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EXHIBIT A
Case 1:07-cv-00551-GMS
Document 19-2
Filed 03/07/2008
Page 2 of 31
Electronic Acknowledgement Receipt
EPS ID:
2620316 11960934
Application Number: International Application Number: Confirmation Number:
5332
Title of Invention:
Omeprazole Solution and Method for Using Same
First Named Inventor/Applicant Name: Customer Number: Filer: Filer Authorized By: Attorney Docket Number: Receipt Date: Filing Date: Time Stamp: Application Type:
Jeffrey O Phillips 26565 Joseph A. Mahoney/Andrea Hutchison Joseph A. Mahoney 01723512 20-DEC-2007
11:55:42 Reissue (Utility)
Payment information:
Submitted with Payment Payment Type Payment was successfully received in RAM RAM confirmation Number Deposit Account Authorized User
yes
Deposit Account $2060 7975 130019
File Listing:
TEST DOCTM, Description Fi,eNan,e £££32 Pa"Tzip
SANTARUS 00000001
Case 1:07-cv-00551-GMS
Document 19-2
Filed 03/07/2008
660336
Page 3 of 31
1
Filings.PDF
ba9ae381 1976737bc366(c1d42d4728 2aa163fa
yes
12
Multipart Description/PDF files in .zip description Document Description Transmittal Reissue Application
Start
1
End
1
Fee Worksheet (PTO-06)
2
3
Reissue dec filed in accordance with MPEP 1414.
4
5
Consent of Assignee accompanying the declaration.
6
7
Preliminary Amendment Warnings: Information:
8
12
1450331
Specification Warnings: Information:
US5840737.pdf
2047b2b193bd1f117b5bf88fb3aaa7881 4C83854
no
16
8561
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Fee Worksheet (PTO-06)
fee-info.pdf
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Warnings: Information: Total Files Size (in bytes): 2119228
This Acknowledgement Receipt evidences receipt on the noted date by the USPTO of the indicated documents, characterized by the applicant, and including page counts, where applicable. It serves as evidence of receipt similar to a Post Card, as described in MPEP 503. New Applications Under 35 U.S.C. 111 If a new application is being filed and the application includes the necessary components for a filing date (see 37 CFR 1.53(b)-(d) and MPEP 506), a Filing Receipt (37 CFR 1.54) will be issued in due course and the date shown on this Acknowledgement Receipt will establish the filing date of the application. National Stage of an International Application under 35 U.S.C. 371 If a timely submission to enter the national stage of an international application is compliant with the condition of 35 U.S.C. 371 and other applicable requirements a Form PCT/DO/EO/903 indicating acceptance of the application as a national stage submission under 35 U.S.C. 371 will be issued in addition to the Filing Receipt, in due course. New International Application Filed with the USPTO as a Receiving Office If a new international application is being filed and the international application includes the necessary components for an international filing date (see PCT Article 11 and MPEP 1810), a Notification of the International Application Number and of the International Filing Date (Form PCT/RO/105) will be issued in due course, subject to prescriptions concerning national security, and the date shown on this Acknowledgement Receipt will establish the international filing date of the application.
SANTARUS 00000002
Case 1:07-cv-00551-GMS
Document 19-2
Filed 03/07/2008
Page 4 of 31
PTO/SB/50 (09-07) Approved for use through 08/31/2010. OMB 0651-0033 U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE Under the Paperwork Reduction Act of 1995. no persons are required to respond to a collection of information unless it displays a valid OMB control number.
REISSUE PATENT APPLICATION TRANSMITTAL
Address to: Mail Stop Reissue Commissioner for Patents P.O. Box 1450 Alexandria, VA 22313-1450 APPLICATION FOR REISSUE OF: (Check applicable box) Attorney Docket No. First Named Inventor Original Patent Number Original Patent Issue Date (Month/Day/Year) Express Mail Label No. r--i I* I Utility Patent |--i | |
01723512
Phillips, Jeffrey O. 5,840,737
11/24/1998
r--i | |
Design Patent
APPLICATION ELEMENTS (37 CFR 1.173)
Plant Patent ACCOMPANYING APPLICATION PARTS
1. IXJ
2. D
Fee Transmittal Form (PTO/SB/56) (Submit a duplicate copy) Applicant claims small entity status. See 37 CFR 1.27. Specification and Claims In double column copy of patent format (amended, if appropriate) Drawing(s) (proposed amendments, if appropriate)
r----i Statement of status and support for all 10. lx I changes to the claims. See 37 CFR 1.173(c). 11.1 12. I Foreign Priority Claim (35 U.S.C. 119) (if applicable) Information Disclosure Statement (IDS) PTO/SB/08 or PTO-1449 I I Copies of citations attached
5
0
Reissue Oath/Declaration (original or copy) (37 C.F.R. 1.175) (PTO/SB/51 or 52) Power of Attorney 13.1
7.
fxl
Original U.S. Patent currently assigned? [Xj Yes | IX (If Yes, check applicable box(es)) |X| [X~| Written Consent of all Assignees (PTO/SB/53) 37 CFR 3.73(b) Statement (PTO/SB/96)
|
No
I English Translation of Reissue Oath/Declaration (if applicable)
14. I*- I Preliminary Amendment (MPEP D Return Receipt Postcarditemized) 503) (Should be specifically 16. LLJ Other: Certificate of Correction
8. [
[ CD-ROM or CD-R in duplicate, Computer Program (Appendix) or large table | j Landscape Table on CD
9. Nucleotide and/or Amino Acid Sequence Submission (if applicable, items a. - c. are required)) a. I--I Computer Readable Form (CRF) b. Specification Sequence Listing on: i II CD-ROM (2 copies) or CD-R (2 copies); or ii [J paper c. I I Statements verifying identity of above copies 17. CORRESPONDENCE ADDRESS The address associated with Customer Number: 26565
OR
DCorrespondence address below
Zip Code Email
Date
Name Address City Country
Signature Name (Print/Type)
State Telephone
A> MAyjOo^
u
|/2-/gVa7-~
Registration No. (Attorney/Agent) ^8,956 Joseph A. Manoney This collection of information Is required by 37 CFR 1.173. The information is required to obtain or retain a benefit by the public which is to file (and by the USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.11 and 1.14. This collection is estimated to take 12 minutes to complete, including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any comments on the amount of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, U.S. Patent and Trademark Office, U.S. Department of Commerce, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS. SEND TO: Mail Stop Reissue, Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450. If you need assistance in completing the form, call 1-800-PTO-9199 and select option 2.
SANTARUS 00000003
Case 1:07-cv-00551-GMS
Document 19-2
Filed 03/07/2008
Page 5 of 31
PTO/SB/56 (10-07) Approved for use through 08/31/2010. OMB 0651-0033 U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE Under the Paperwork Reduction Ac! of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number.
