UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Aurobindo Pharma USA Inc.
`
`Petitioner
`
`V.
`
`Andrx Corporation,
`Andrx Laboratories, Inc.
`Andrx Laboratories (NJ), Inc.
`Andrx EU Ltd.
`
`Andrx Pharmaceuticals, LLC,
`
`Teva Pharmaceutical Industries Inc.
`
`Patent Owner(s).
`
`US. Patent No. 6,790,459 to Cheng et a1.
`Issue Date: September 14, 2004
`Title: Methods for Treating Diabetes Via Administration of
`Controlled Release Metformin
`
`Declaration of Dr. Fatemeh Akhlaghi, Pharm.D., Ph.D.
`
`AUROBINDO EX. 1009, 1
`
`AUROBINDO EX. 1009, 1
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Aurobindo Pharma USA Inc.
`
`Petitioner
`
`V.
`
`Andrx Corporation,
`Andrx Laboratories, Inc.
`Andrx Laboratories (NJ), Inc.
`Andrx EU Ltd.
`
`Andrx Pharmaceuticals, LLC,
`
`Teva Pharmaceutical Industries Inc.
`
`Patent Owner(s).
`
`US. Patent No. 6,790,459 to Cheng et a1.
`Issue Date: September 14, 2004
`Title: Methods for Treating Diabetes Via Administration of
`Controlled Release Metformin
`
`Declaration of Dr. Fatemeh Akhlaghi, Pharm.D., Ph.D.
`
`AUROBINDO EX. 1009, 1
`
`AUROBINDO EX. 1009, 1
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`QUALIFICATIONS
`
`II.
`
`SCOPE OF WORK
`
`III. OVERVIEW OF THE '459 PATENT
`
`IV. BRIEF SUMMARY OF THE FILE HISTORY OF THE ’459
`
`PATENT
`
`V.
`
`LEGAL STANDARDS
`
`VI.
`
`LEVEL OF ORDINARY SKILL AND RELEVANT TIME
`
`VII. CLAIM CONSTRUCTION
`
`VIII. THE STATE OF THE ART
`
`IX.
`
`PRIOR ART REFERENCES DISCLOSE CLAIMED ELEMENTS
`
`IN THE '459 PATENT AND THE MOTIVATION FOR THE
`
`COMBINING OF SUCH ELEMENTS TO EVENTUATE IN THE
`
`SUBJECT MATTER OF THE '459 PATENT
`
`A.
`
`Brief Overview of the Asserted References
`
`1.
`
`2.
`
`Chen et al., W0 00/ 12097 (the '097 publication") with a
`publication date of March 9, 2000 claiming priority to
`US application filed on August 31, 1998 (Ex. 1011)
`
`Cheng et al., WOl999/047125 (the “125 publication")
`with an International publication date of Sept. 23, 1999
`claiming priority from provisional application no.
`90/045,330 filed on March 20, 1998. Thus, ‘the ‘ 125
`publication, qualifies as prior art to the ‘459 patent
`claims under 35 U.S.C. §102(b). (Ex. 1002)
`
`3
`
`4
`
`5
`
`1 5
`
`30
`
`33
`
`35
`
`42
`
`44
`
`44
`
`44
`
`46
`
`AUROBINDO EX. 1009, 2
`
`AUROBINDO EX. 1009, 2
`
`
`
`3.
`
`4.
`
`5.
`
`Timmins et al., WO 99/47128 was published on
`September 23, 1999. The ‘128 publication, therefore
`qualifies as prior art to the ‘459 patent claims under 35
`U.S.C. §102(a) (Ex. 1013)
`
`Tucker et al., “Metformin kinetics in healthy subjects and
`in patients with diabetes mellitus.” University
`Department of Therapeutics: The Royal Hallamshire
`Hospital, Sheffield, 810 21F. Br. J. Clin. Pharmac.
`(1981), 12, 235-246. The ‘G.T. TUCKER et al.,
`publication, therefore qualifies as prior art to the ‘459
`patent claims under 35 U.S.C. §102(b) (Ex. 1005)
`
`Lewis et al., WO 00/28989 Al was published on 25 May
`2000. The ‘989 publication, therefore qualifies as prior
`art to the ‘459 patent claims under 35 U.S.C. §102(a)
`(Ex. 1003).
`
`B.
`
`
`Detailed Analysis of the Claims
`
`1.
`
`2.
`
`Ground 1: Claims 1-21 Are Unpatentable Under 35
`U.S.C. § 102 Over Chen et al., WO 00/12097 (Ex. 1011)
`AS Being Anticipated
`
`Ground 2: Claims 1-21 are Unpatentable Under 35
`U.S.C. § 103(a) AS Being Obvious Over WO
`99/47125)("Cheng et al.") (Ex. 1002) In View of WO
`99/47128 ("Timmins et al. ") (Ex. 1013), Tucker et al.,
`“Metformin kinetics in healthy subjects and in patients
`with diabetes mellitus.” University Department of
`Therapeutics: The Royal Hallamshire Hospital, Sheffield,
`810 2JF. Br. J. Clin. Pharmac. (1981), 12, 235-246
`("Tucker et al.") (EX. 1005), and WO 00/28989 ("Lewis
`et a1. ")(Ex. 1003)
`
`X.
