
R
3 or 25 0 R0 N
(CH
2 )n
NR
2
R
3 30 -5 wherein R2, R 2 , and R 3 are independently the same or different and are hydrogen, a CI-C 6 alkyl group, an aralkyl group, or an aryl group, and n is an integer which is greater than or equal to 0 and less than or 5 equal to 3, or a compound containing a valproic or a 2 -valproenic moiety, as well as pharmaceutical compositions comprising these derivatives or compounds. 10 Detailed Description of the Invention Disclosed is a method of treating bipolar disorder in a subject comprising administering to the subject a therapeutically effective amount of a derivative of a 15 valproic acid amide or a 2 -valproenic acid amide having one of the following structures: O RI 0 20 I(CH
NR
2
R
3 or 25 O R, 0 II (CH.)n
NR
2
R
3 30 -6 wherein R 1 , R 2 , and R, are independently the same or different and are hydrogen, a Ci-C alkyl group, an aralkyl group, or an aryl group, and n is an integer which is greater than or equal to 0 and less than or equal to 3, to 5 thereby treat the bipolar disorder. The derivative may have the structure: 0 10 NH2 N H 0 15 The derivative used in the method may be in the form of a pharmaceutical composition with a pharmaceutically acceptable carrier. The derivative may also be in the form of a pharmaceutically acceptable salt. 20 The bipolar disorder may be mania. The subject may be human. 25 In one embodiment, the invention provides the derivative of formula I hereinabove shown wherein the C,-C. alkyl group is a linear chain alkyl group. In another embodiment, the invention provides the derivative of formula I hereinabove shown wherein the C,-C. alkyl group is a branched chain 30 alkyl group. In yet another embodiment, the invention provides the derivative of formula I hereinabove shown -7 wherein the aralkyl group is a benzyl, alkyibenzyl, hydroxybenzyl, alkoxycarbonylbenzyl, aryloxycarbonylbenzyl, carboxybenzyl, nitrobenzyl, cyanobenzyl, or halobenzyl group. In still another embodiment, the invention provides 5 the derivative of formula I wherein the aryl group is a phenyl, naphthyl, anthracenyl, pyridinyl, indolyl, furanyl, alkylphenyl, hydroxyphenyl, alkoxycarbonylphenyl, aryloxycarbonylphenyl, nitrophenyl, cyanophenyl, halophenyl group, mercaptophenyl, or aminophenyl group. 10 In one embodiment, the invention provides the derivative of formula II hereinabove shown wherein the C 1 -C. alkyl group is a linear chain alkyl group. In another embodiment, the invention provides the derivative of formula II hereinabove 15 shown wherein the C 1 -C, alkyl group is a branched chain alkyl group. In still another embodiment, the invention provides the derivative of formula II hereinabove shown wherein the aralkyl group is a benzyl, alkylbenzyl, hydroxybenzyl, alkoxycarbonylbenzyl, aryloxycarbonylbenzyl, 20 carboxybenzyl, nitrobenzyl, cyanebh-enzyl, or halobenzyl group. In yet another embodiment, the invention provides the derivative of formula II hereinabove shown wherein the aryl group is a phenyl, naphthyl, anthracenyl, pyridinyl, indolyl, furanyl, alkylphenyl, hydroxyphenyl, 25 alkoxycarbonylphenyl, aryloxycarbonylphenyl, nitrophenyl, cyanophenyl, halophenyl group, mercaptophenyl, or aminophenyl group. Some of the derivatives used in this invention possess -8 chiral centers. It is a further embodiment of this invention that these derivatives may comprise substantially pure D or L enantiomers or racemic mixtures. It is to be understood that derivatives of the general formula II may 5 be of the E-(trans) or Z-(cis) geometric configuration, or a mixture thereof. In the practice of the invention, the amount of the derivative incorporated in the pharmaceutical composition 10 may vary widely. Factors considered when determining the precise amount are well known to those skilled in the art. Examples of such factors include, but are not limited to, the subject being treated, the specific pharmaceutical carrier, and route of administration being employed and the 15 frequency with which the composition is to be administered. In one embodiment, the effective amount of derivatives of valproic acid amides and 2-valproenic acid amides 'for the treatment of mania in bipolar disorder comprises an amount 20 from about 10 to about 1,000 mg. The effective amount may also be an amount from about 10 mg to about 500 mg. Additionally, the effective amount may comprise an amount from about 50 mg to about 500. The effective amount may additionally comprise an amount from about 100 mg to about 25 250 mg. Also, the effective amount may comprise an amount from about 150 mg to about 200 mg. In a preferred embodiment, the derivative is administered in a pharmaceutical composition which comprises the -9 derivative and a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" encompasses any of the standard pharmaceutically accepted carriers, such as a phosphate-buffered saline solution, 5 water, emulsions such as an oil/water emulsion or a triglyceride emulsion, various types of wetting agents, tablets, coated tablets, and capsules. An example of an acceptable triglyceride emulsion useful in the intravenous and intraperitoneal administration of the derivatives is 10 the triglyceride emulsion commercially known as Intralipid*. Typically, such carriers contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid, 15 talc, vegetable fats or oils, gums, glycols, or other known excipients. Such carriers may also include flavor and color additives or other ingredients. In the practice of the invention, the administration of the 20 pharmaceutical composition may be effected by any of the well known methods including, but not limited to, rectal, oral, intravenous, intraperitoneal, parenteral, intramuscular, transmdermal, subcutaneous or topical administration. Topical administration can be effected by 25 any method commonly known to those skilled in the art and include, but are not limited to, incorporation of the pharmaceutical composition into creams, ointments, or transdermal patches.