REISSUE APPLICATION FEE TRANSMITTAL FORM
(1) Claims in Patent
Total Claims
(37CFR 1.16(i))
(A)
Docket Number (Optional) 01723512 Other than a Small Entity Rate ($) Fee ($)
(2) Claims Filed in Reissue Application
(B)
Application as Filed - Part 1 Small Entity (3) Number Extra Rate ($) Fee ($)
12
24
573 884-
50 x
210
= =
200
Independent Claims (37CFR1.16(h))
iPl
10/79
(D)
420
Application Size Fee (37CFR1.16(s))
If the specification and drawings exceed 100 sheets of paper, the application size fee due is $260 ($130 for small entity) for each additional 50 sheets or fraction thereof. See 35 U.S.C. 41(a)(1)(G)and37CFR 1.16(s). Filing Fee (37 CFR1.16(e)) Search Fee (37 CFR 1.16(n)) Examination Fee (37 CFR 1.16(r)) Total Filing Fee
310 510
620
2060 Other than a Small Entity Rate ($) Fee ($)
d) Claims Remaining After Amendment
Total Claims (37CFR1.16(i))
Independent Claims (37 CFR 1.16(h)) Application Size Fee (37CFR1.16(s))
Application as Amended - Part 2 (2) (3) Small Entity Highest Number Extra Rate ($) Fee ($) Previously Claims Paid For Present
MINUS
MINUS
24
573 884-
20 or
x
50
210
=
200 420
=
If the specification and drawings exceed 100 sheets of paper, the application size fee due is $260 ($130 for small entity) for each additional 50 sheets or fraction thereof. See 35 U.S.C. 41 (a)(1)(G) and37CFR1.16(s). Total Additional Fee
620
* If (D) is less than (C), enter "0" in column 3. For reissues filed on or after Dec. 8, 2004, enter (D) minus 3 or "0" if (D) is less than 3. ** If the "Highest Number of Total Claims Previously Paid For" is less than 20, enter "20" in this space. *** After any cancellation of claims. **** If (A) is greater than 20, enter (B) - (A); if (A) is 20 or less, enter (B) - 20. For reissues filed on or after Dec. 8, 2004, enter (B) - 20. ***** For amendments filed on or after Dec. 8, 2004, enter the "Highest Number of Independent Claims Previously Paid For." For amendments filed prior to Dec. 8, 2004, enter the higher of the Number Previously Paid or Number of Independent Claims in Patent. I I Applicant claims small entity status. See 37 CFR 1.27. in the amount of $2.060
[x~l Please charge Deposit Account No. 13-0019 '--IA duplicate copy of this sheet is enclosed.
iThe Director is hereby authorized to charge any additional fees under 37 CFR 1.16 or 1.17 which may be required, or ' credit any overpayment to Deposit Account No. 13-0019 . A duplicate copy of this sheet is enclosed. [ | | A check in the amount of $ . to cover the filing/additional fee is enclosed.
| Payment by credit card. Form PTO-2038 is attached. WARNING: Information on this form may become public. Credit card information should not be mcludedTbn this form. Provide credit card information and authorization on PTO-2038. December 20, 2007 Date Joseph A. Mahonev Typed or printed name 38,956 Registration Number, if applicable
312-701-8979 Telephone Number
This collection of information is required by 37 CFR 1.16. The information is required to obtain or retain a benefit by the public which is to file (and by the USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.11 and 1.14. This collection is estimated to take 12 minutes to complete, including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any comments on the amount of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, U.S. Patent and Trademark Office, U.S. Department of Commerce. P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS. SEND TO: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
If you need assistance in completing the form, call 1-800-PTO-9199 and select option 2.
SANTARUS 00000004
Case 1:07-cv-00551-GMS
Document 19-2
Filed 03/07/2008
Page 6 of 31
PTO/SB/56 (10-07) Approved for use through 08/31/2010. OMB 0651-0033 U.S Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE Under the Paperwork Reduction Act o( 1995, no persons are required to respond lo a collection of information unless it displays a valid OMB control number.
REISSUE APPLICATION FEE TRANSMITTAL FORM
(D Claims in Patent
Total Claims
(37CFR 1.16(i)> Independent Claims (37CFR 1.16(h))
(A)
Docket Number (Optional) 01723512 Other than a Small Entity Rate ($) Fee ($)
(2) Claims Filed in Reissue Application
(B)
Application as Filed - Part 1 Small Entity (3) Number Extra Rate ($) Fee ($}
12
24
573 884-
50
x
210
=
=
200 420
Application Size Fee (37CFR 1.16(s))
M.
10/79
If the specification and drawings exceed 100 sheets of paper, the application size fee due is $260 ($130 for small entity) for each additional 50 sheets or fraction thereof. See 35 U.S.C. 41(a)(1)(G) and 37 CFR 1.16(s). Filing Fee (37 CFR 1.16(e)) Search Fee (37 CFR 1.16(n)) Examination Fee (37 CFR 1.16(r)) Total Filing Fee
M.
or
310
510 620
2060 Other than a Small Entity Rate ($) Fee ($)
(1) Claims Remaining After Amendment
Total Claims (37CFR1.16(i))
Independent Claims (37 CFR l.16(h)) Application Size Fee (37CFR1.16(s))
24
573 884-
Application as Amended - Part 2 (2) (3) Small Entity Highest Number Extra Rate ($) Fee ($) Previously Claims Paid For Present
MINUS MINUS
20
50
x
210
200
=
420
If the specification and drawings exceed 100 sheets of paper, the application size fee due is $260 ($ 130 for small entity) for each additional 50 sheets or fraction thereof. See 35 U.S.C. 41(a)(1)(G) and 37 CFR 1.16(s).
Total Additional Fee
620
If (D) is less than (C), enter "0" in column 3. For reissues filed on or after Dec. 8, 2004, enter (D) minus 3 or "0" if (D) is less than 3. * If the "Highest Number of Total Claims Previously Paid For" is less than 20, enter "20" in this space. ** After any cancellation of claims. *** If (A) is greater than 20, enter (B) - (A); if (A) is 20 or less, enter (B) - 20. For reissues filed on or after Dec. 8, 2004, enter (B) - 20. **** For amendments filed on or after Dec. 8, 2004, enter the "Highest Number of Independent Claims Previously Paid For." For amendments filed prior to Dec. 8, 2004, enter the higher of the Number Previously Paid or Number of Independent Claims in Patent. [~| Applicant claims small entity status. See 37 CFR 1.27. nn Please charge Deposit Account No. 13-0019 I--IA duplicate copy of this sheet is enclosed. in the amount of $2,060
fsTlThe Director is hereby authorized to charge any additional fees under 37 CFR 1.16 or 1.17 which may be required, or I--'credit any overpayment to Deposit Account No. 13-0019 . A duplicate copy of this sheet is enclosed. | | | A check in the amount of $ . to cover the filing/additional fee is enclosed.
| Payment by credit card. Form PTO-2038 is attached. WARNING: Information on this form may become public. Credit card information should not be ipclude/flbn this form. Provide credit card information and authorization on PTO-2038. / f 1 » -- S December 20, 2007 Date Signature Joseph A. Mahonev Typed or printed name 38,956 Registration Number, if applicable
312-701-8979
Telephone Number
This collection of information is required by 37 CFR 1.16. The information is required to obtain or retain a benefit by the public which is to file (and by the USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.11 and 1.14. This collection is estimated to take 12 minutes to complete, including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any comments on the amount of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, U.S. Patent and Trademark Office, U.S. Department of Commerce, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS. SEND TO: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
If you need assistance in completing the form, call 1-800-PTO-9199 and select option 2.