-10 The invention further provides a pharmaceutical composition which comprises any derivative of Formula I or II in a amount which is therapeutically effective to treat mania in bipolar disorder and a pharmaceutically acceptable carrier. 5 The invention encompasses a pharmaceutical composition as hereinabove described wherein the carrier is a solid and the composition is a tablet. The invention also encompasses a pharmaceutical composition as hereinabove described wherein the carrier is a gel and the composition 10 is a suppository. The invention further encompasses a pharmaceutical composition as hereinabove described wherein the carrier is a liquid and the composition is a solution. The following Experimental Details are set forth to aid in 15 an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims which follow thereafter. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
-11 Experimental Details I. Synthesis of Compound 1 0 NH-, 5 Compound 1 N H 0 Compound 1 was prepared as disclosed by Bialer et al. (U.S. Patent 5,585,358). 10 II. Experimental Examples Evaluation of possible anti-bipolar effects of Compound 1 was followed in the amphetamine-induced hyperactivity model of mania in rats. Activities of rats were followed in an 15 activity meter (Elvicom, Israel) based on 2 levels laser beams and equipped with a computerized system that can count the vertical movements of rats (rearing) . Activities were recorded for -30 min for each session, and the resultant appropriate movement reported per 30 min. Rats 20 were housed under a 12 hr light/dark cycle and the behavioral testing was conducted in the light phase. The activities of rats following treatment with Compound 1, Li+ (the standard drug for mania), and a control group were 25 followed before and after being challenged with amphetamine. The statistical analyses were conducted using a two way ANOVA for the effects of drugs, amphetamine -12 (repeated measure) and the drug-amphetamine interaction. In these experiments 30 male Sprague Dawley (weighing 200 250 g) rats were equally divided into 3 treatment groups: 5 control, Li' (6 mg/kg by gavage)), and Compound 1 (200 mg/kg by gavage) (Drugs were suspended in 5% methyl cellulose) . Half of the rats in each group were challenged (administered) amphetamine (0.5 mg/kg subsutaneously (s. c. ) ) and the other half was given saline (s.c.) . Ten 10 minutes later all rats were placed in the activity meter. One week later the procedure was repeated, except that the order of treatment was reversed; those rats which received saline on the first day were given amphetamine and those given amphetamine the first day were administered saline. 15 III. Results The results of the experiment employing Compound 1 are shown in Table 1. Hyperactivity in the rats was induced after the amphetamine challenge, as indicated by the 20 increase in rearing (vertical movements) compared to saline challenged animals in the control group. Treatment with Compound 1 reduced the rearing when animal were challenged with amphetamine compared to control 25 animals challenged with atmnhe t amine (p=0.06) (Table 1). This effect is in a similar direction to that observed with Li'.
-13 Table 1 Activities of rats on Compound 1 or Li+ after a challenge with saline or amphetamine. 5 Challenge Saline Amphetamine Mean SD Mean Activity SD activityIIL Vertical Activity (Rearing) Treatments 10 Control 102.9 83.7 181.4 138.3 Li 59.8 45 126.7 173.1 Compound 1 34.1 26 71.3 49.4 SD, standard deviation 15 Discussion The effects of Compound 1 in rats have been evaluated in comparison with that of Li+, a well established drug for the treatment of bipolar disease. Compound 1 was tested in 20 the amphetamine-induced hyperactivity model, that is well accepted as a model of bipolar disease (mania phase) . The end point criteria was reduction in vertical movements (rearing). Compound 1 decreased the induced rearing in a similar manner as Li', indicating that Compound 1 and the 25 claimed valproic acid amides and 2 -valproenic acid amides are effective for the treatment of mania in bipolar disorder.
-14 References U.S. Patent No. 5,585,358, Bialer et al., issued December 6, 1996. Belmaker, R.H. and Y. Yaroslavsky, Basic Mechanism and 5 Therapeutic Implications of BP disorder, Marcel Dekker, Inc., Ed. S. Gershon and J. Soares, 2000. Bowden et al., Efficacy of divalproex vs. lithium and placebo in the treatment of mania, JAMA 1994: 271:918-924. Calabrese, J.R. et al., Lithium and the anticonvulsants in 10 the treatment of bipolar disorder, in: Psychopharmacology: The fourth generation of progress, eds. R. Bloom and D. Kupfer, Raven Press, Ltd., 1995. Lyon, M., Animal model mania and schizophrenia in: Willner, P. Behavior Model in Psychopharmacology, Cambrige 15 University Press, NY, 1991, pp. 253-310. Johnson, F.N., Association of vertical and horizontal components of activity in rats treated with lithium chloride, Experientia, 1972, 28: 533-535. Rang, H.P., M.M. Dale and J.M. Ritter, Pharmacology 3 r Ed., 20 Churchill Livingstone, p. 576.