SANTARUS 00000005
Case 1:07-cv-00551-GMS
Document 19-2
Filed 03/07/2008
Page 7 of 31
PTOSH-5J ·«·:·· Approved for *ne *rouj>i Of. 3t 'K1(J 3MB 36$' -OC3.'! 'J S Parw aivj Treae-nar*. OWtoe, U S. 06PAH1MENT OF COMMERCE Uncct Ihe P«p«r-*ctK fifiauMo Act of f550. TO c*'wns are -quires; iqiespcre '·: a lyifracf ot..i"tonnaiion unless li *sp
Docket Number (optional) REISSUE APPLICATION DECLARATION BY THE ASSIGNEE 01723512
' hereby declare lhat: The residence, mailing address and citizenship of the inventors are stated beiow. i an authorized to act on behalf of the following assignee: and the title of my position with said assignee is ''he Curaio-s of the University of Missouri
Vice President of Research and Economic Deveiopme.nl
The entire,.title to the paiert identified below is vested in sa-d assignee lnvflrtor Jeffrey O. Ffull.ps ' [Citizenship RflsidencefMaNing Address Inventor Residence/Mailing Address
125Q £ Nastwt|!e Church Hd
USA
. Ash||and
MO 65010
Citizenship
Q Add.Hkinat Inventors are named on separately numbered sheets attached^herelo. Patent Number j Date of Patent Issued 1 ^4/1998 5.840.737 I believe said inventors) to be the original and first inventor's) of tlie subject matter which is described and claimed in saio patent, for which a reissue patent is sought on the invention entitled: Omeprazoie Solution and Method for Using Same
the speofication of which |xT] is attached hereto.
D wasfiledon
as reissue application number. (rf applicable)
and was amended on I have reviewed and understand the contents of the above identified specification, including the claims, as amended by any amendment referred to above. I acknowledge the duty to disclose information which is material to patentability as defined in 37 CFR 1.55. [""I I hereby ctaim foreign priority benefits under 35 U.S.C. 119<3)-(d) or
JX { by reason of the patentee claiming more or less than he had the right to daim in the patent. (XJ by reason of other errors. Pagei of 2}
T^l*«
SANTARUS 00000006
Case 1:07-cv-00551-GMS
Document 19-2
Filed 03/07/2008
Page 8 of 31
PTO'58-W :35-C'-:
App-owat-f usetf'fix-;" '"'£'?" '·?-'·"' 'JMBasi'.-aoa.'
..·S P.vitf-1 8W Trademark Q«c« US Cf-PABTMFNTOf · CGMMEHCE und** ihc Papyvycfh Racucicn. Act ol 1865, ro cersey-iS arg "g^uinc 'p.'.vw
REISSUE APPLICATION DECLARATION BY THE ASSIGNEE
At least one error upon v/hich reissue is based s described as follows. Failure io appreciate (he fuif scope oi the invention M P E.P *4C2.
_L
Docket Number 01723512
One reason, for example, is that "powder' ts added to claim 1 (c clarify the invention. [Attach additional sfteeis.. ifflaffidad] All errors corrected in this reissue application arose without any deceptive intention on the part of the applicant. I hereby appoint: I 26565 JXJ Practitioners associated wilh Customer Number OR nI Pfactttionef(s) named below: I Registration Number Name
as mytoue atlomey(s) or agent(s) Jo prosecute the application identified above, ancf to transact all business >n (he Ur-.ited Slates Patent arxJ Trademark Office connected therewith Correspondence Address: Direct ad communications aocu; the application la The address assoaated wrih Customer Number Firm or Individual _ Name __ Address 26565
a
OR
C«y
Country Telephone
--a
I State
2p
WARNING? Petltraner/sppficant is cautioned to avokJ submitting personal information in
w^^-
fL/njJSjT)
name, family name)
MJcJ)ae, p Njcfto)& RK D
SANTARUS 00000007
Case 1:07-cv-00551-GMS
Document 19-2
Filed 03/07/2008
Page 9 of 31
PTG/SB'55 ·'«·/).·· A£prov«a tor use trsroiign w,j vzsiC OMB 'i*s< «·;·:· ij ? =.VP- «!·.<: Vademart OffK*: U S DEPARTMENT OF COMMERCE Unaer Ifre Paperwork RKUCJIO? AC' r.t 1935. ra p«j
Docket Number (Optional)
REISSUE APPLICATION: CONSENT OF ASSIGNEE; STATEMENT OF NON-ASSIGNMENT
01723512
This is part of the application for a reissue patent based on the original patent identified beiow.
Name of Patenteefs) Th« Curators of trve University ol Missouri
Patent Number
Title of Invention
^^
1 ate Patent Issued
, ^4/1993
Omeprajzolft Solution and Method for Using Same
1 [ XJ
Filed herein is a statement under 37 CFR 3 73(b) (Fonrn PTO/S8/96)
2. [_ j Ownership of the patent is in the trsventorfs}. and no assignment of the patent is in effect
One of boxes 1 or 2 above must be checked If multiple assignees, complete this form for each assignee If box 2 is checked, skip the next entry and go directly to "Name of Assignee" The written consent of alt assignees and inventors owning an undivided interest in the original patent is included in this application for reissue The assignee(s) owning an undivided interest in sakl original patent is/are "ft"* Curators of tfw University of Missouri and the assignees) consents to the accompanying application for reissue. Name of assignee/inventor
The Curators of me UniVMS({y of Migsoufj
Signature/^, jn^
J /
( **e
t^/{r/z^n
Typeo or printed name and title of person signing for assignee (if assigned)
Michael F. Nichols Ph. 0. Vice President of Research and Economic Development
This coBeaion o* wftwriaBaft is requires ey 37 CFR 1 172 The ineormatyon is reqcweo to dbsaiocr i«8,rt 3 bwneft bf S>* puste wt**i«to We (ana By th* USPTO to process) an sppfcSBSon. Cor*aentiality ts govemed by 35 U S.C. )22 and 37 CFR i M. Ws eoawilon i» esSwatotS w iafc« « mtnuhw to ecntp6«t«. mauainj §Kti««ing, pt«panng, ana submiTonj me completed application tont to me USPTQ Tim* w£ vac,- s«owid^ ueon the andtvidual c»s* Any commcrts on *ie amount of !lm* y«j >*quir» to complete (nii form andsx suggwsliofus ft* re&dcng th«s Bo«!««. snouw 0* ««« to th« Owe* InfownKicn OJSoef. U S Pasnt and TrsdffJWMti Odice, US Oep»nfn«M of Commerce. PO Sox M50. A»x*wfl*. VA 2^313-1450 OO MOT SEND PEE$ OR COMPtETEO FORUS TO THIS AOORESS. S6WJTO: Commissioner for Patents, P.O. Bon 1*50, AJeaandrte, VA 22313-1450.
f/ you wee1 assisonoe m cementing the tern. csO r-80ff-Pro»9r9$ and setetf opftw 2.
SANTARUS 00000008
Case 1:07-cv-00551-GMS
Document 19-2
Filed 03/07/2008
Page 10 of 31
PTC'S3,'%/2iy: '.rr-'-:verf^f -.lie !!·"·<: i.-jr> <2'3"JC07' OMB Mil 5W v.'S ;:s;<:"' a-fl T:aritt-iari. ;:«·« 'J J DEP'RTMEN" C-~ COIW!:?'.:;;. Jneet Ihe "j.-<:r,v;-" -·::..·:·. :·'· <:i of 199.*:. nc pfttvina if6 igauif&j :o 'espo.'-.a K s co 'CC1. rn ·-.? ffifuinjAion .n-fijSi -I Displays a vsl'-d CMS co^iny 0;'?.-*'_.