Claims (16)

1. A method of treating a subject afflicted with a bipolar disorder comprising administering to the subject a therapeutically effective amount of a compound having one of the following structures: N (CH2)n NR 2 R 3 H or 0 N J ( C H 2 ) n " 1 0 N R 2 R 3 II or a pharmaceutically acceptable salt of the compound; wherein R 1 , R 2 , and R 3 are independently the same or different and are hydrogen, a Ci-C 6 alkyl group, an aralkyl group, or an aryl group, and n is an integer which is greater than or equal to 0 and less than or equal to 3, to thereby treat the mania phase of the bipolar disorder in the subject. 15
2. A method of treating a subject afflicted with a bipolar disorder comprising administering to the subject a therapeutically effective amount of a compound having one of the following structures: N (CH2)n "k N.R2R3 IH or O R0 N (CH 2 )n NR 2 R 3 II wherein R 1 , R 2 , and R 3 are independently the same or different and are hydrogen, a Ci-C 6 alkyl group, an aralkyl group, or an aryl group, and n is an integer which is greater than or equal to 0 and less than or equal to 3, to thereby treat the mania phase of the bipolar disorder in the subject.
3. The method of claim 1 or 2, wherein the compound has the structure: 16 O R, 0 N) (CH2)n ", NRR3 H
4. The method of claim 1 or 2, wherein the compound has the structure: O R0 N (CH 2 )n NR 2 R 3
5. The method of any one of claims 1-4, wherein the Ci C 6 alkyl group is a linear chain alkyl group.
6. The method of any one of claims 1-4, wherein the Ci C 6 alkyl group is a branched chain alkyl group. 17
7. The method of any one of claims 1-4, wherein the aralkyl group is selected from the group consisting of a benzyl, alkylbenzyl, hydroxybenzyl, alkoxycarbonylbenzyl, aryloxycarbonylbenzyl, carboxybenzyl, nitrobenzyl, cyanobenzyl, and halobenzyl group.
8. The method of any one of claims 1-4, wherein the aryl group is selected from the group consisting of a phenyl, naphthyl, anthracenyl, pyridinyl, indolyl, furanyl, alkylphenyl, hydroxyphenyl, alkoxycarbonylphenyl, aryloxycarbonylphenyl, nitrophenyl, cyanophenyl, halophenyl group, mercaptophenyl, and aminophenyl group.
9. The method of any one of claims 1-3, wherein the compound has the structure: O NH 2
10. The method of any one of claims 1 or 3-8, wherein the compound is in the form of a pharmaceutically acceptable salt.
11. The method of any one of claims 1-10, wherein the compound or its pharmaceutically acceptable salt is in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. 18
12. The method of any one of claims 1-11, wherein the effective amount is an amount from 10 mg to 1,000 mg.
13. The method of claim 12, wherein the effective amount is an amount from 50 mg to 500 mg.
14. The method of any one of claims 1-11, wherein the route of administration of the compound is selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intramuscular, transdermal, subcutaneous, topical and rectal administration.
15. The method of any one of claims 1-11, wherein the route of administration is oral.
16. The method of any one of claims 1-15 as hereinbefore described by reference to the Examples. 19
AU2007200901A 2000-07-21 2007-03-01 Use of derivatives of valproic acid and 2-valproenic acid amides for the treatment of mania in bipolar disorder Ceased AU2007200901B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2007200901A AU2007200901B2 (en) 2000-07-21 2007-03-01 Use of derivatives of valproic acid and 2-valproenic acid amides for the treatment of mania in bipolar disorder