STATEMENT UNDER 37 CFR 3,73tb) Appacan.tfParept 0\v.er Applicatio-" No 'f's'.ent Nc Elt.'ied' ^wpruj-.:v^.i.,:
B Curators, of the Unmet&llv o-' Mi&saufi t SSQ.7.37
PilecJ'issufi Dale. Nhvi-.r&c-r ^4 !S98
'··J Method (of Using Same
]'Kl? f'jUTUfnfN f>' i-:t.n ;^--y.'!--'. i; STIC- 0* ".Wn *'?Tl
. .' Ml
a university, public corporation and body politic of the state of Missouri
.' )-pe of Afvgnrtc c .- ii-'^tAl.r:^ t;fti^^-fsn:0 'jn-ve^'Cy ":-ovC!r«i(?'H ii^ency *'- ·
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states mat >'. is ·i. [71 >he assignee o'tre S'^.re right, titte, and interest: or 2 [~j an assignee of less ihs" the entire right, titte and interest (The extent (by perc3.'-;sge) of its ownership interest is in the patent spp'icsfic/vpatent identified above by virtue of either. A.E'An assignme--. rroti the inventor(s) of the patent applicattontogtent idenfcfiea above The assignment was recorded h the Uni'.ed States Pa;e;-i and Trademark Office at Ree! JM/J^ .· Frame 0335 or for which a copy thereof ;s anschao OR B P] A cha;n c-f we frjni t^s mventor(s), of the patent appiication/patc-t identified atiove. to the c^ent assignee as follows' 1 From To. The cfccu-Tier.' was rea^rded in the United States Patent anci Trademark Office at Reel . Frame . o-T for whicn a copy thereof's attached. 2 F-rom To! he de-current was recorded in the United States Patent snd Trademark Office at Reel , Frame . or fc* wMch a copy 'hereof is attached. 3. From. To: The docyrrent was recorded in the United States Patent and Traeernark Office at ! Ree . , . Frame ,.. of fof wmch a coov thereof is attached I | Additional documents in the chain of side are listed on 3 suppfementaf sheet. [71 As recurred Dy 37 CFR 3 73(t>K1 ){i), the documentary evidence of the chain of title from the onginal owner to ttse assignee was or corcurrer.My is being, submitted for recordatfon pursuant to 37 CFR 3.11. (NOTE: A separate copy (i.e., a true copy of the origmat assignment document(sj) must be submitted to Assignment Division in accordance with 37 CFR Part 3, to record the assignment in the records of the USPTO §§§. MPEP 302 08] The undersigned i, iw) ts authorized to act on behaif of the assignee.
. *AJ
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Signature Michael F. Michols Ph. 0. Printed of Typed Name
'2//?/ZS47 ' 4e
..,._. 573 8BJ'35S3
Telephone Number
Vice Presiaerit of Research and Economic Development Title
This cclletfean of mtormaton is recjui-ftd by 37 CFR 3 73ib). Tha informalico is required to ofitasn or retain s bw«fa by the twtsfc which i* tu Ke (ant) by Uift USPTO la KOC*S») an s»f>ft«sHar, ConfiSertilalrty is gennsnved s>y 15 U.S.C. '22 snd 37 CFR *.M and 1 t4. TKs collectioo sj
FORMS TO TriiS ADDRESS. SEND TO: Commissioner for Patents, P.O. Box 1««, Alexandria, VA 22313-1450. if you need assistance in completing the form, caff 1-8QO-PTQ-Q139 and select option 2.
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Docket No. 01723512 IN THE UNITED STATES PATENT AND TRADEMARK OFFICE APPLICANT: PATENT NO.: FILED: TITLE: DATE: Phillips, J. O. ) ATTORNEY DOCKET: ) 5,840,737 ) GROUP ART UNIT: ) July 15, 1996 ) EXAMINER: ) Omeprazole Solution and Method for Using Same ) December 20, 2007 ) CUSTOMER NO.: 01723512 1625 Unknown
26565
Mail Stop: Reissue Commissioner for Patents P.O. Box 1450 Alexandria, VA 22313-1450
PRELIMINARY AMENDMENT Dear Sir: The above referenced patent, enclosed herewith, is filed under 35 U.S.C. § 251 as a reissue of U.S. Patent No. 5,840,737. Prior to examination of this new reissue application, please amend the application as requested herein. Amendments to the Claims begins on page 2. Remarks begins on page 5.
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Docket No. OJ723512 Amendments to the Claims; This listing of claims will replace all prior versions and listing of claims in the application. The following amendments are without prejudice and do not constitute an admission regarding the patentability of the amended subject matter and should not be so construed. Complete Listing of Claims; What is claimed is: 1. (Currently Amended) A method for treating gastric acid disorders by
administering to a patient a single dose of a pharmaceutical composition of omeprazole or lansoprazole powder in a pharmaceutically acceptable carrier consisting essentially of a bicarbonate salt of a Group IA metal wherein said administering step consists of providing to the patient orally a single dose of an aqueous solution or[,] suspension of the pharmaceutical composition without requiring further administration of the bicarbonate salt of the Group IA metal. 2. 3. potassium. 4. (Currently Amended) A method according to claim 1, wherein the concentration (Original) A method according to claim 1, wherein the Group LA metal is sodium. (Original) A method according to claim 1, wherein the Group IA metal is
of omeprazole in the composition ranges from approximately 0.5 mg/ml to approximately 6.0 mg/ml. 5. (Currently Amended) A method according to claim 3, wherein the concentration
of omeprazole in said composition ranges from approximately 1.0 mg/ml to approximately 4.0 mg/ml. 6. (Original) A method as set forth in claim 5, wherein the concentration of
omeprazole in the composition is approximately 2.0 mg/ml. 7. (Original) A method as set forth in claim 1, wherein the concentration of the
bicarbonate salt of the Group IA metal in the composition ranges from approximately 5.0% to approximately 60.0%. 8. (Original) A method as set forth in claim 7, wherein the concentration of the
bicarbonate salt of the Group IA metal in the composition ranges from approximately 7.5% to approximately 10.0%.
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Docket No. 01723512 9. (Original) A method as set forth in claim 8, wherein the concentration of the
bicarbonate salt of the Group IA metal is approximately 8.4%. 10. (Original) A method as set forth in claim 1, wherein the single dosage form
includes a concentration of bicarbonate ranging from approximately 0.75 meq to 1.5 meq per mi Hi liter. 11. (Original) A method as set forth in claim 10, wherein the amount of the
bicarbonate in the single dosage form is less than approximately 12 mEq/20 mg dose of omeprazole. 12. (Original) A method as set forth in claim 1, wherein the single dosage form is
administered in a volume of between approximately 10 ml and 20 ml. 13. (New) A method for treating gastric acid disorders by administering to a patient a
single dose of a pharmaceutical composition of omeprazole in a pharmaceutically acceptable earner consisting essentially of a bicarbonate salt of a Group LA metal wherein said administering step consists of providing to the patient orally a single dose of an aqueous solution or suspension of the pharmaceutical composition without requiring further administration of the bicarbonate salt of the Group IA metal, wherein the concentration of omeprazole in said composition ranges from approximately 1.0 mg/ml to approximately 4.0 mg/ml. 14. (New) A method for treating gastric acid disorders by administering to a patient a
single dose of a pharmaceutical composition of omeprazole in a pharmaceutically acceptable carrier consisting essentially of a bicarbonate salt of a Group IA metal wherein said administering step consists of providing to the patient orally a single dose of an aqueous solution or suspension of the pharmaceutical composition without requiring further administration of the bicarbonate salt of the Group IA metal, wherein the concentration of omeprazole in said composition is approximately 2.0 mg/ml. 15. (New) A method for treating gastric acid disorders by administering to a patient a single dose of a pharmaceutical composition of omeprazole in a pharmaceutically acceptable carrier consisting essentially of a bicarbonate salt of a Group IA metal wherein said administering step consists of providing to the patient orally a single dose of an aqueous solution or suspension of the pharmaceutical composition without requiring further administration of the bicarbonate salt of the Group IA metal, wherein the amount of the bicarbonate in the single dosage form is less than approximately 12 mEq/20 mg dose of omeprazole.
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Docket No. 01723512 16. (New) A method for treating gastric acid disorders by administering to a patient a
single dose of a pharmaceutical composition of omeprazole or lansoprazole in a pharmaceutically acceptable carrier consisting essentially of a bicarbonate salt of a Group IA metal wherein said administering step consists of providing to the patient orally a single dose of an aqueous solution or suspension of the pharmaceutical composition without requiring further administration of the bicarbonate salt of the Group IA metal, wherein the single dosage form is administered in a volume of between approximately 10 ml and approximately 20 ml. 17. (New) The method of claim 1, wherein the pharmaceutical composition
comprises omeprazole powder and the bicarbonate salt of a Group IA metal is sodium bicarbonate. 18. (New) The method of claim 17, wherein the pharmaceutical composition further comprises a thickening agent. 19. (New) The method of claim 17, wherein the sodium bicarbonate is present in an
amount of about 0.375 to about 0.75 mEq sodium bicarbonate per mg of omeprazole powder. 20. (New) The method of claim 18, wherein the sodium bicarbonate is present in an
amount of about 0.375 to about 0.75 mEq sodium bicarbonate per mg of omeprazole powder. 21. 22. (New) The method of claim 19, wherein the omeprazole powder is present in an (New) The method of claim 20, wherein the omeprazole powder is present in an
amount of about 10 mg to about 40 mg. amount of about 10 mg to about 40 mg. 23. (New) The method of claim 21, wherein upon oral administration of the
suspension at least some of the omeprazole is absorbed within about 10 to about 12 minutes after administration. 24. (New) The method of claim 22, wherein upon oral administration of the suspension at least some of the omeprazole is absorbed within about 10 to about 12 minutes after administration.
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Docket No. 01723512 REMARKS Support for the new claims can be found throughout the specification and claims as originally filed and in the priority documents for this application. Support for the amendment to claim 1 can be found in the specification as issued at least at column 9, lines 43 to 57. New claims 13-16 have been written in independent form. Support for new claim 13-16 can be found in the claims as issued at least at original claims 5,6, 11 and 12 respectively. Support for new claims 17-24 can be found throughout the specification and claims as filed. No new matter has been added. Conclusion For at least the foregoing reasons, it is respectfully submitted that claims 1-24 are in condition for allowance. Early and favorable consideration is respectfully requested, and the Examiner is encouraged to contact the undersigned with any questions or to otherwise expedite prosecution. Further, none of Applicant's amendments or cancellations are to be construed as dedicating any such subject matter to the public, and Applicant reserves all rights to pursue any such subject matter in this or a related patent application. Kindly contact the undersigned with any questions or to otherwise expedite prosecution. Respectfully submitted,
Joseph A. Mahoney Registration No. 38,956 CUSTOMER NUMBER 26565 MAYER BROWN LLP P.O. Box 2828 Chicago, IL 60690-2828 Telephone: (312) 701-8979 Facsimile: (312)706-9000
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United States Patent [«]
Phillips
[54] [75] OMEPRAZOLE SOLUTION AND METHOD FOR USING SAME Inventor: Jeffrey Owen Phillips, Columbia, Mo.
US005840737A [ii] Patent Number: 5,840,737 Nov. 24,1998 [45] Date of Patent:
Cantu and Korek (1991) Central nervous system reactions to histamine-2 receptor blockers. Ann Intern Med, 114:1027-1034. Cioffi et al., (1994) Comparison of acid neutralizing and non-acid neutralizing stress ulcer prophylaxis in thermally injured patients. J. Trauma, 36:541-547. Cook et al., (1994) Risk factors for gastrointestinal bleeding in critically ill patients. N. Engl. J. Med., 330:377-381. Cook et al., (1991) Stress ulcer prophylaxis in the critically ill: a meta-analysis. Am. J. Med., 91:519-527. Cook et al., (1991) Nasocomial pneumonia and the role of gastric pH: a meta-analysis. Chest, 100:7-13. Czaja et al., (1974) Acute gastroduodenal disease after thermal injury: an endoscopic evaluation of incidence and natural history. N. Engl. J. Med., 291:925-929. Dobkin et al., (1990) Does pH paper accurately reflect gastic ph? Crit. Care Med., 18:985-988. Driks et al., (1987) Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or histamine type 2 blockers. N. Engl. J. Med., 317:1376-1382. Eisenberg et al., (1990) Prospective trial comparing a combination pH probe-nasogastric tube with aspirated gastric pH . . . Crit. Care Med., 18:1092-1095. Fabian et al., (1993) Pneumonia and stress ulceration in severly injured patients. Arch. Surg., 128:1855. Fellenius et al. (1981) Substituted benzimidazoles inhibit gastric acid secretion by blocking H+/K+-ATPase. Nature, 290:159-161. Fiddian-Green et al., (1983) Predictive value of intramural pH and other risk factos for massive bleeding from stress ulceration. Gastroenterology, 8:613-620. Fryklund et al. (1988) Function and structure of parietal cells after H+/K-i-ATPase blockade. Am. J. Physiol, 254 (3 pt 1); G399-407. (List continued on next page.) Primary Examiner--Jane Fan Attorney, Agent, or Firm--Kohn & Associates
[57]
[73] Assignee: The Curators of the University of Missouri, Columbia, Mo. [21] [22] Appl. No.: 680,376 Filed: Jul. 15,1996 Related U.S. Application Data
[60] Provisional application No. 60/009,608, Apr. 4, 1996.
[51] [52] [58]
Int. Cl.s U.S. Cl Field of Search
A61K 31/44 514/338 514/338
[56]
References Cited U.S. PATENT DOCUMENTS
4,182,766 1/1980 Krasso et al 4,255,431 3/1981 Junggren et al 4,472,409 9/1984 Senn-Bilfinger 4,786,505 11/1988 Lovgren et al 5,219,870 6/1993 Kim 5,385,739 1/1995 Debregeas et al 5,391,752 2/1995 Hoerrner et al 5,395,323 3/1995 Berglund 5,399,700 3/1995 Min et al 5,417,980 5/1995 Goldman et al 424/263 424/263 424/263 424/468 514/338 424/494 546/271 604/84 546/271 424/464
OTHER PUBLICATIONS Journal of Clinical Therapeutics & Medicines Nakagawa et al. vol. 7, No. 1, pp. 33-50 Abstract is inclosed, 1991. Wade, Organic Chemistry, p. 349, Pritice-Hall, Inc, 1987. The American Midical Association Drug Evaluation, vol. II, Gastrointestinal Drugs; Bennett, DR, Dickson BD (eds.) The American Medical Association, Chicago 1:8. Andersson et al., (1993) Pharmacokinetics of [14C] omeprazole in patients with liver cirrhosis. Clin. Pharmacokinet., 24(1): 71-8. Andersson et al., (1990) Pharmacokinetics and bioavailability of omerprazole after single and repeated oral administration . . . Br. J. Clin. Pharmacol, 29(5):557-63. Andersson et al., (1990) Pharmacokinetics of various single intravenous and oral doses of omeprazole. Ear. J. Clin. Pharmacol., 39(2):195-7. Ballesteros et al., (1990) Bolus or intravenous infusion of ranitidine: effects on gastric pH and acid secretion ... Ann. Intern. Med., 112:334-339. Barie and Hariri (1992) Therapeutic use of omeprazole for refractory stress-induced gastric mucosal hemorrhage. Crit. Care Med., 20:899-901. Bone (1991) Let's agree on terminology: definition of sepsis. Crit. Care Med., 19:27. Borrero et al., (1986) Antacids vs sucralfate in preventing acute gastrointestinal tract bleeding in abdominal aortic surgery. Arch. Surg., 121:810-812. Brunton (1990) in The Pharmacologic Basis of Therapeutics. Goodman AG, Rail TW, Nies AS, Taylor P (eds), New York, p. 907.