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US60220102 2000-07-21
AU2001280699 2001-07-20
AU2007200901A AU2007200901B2 (en) 2000-07-21 2007-03-01 Use of derivatives of valproic acid and 2-valproenic acid amides for the treatment of mania in bipolar disorder

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
AU2001280699 Division 2000-07-21 2001-07-20

Publications (2)

Publication Number Publication Date
AU2007200901A1 AU2007200901A1 (en) 2007-03-22
AU2007200901B2 true AU2007200901B2 (en) 2009-05-14

Family

ID=37909139

Family Applications (1)

Application Number Title Priority Date Filing Date
AU2007200901A Ceased AU2007200901B2 (en) 2000-07-21 2007-03-01 Use of derivatives of valproic acid and 2-valproenic acid amides for the treatment of mania in bipolar disorder

Country Status (1)

Country Link
AU (1) AU2007200901B2 (en)

Also Published As

Publication number Publication date
AU2007200901A1 (en) 2007-03-22

Similar Documents

Publication Publication Date Title
US6555585B2 (en) Use of derivatives of valproic acid and 2-valproenic acid amides for the treatment of mania in bipolar disorder
ES2354417T3 (en) NEW USE OF A CLASS OF PEPTIDE COMPOUNDS TO TREAT ALLODINIA OR OTHER DIFFERENT TYPES OF CHRONIC PAIN OR GHOST.
TWI397417B (en) Pharmaceutical composition with synergistic anticonvulsant effect
KR100758609B1 (en) Composition comprising a tramadol material and an anticonvulsant drug
Pei A review of pharmacology and clinical use of piperine and its derivatives
JP5190334B2 (en) New uses of amino acid antispasmodic drugs
ES2500053T3 (en) Pharmaceutical composition comprising droxidopa for the treatment of fibromyalgia
JP4452255B2 (en) Use of gaba analogs such as gabapentin in the manufacture of a medicament for the treatment of inflammatory diseases
ES2385087T3 (en) Procedures for treating substance-related disorders
CN106456583B (en) Combinations of baclofen, acamprosate and medium chain triglycerides for the treatment of neurological disorders
CZ20032763A3 (en) Use of novel class of peptide compounds for treating neuropathic inflammatory pain
AU2002257680A1 (en) Novel use of a peptide class of compound for treating allodynia or other different types of chronic or phantom pain
ES2649492T3 (en) (S) -pirlindole or its pharmaceutically acceptable salts for use in medicine
KR20010071572A (en) The Use of Valproic Acid Analog for the Treatment and Prevention of Migraine and Affective illness
AU2007200901B2 (en) Use of derivatives of valproic acid and 2-valproenic acid amides for the treatment of mania in bipolar disorder
HU211529A9 (en) Compounds for the treatment of neurodegenerative disorders
TWI804568B (en) Amino acid derivatives containing a disulfanyl group as an inhibitor of nep and apn for the prevention and treatment of trigeminal nerve pain
Bustamante et al. Ketorolac tromethamine: an experimental study of its analgesic effects in the rat
FR2755013A1 (en) NOVEL THERAPEUTIC APPLICATION OF ANTAGONISTS OF SUBSTANCE P
JP2006306738A (en) Cure for neuropathic pain
KR20080076897A (en) Thiazolopyrimidines for use in therapy

Legal Events

Date Code Title Description
FGA Letters patent sealed or granted (standard patent)
PC Assignment registered

Free format text: FORMER OWNER WAS: YISSUM RESEARCH DEVELOPMENT COMPANY OF THE HEBREW UNIVERSITY OF JERUSALEM ( SHIRELLC ) MORTGAGES REGISTERED -SECTION 187, REG. 19 (THE NAME IN THE PARENTHESES IS THAT OF THE MORTGAGEE)

MK14 Patent ceased section 143(a) (annual fees not paid) or expired