ABSTRACT
Apharmaceutical composition includes an aqueous solution/ suspension of omeprazole or other substituted benzimidazoles and derivatives thereof in a pharmaceutically acceptable carrier comprising a bicarbonate salt of a Group LA metal. A method for treating and/or preventing gastrointestinal conditions by administering to a patient a pharmaceutical composition including an aqueous solution/suspension of omeprazole or other substituted benzimidazoles and derivatives thereof in a pharmaceutically acceptable carrier including a bicarbonate salt of a Group IA metal wherein the administering step consists of a single dosage form without requiring further administering of the bicarbonate salt of the Group IA metal. Apharmaceutical composition for making a solution/suspension of omeprazole or other substituted benzimidazoles and derivatives thereof includes omeprazole or other substituted benzimidazoles and derivatives thereof and a bicarbonate salt of a Group IA metal in a form for convenient storage whereby when the composition is dissolved in aqueous solution, the resulting solution is suitable for enteral administration. 12 Claims, 1 Drawing Sheet
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OTHER PUBLICAnONS Gafter et al., (1989) Thrombocytopenia associated with hypersensitivity to rantidine: possible cross-reactivity . . . Am. J. Gastroenterol, 64:560-562. Garner et al., (1988) CDC definitions for nosocomial infections. Am. J. Infect. Control, 16:128-140. Heath et al., (1988) Intragastic pH measurement using a novel disposable sensor. Intens. Care Med., 14:232-235. Kiilerich et al., (1995) Effect of intravenous infusion of omeprazole and ranitidine on twenty-four-hour intragastic pH . . . Digestion, 56:25-30. Laggner et al., (1989) Prevention of upper gastrointestinal bleeding in long-term ventilated patients. Am. J. Med., 86(suppl 6A):81-84. Landahl et al., (1992) Pharmacokinetic study of omeprazole in elderly healthy volunteers. Clin. Pharmacdti.net., Dec:23(6):469-76. Larson et al., (1984) Gastric response to severe head injury. Am. J. Surg., 147:97-105. Marrone and Silen, (1984) Pathogenesis, diagnosis and treatment of acute gastric mucosa lesions. Clin. Gastroenterol, 13:635-650. Martin et al., (1993) Continuous intravenous cimetidine decreases stress-related upper gastrointestinal hemorrhage . . . Crit. Care Med., 21:19-39. Martin et al., (1992) Stress ulcers and organ failure in intubated patients in surgical intensive care units. Aral. Surg., 215:332-337. Meiners et al., (1982) Evaluation of various techniques to monitor intragastic pH. Arch. Surg., 117:288-291. Oh and Carroll (1994) Electrolyte and acid-base disorders, in The Phamacologic Approach to the Critically III Patient. (Chernow B, ed) Williams & Wilkins, Baltimore, pp. 966-967. Ostro et al. (1985) Control of gastric pH with cimetidine boluses versus primed infusions. Gastroeneterology, 89:532-537. Peura and Johnson (1985) Cimetidine for prevention and treatment of gastroduodenal mucosal lesions in patients . . . Ann Intern Med., 103:173-177. Phillips and Metzler (1994) Simplified omeprazole solution for the prophylaxis of stress-related mucosal damage . . . Crit. Care Med., 22:A53. Pickworth et al., (1993) Occurrence of nasocomial pneumonia in mechanically ventilated trauma patients... Crit. Care Med., 12:1856-1862. Pilbrant et al. (1985) Development of an oral formulation of omeprazole. Gastroenterol Suppl., 108:113-20. Priebe and Skillman, (1981) Methods of prophylaxis in stress ulcer disease. World J. Surg., 5:223-233. Regardh et al., (1990) The pharmacokinetics of omeprazole in humans--a study of single intravenous and oral doses. Ther. Drug Monit., Mar: 12(2):163-72.
Ryan et al., (1993) Nasocomial pneumonia during stress ulcer prophylaxis with cimetidine and sucralfate. Arch. Surg., 128:1353-1357. Sax (1987) Clinically important adverse effects and drug interactions with H2-receptor antagonists: an update. Pharmacotherapy, 7(6 pt 2): 110S-115S. Schepp (1993) Stress ulcer prophylaxis: still a valid option in the 1990? Digestion, 54:189-199. Schuman et al., (1987) Prophylactic therapy for acute ulcer bleeding: a reappraisal. Ann Intern. Med., 106:562-567. Schuster (1993) Stress ulcer prophylaxis: in whom? with what? Crit. Care Med., 21:4-6. Siepler (1986) A dosage alternative for H-2 receptor antagonists, continuous-infusion. Clin. Ther., 8(Suppl A):24-33. Simms et al., (1991) Role of gastric colonizmation in the development of pneumonia in critically ill trauma patients . . . J. Trauma, 31:531-536. Skillman et al., (1969) Respiratory failure, hypotension, sepsis and jaundice: a clinical syndrome associated with lethal. . . Am. J. Surg., 117:523-530. Skillman et al., (1970) The gastric mucosal barrier: clinical and experimental studies in critically ill and normal man ... Ann Surg., 172:564-584. Smythe and Zarowitz (1994) Changing perspectives of stress gastritis prophylaxis. Ann Pharmacother., 28:1073-1084. Spychal and Wickham (1985) Thrombocytopenia associated with ranitidine. Br. Med. J., 291:1687. Tryba (1994) Stress ulcer prophylaxis--quo vadis? Intens. Care Med., 20:311-313. Tryba (1987) Risk of acute stress bleeding and nosocmial pneumonia in ventilated intensive care patients. Sucralfate vs. antacids. Am. J. Med., 87(3B): 117-124. Vial et al., (1991) Side effects of ranitidine. Drug Saf., 6:94-117. Wallmark et al., (1985) The relationship between gastric acid secretion and gastric H+/K+--ATPase activity. J. Biol. Chem., 260:13681-13684. Wilder-Smith and Merki (1992) Tolerance during dosing with H2 receptor antagonists. An overview. Scand. J. Gastroenterol., 27(suppl 193): 14-19. Zinner et al., (1981) The prevention of gastro-intestinal tract bleeding in patients in an intensive care unit. Surg. Gynecol. Obstet., 153:214-220. Gray et al. (1985) Influence of insulin antibodies on pharmacokinetics and bioavailability of recombinant human ... British MedicalJoumal, 290:1687-1690. Lind et al., (1986) Inhibition of basal and betazole- and sham-feeding-induced acid secretion by omeprazole in man. Scand. J. Gastroenterol, 21:1004-1010. Nakagawa et al., (1991) Lansoprazole: Phase I Study of Lansoprazole (AG-1749) antiulcer agent Abstract in english; text in Japanese.
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8-1
Nov. 24,1998
5,840,737
7-
7+0.6
*§. «£J
0
533+0.7
I 4-
2-
1pre-SOS
2 hr p 1st DOSE
te-L
DAILY, PRE DOSE (xj
THE LOWEST GASTRIC pR
NO PRIOR SRMD PROPHYLAXIS
n=65
H-2 ASSOCIATED CLINICAL FAILURES n=8 77 PATIENTS RECEIVED OMEPRAZOLE 2 PATIENTS WERE INEVALUABLE
H-2 ASSOCIATED ADVERSE EFFECTS n=4
75 PATIENTS TORE EVALUABUS OVERALL PATIENT ENROLLMENT SCHEME
GASTRIC pH pre SOS 3.5 ±19
pH 4 hr post SOS 7.1 + 11
MEAN pH post SOS 6.8 ±0.6
LOWEST pH post SOS 5.6 + 1.3
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OMEPRAZOLE SOLUTION AND METHOD FOR USING SAME
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reported mortality of thirty percent to fifty percent (Czaja et al., 1974; Peura and Johnson, 1985). Those who do not need surgery often require multiple transfusions and prolonged This application is a continuation-in-part of U.S. Prov. hospitalization. Prevention of stress-related upper gasApp. Ser. No. 60/009,608 filed on Jan. 4,1996. 5 tromtestinal bleeding is an important clinical goal. In addition to general supportive care, the use of drugs to TECHNICAL FIELD prevent stress-related mucosal damage is considered by T, .. .. i. . u .·! many to be the standard of care (AMA Drug Evaluations). 6 The present invention relates to a pharmaceutical prepaHQ J d consensus is ^ about which drugs £ ration containing a substituted benzimidazoK More L setting (Martin et al., 1993; Gafter et al., 1989; use m th particularly, the present mvenuon relates to a substituted ^^ ^ Martin ^ al ^ me'ta.analyses (Cook e, benzimidazole solution/suspension suitable for oral adimn^ 1M1; ^^ 1994)> antacids> 8U
18 ra lon
H2-antagonists were all found to be superior to placebo and similar to one another in preventing upper gastrointestinal 15 bleeding. Yet, prophylactic agents are withdrawn in fifteen Omeprazole is a substituted benzimidazole, 5-methoxyto twenty percent of patients in which they are employed 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl]because of failure to prevent bieeding) or controi pH (Ostro IH-benzimidazole, that inhibits gastric acid secretion. Omeet al.7 19gs; giepler, 1986; Ballesteros et al., 1990), or prazole belongs to a class of antisecretory compounds, the because of adverse effects (Gafter et al., 1989; Sax, 1987; substituted benzimidazoles, that do not exhibit anti- 2Q Vial et al., 1991; Cantu and Korek, 1991; Spychal and cholinergic or H2 histamine antagonist properties. Drags of Wickham, 1985). In addition, the characteristics of an ideal this class suppress gastric acid secretion by the specific agent for the prophylaxis of stress gastritis and concluded inhibition of the H*/K+ ATPase enzyme system at the mat none of the agents currently in use fulfiU their criteria secretory surface of the gastric parietal cell. (Smythe and Zarowitz, 1994). Typically, omeprazole in the form of a delayed-release 25 Omeprazole reduces gastric acid production by irreverscapsule, is prescribed for short-term treatment of active jbly inhibiting the H+/K+ ATPase of the parietal cell--the duodenal ulcers, gastric ulcers, gastroesophageal reflux dis- finai common pathway for gastric acid secretion (Fellenius ease (GERD), severe erosive esophagitis, poorly responsive et al., 1981; Wallmark et al., 1985; Frylund et al., 1988). systematic GERD, and pathological hypersecretory condiBecause this drug maintains gastric pH control throughout tions such as Zollinger Ellison syndrome. These conditions 30 the dosing interval and has a very good safety profile, it is are caused by an imbalance between acid and pepsin a logical choice for stress ulcer prophylaxis. The absence of production, called aggressive factors, and mucous, an intravenous or oral liquid dosage form in the United bicarbonate, and prostaglandin production, called defensive States, however, has limited the testing and use of omeprafactors. zoie jn the critical care patient population. Subsequently, These above-listed conditions commonly arise in healthy 35 Barie et al (Bane and Hariri, 1992) described the use of or critically ill patients and may be accompanied by signifiomeprazole enteric-coated pellets administered through a cant upper gastrointestinal bleeding. H2 antagonists, nasogastric tube to control gastrointestinal hemorrhage in a antacids, and sucralfate are commonly administered to minicritical care patient with multi-organ failure, mize the pain and the complications related to these condiStress ulcer prophylaxis has become routine therapy in tions. These drugs have certain disadvantages associated 40 intensive care units in most hospitals (Fabian et al, 1993.; with their use. Some of these drugs are not completely Cook et al., 1991). Controversy remains regarding pharmaeffective in the treatment of the aforementioned conditions cologic intervention to prevent stress-related bleeding in and/or produce adverse side effects, such as mental critical care patients. It has been suggested that the incidence confusion, constipation, diarrhea, thrombocytopenia, and risk of gastrointestinal bleeding has decreased in the last (lowered platelet count) and/or are relatively costly modes 45 ten years and drug therapy may no longer be needed (Cook of therapy as they require the use of automated infusion et al., 1994; Tryba, 1994; Schepp, 1993). This reasoning is pumps for continuous intravenous delivery. not supported by a recent placebo-controlled study. Martin Patients with significant physiologic stress are at risk for et al. conducted a prospective, randomized, double-blind, stress-related gastric mucosal damage and subsequent upper placebo-controlled comparison of continuous-infusion gastrointestinal bleeding (Marrone and Silen, 1984). Risk so cimetidine and placebo for the prophylaxis of stress-related factors that have been clearly associated with the developmucosal damage (Marten et al., 1993). The study was ment of stress-related mucosal damage are mechanical terminated early because of excessive bleeding-related morventilation, coagulopathy, extensive burns, head injury, and tality in the placebo group. It appears that the natural course organ transplant (Zinner et al., 1981; Larson et al., 1984; of stress-related mucosal damage in a patient at risk who Czaja et al., 1974; Skillman et al., 1969; and Cook et al., 55 receives no prophylaxis remains significant. In the placebo 1994). One or more of these factors are often found in group, thirty-three percent of patients developed clinically critically ill, intensive care unit patients. A recent cohort significant bleeding, nine percent required transfusion, and study challenges other risk factors previously identified such six percent died due to bleeding-related complications. In as acid-base disorders, multiple trauma, significant comparison, fourteen percent of cimetidine-treated patients hypertension, major surgery, multiple operative procedures, 60 developed clinically significant bleeding, six percent acute renal failure, sepsis, and coma (Cook et al., 1994). required transfusions, and 1.5% died due to bleeding-related Regardless of the risk type, stress-related mucosal damage complication; the difference in bleeding rates between treatresults in significant morbidity and mortality. Clinically ment groups was statistically significant. This study clearly significant bleeding occurs in at least twenty percent of demonstrated that continuous-infusion cimetidine reduced patients with one or more risk factors who are left untreated 65 morbidity in critical care patients. Although, these data were (Martin et al., 1993). Of those who bleed, approximately ten used to support the approval of continuous-infusion cimepercent require surgery (usually gastrectomy) with a tidine by the Food and Drug Administration for stress ulcer BACKGROUND OF THE INVENTION
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prophylaxis, H2-antagonisls fall short of being the optimal for complications related to stress-related mucosal damage, pharmacotherapeutic agents for preventing of stress-related However, in its current form (capsules containing an entericmucosal bleeding. coated granule formulation of omeprazole), omeprazole can Another controversy surrounding stress ulcer prophylaxis be difficult or impossible to administer to patients who are is which drug to use. In addition to the various 5 unable (critically ill patients, children, elderly, patients sufH2-antagonists, antacids and sucralfate are other treatment fering from dysphagia) or patients who are either unwilling options for the prophylaxis of stress-related mucosal damor unable to swallow tablets or capsules. Therefore it would age. An ideal drug in this setting should possess the followbe desirable to formulate an omeprazole solution which can ing characteristics: prevent stress ulcers and their be enteraiiy delivered to a patient thereby providing the complications, be devoid of toxicity lack drug interactions, ,,, benefits of omeprazole without the drawbacks of the current be selective, have minimal associated costs (such as personcapsule dose form nel time and materials), and be easy to administer (Smythe and Zarowilz 1994) Omeprazole has been formulated in many different Some have suggested that sucralfate is possibly the ideal embodiments such as in a mixture of polyethylene glycols formed a agent for stress ulcer prophylaxis (Smythe and Zarowitz, mixture of adeps solidus and sodium lauryl sulfate 15 m a 1994). Randomized, controlled studies support the use of soluble, basic amino acid to yield a formulation sucralfate (Borrero et al, 1986; Tryba, 1987; Cioffi et al., designed for administration in the rectum as shown in U.S. 1994; Driks et al., 1987), but data on critical care patients Pat. No. 5,219,870 to Kim. U.S. Pat No. 5,395,323 to with head injury, trauma, or burns are limited. In addition, a Berglund ('323) discloses a device for mixing a pharmarecent study comparing sucralfate and cimetidine plus antceutical from a solid supply into a parenterally acceptable acids for stress ulcer prophylaxis reported clinically signifl- 2° liquid form for parenteral administration to a patient. The cant bleeding in three of forty-eight (6%) sucralfate-treated '323 patent teaches the use of an omeprazole tablet which is patients, one of whom required a gastrectomy (Cioffi et al., placed in the device and dissolved by normal saline, and 1994). In the study performed by Driks and coworkers that infused into the patient. This device and method of infusing compared sucralfate to conventional therapy (H2- omeprazole does not provide the omeprazole solution as an antagonists, antacids, or H2-antagonists plus antacids), the 25 enteral product nor is this omeprazole solution directly only patient whose death was attributed to stress-related administered to the diseased or affected areas, namely the upper gastrointestinal bleeding was in the sucralfate arm stomach ^ upper gastrointestmai tract, nor does this ome(Driks et al., 1987). prazole formulation provide the immediate anti-acid effect H2-antagonists fulfill many of the criteria for an ideal of the nt formuiatiOn. stress ulcer prophylaxis drug. Yet, clinically significant 30 TTO ,, . vr ,, ,,,,, ,,,, . r . . ,. , Pat N et al disclose a bleeds can oc^ur during ^-antagonist prophylaxis (Martin TM°- 4>786'505 to ^.^ " * et al., 1993; Cook et al., 1991; Schuman et al., 1987) and pharmaceutical preparation containing omeprazole together Wlth an a £alme reactln adverse events are not uncommon in the critical care popu" S compound « an alkalme salt of lation (Gafter et al., 1989; Sax, 1987, Vial el al., 1991; Cantu omeprazole optionally together with an alkaline compound and Korek, 1991; Spychal and Wickham, 1985). One reason 35 af, acore mate"al m a tab1^ Emulation. The use of the proposedforthe therapeutic H2-antagonist failures is lack of *^1TM matena1' ^ ^n be chosenfromsuch substances pH control throughout the treatment period (Ostro et al., f me sodf m **l of <;atbonic ac,ld> m. used to form » 1985). Although the precise pathophysiologic mechanism(s) "micro-PH" around each omeprazole particle to protect the involved in stress ulceration are not clearly established, the omeprazole which is highly sensitive to acid pH. The high concentration of hydrogen ions in the mucosa (Fiddian- 40 PTMder m«tuIB » mfn formulated to smaU beads> PeUets; tablets and ma Green et al., 1987) or gastric fluid in contact with mucosal y be ""wled into capsules by conventional cells appears to be an important factor. Agastric pH >3.5 has Pharmaceutical procedures. been associated with a lower incidence of stress-related Th15 formulation of omeprazole does not provide an mucosal damage and bleeding (Larson et al., 1984; Skillman omeprazole dose form which can be enteraiiy administered et al., 1969; Skillman et al., 1970; Priebe and Skillman, 45 to a patient who may be unable and/or unwiUing to swallow 1981). Several studies have shown that H2-antagonists, even capsules or pellets nor does it teach a convenient form which ca in maximal doses, do not reliably or continuously increase n be used to make an omeprazole solution, intragastric pH above commonly targeted levels (3.5 to 4.5). Several buffered omeprazole solutions have been disThis is true especially when used in fixed-dose bolus regiclosed. Andersson et al., 1993; Landahl et al., 1992; Andermens (Ostro, 1985; Siepler, 1986; Ballesteros et al., 1990). 50 sson et al., 1990; Regardh et al., 1990; Andersson et al., In addition, gastric pH levels tend to trend downward with 1990; Pilbrant et al., 1985. time when using a continuous-infusion of H2-antagonists, All of the buffered omeprazole solutions described in which may be the result of tachyphylaxis (Ostro et al., 1985; these references were administered orally and were given to Wilder-Smith and Merki, 1992). healthy subjects who were able to ingest the oral dose. In all Because stress ulcer prophylaxis is frequently employed 55 of these studies, omeprazole was suspended in a solution in the intensive care unit, it is essential from both a clinical including sodium bicarbonate, as a pH buffer, in order to and economic standpoint to optimize the pharmacotherapeuprotect the acid sensitive omeprazole during administration, tic approach. In an attempt to identify optimal therapy, cost In all of these studies, repeated administration of sodium of care becomes an issue. All treatment costs should be bicarbonate both prior to, during, and following omeprazole considered, including the costs of treatment failures and eo administration were required in order to prevent acid degdrug-related adverse events. While the actual number of radation of the omeprazole given via the oral route of failures resulting in mortality is low, morbidity (e.g., bleedadministration. As a result, the ingestion of the large ing that requires blood transfusion) can be high, even though amounts of sodium bicarbonate and large volumes of water its association with the failure of a specific drug is often were required. In the above-cited studies, as much as 48 unrecognized. 65 mmoles of sodium bicarbonate in 300 ml of water must be Omeprazole represents an advantageous alternative to the ingested for a single dose of omeprazole to be orally use of H2 antagonists, antacids, and sucralfate as a treatment administered.
SANTARUS 00000019
Case 1:07-cv-00551-GMS
Document 19-2
Filed 03/07/2008
Page 21 of 31
5,840,737
5 6
Initial reports of increased frequency of pneumonia in (1985) reference, the oral omeprazole administration protopatients receiving stress ulcer prophylaxis with agents that col
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