`
`CONCLUDING STATEMENTS
`
`XI. APPENDIX — LIST OF EXHIBITS
`
`49
`
`50
`
`51
`
`52
`
`52
`
`62
`
`85
`
`87
`
`ii
`
`AUROBINDO EX. 1009, 3
`
`AUROBINDO EX. 1009, 3
`
`
`
`I, Fatemeh Akhlaghi, declare as follows:
`
`I. QUALIFICATIONS
`
`1.
`
`My name is Fatemeh Akhlaghi. I have been working in the areas of
`
`pharmacokinetics, clinical pharmacology and drug metabolism since 1990.
`
`In particular, I have worked for the past 15 years on the clinical pharmacology of oral
`
`hypoglycemic agents, including metformin, to treat type 2 diabetes mellitus.
`
`I have
`
`in-depth understanding to the physiological and pathological factors affecting drug
`
`deposition in patients with type 2 diabetes. In addition to 70 peer-reviewed articles, I
`
`have published 15 articles on the pharmacokinetics of various drugs in patients with
`
`type 2 diabetes.
`
`2.
`
`I am presently a full Professor (since 2011) at the University of Rhode
`
`Island, School of Pharmacy and an Adjunct Professor of Medicine at Brown University
`
`Medical School (since July 2014).
`
`I am currently Professor of Pharmacokinetics and
`
`the Ernest Mario Distinguished Chair of Pharmaceutics in the College of Pharmacy,
`
`University of Rhode Island.
`
`3.
`
`I received my Pharm.D. Degree from the University of Mashhad, Iran, in
`
`1990, and my Ph.D. degree in Pharmaceutical Sciences from the University of Sydney
`
`Australia in 1997.
`
`I undertook a post-doctorate positon at the University of Sydney
`
`until 1998, followed by a position as Senior Clinical Scientist, at the University of
`
`Cambridge, UK. until January 2001.
`
`AUROBINDO EX. 1009, 4
`
`AUROBINDO EX. 1009, 4
`
`
`
`4.
`
`In February 2001, I was employed as an Assistant Professor at the
`
`University of Rhode Island. I received tenure in 2006, being appointed as an Associate
`
`Professor.
`
`5.
`
`I have received numerous honors and award, including the Levy Maill
`
`Pattison Award at the University of Sydney, the Paul-Ehrlich Magic Bullet Award,
`
`Nurnberg, Germany, and the Outstanding Intellectual Property Award from the
`
`University of Rhode Island.
`
`6.
`
`I have extensive experience in pharrnacokinetic and pharmacodynamics,
`
`drug development, and design and execution of bioequivalence and drug interaction
`
`studies.
`
`7.
`
`A summary of my experience, education, publications and other
`
`qualifications is provided in my CV, a copy of which is submitted separately. (Ex.
`
`1010).
`
`II.
`
`SCOPE OF WORK
`
`8.
`
`I understand that a petition is being filed with the United States Patent
`
`and Trademark Office ("USPTO") to challenge the validity of all of the claims of US.
`
`Patent No. 6,790,459 to Cheng et al, (“the '459 patent”, Ex. 1001) through the USPTO
`
`procedure known as Inter Partes Review.
`
`I have been retained by Aurobindo Pharma
`
`USA. to provide my opinion as to the validity of the claims of the '459 patent.
`
`9.
`
`I have reviewed the '459 patent and its prosecution history generated at
`
`the United States Patent and Trademark Office in full (Ex. 1006). I have also reviewed
`
`4
`
`AUROBINDO EX. 1009, 5
`
`AUROBINDO EX. 1009, 5
`
`
`
`and considered various other documents in arriving at my opinions, and I cite them in
`
`this declaration. For convenience, documents cited in this declaration are listed in the
`
`Appendix in Section X111.
`
`10.
`
`I am being compensated by the petitioner at the rate of $400/hour for my
`
`work. I have no financial interest in the outcome of this matter.
`
`III. OVERVIEW OF THE '459 PATENT
`
`11.
`
`The
`
`'459 patent
`
`is
`
`titled “Methods
`
`for Treating Diabetes via
`
`Administration of Controlled Release Metformin.”
`
`The ’459 patent
`
`issued on
`
`September 14, 2004 claiming priority through US. Application No. 09/705,625 to a
`
`filing date of November 3, 2000.
`
`12.
`
`As noted in the Abstract,
`
`the '459 patent discloses a "[a] method for
`
`treating patients having non-insulin-dependent diabetes mellitus (NIDDM) by
`
`administering a controlled release oral solid dosage form containing preferably a
`
`biguanide drug, such as metformin, on a once-a-day basis. The dosage form provides
`
`a mean time to maximum plasma-concentration (Tmax) of the drug which occurs at 5.5
`
`to 7.5 hours after oral administration on a once-a—day basis to human patients.
`
`Preferably, the dose of drug is administered at dinnertime to a patient in the fed state.”
`
`13.
`
`The "Summary of the Invention," notes that: "In preferred embodiments,
`
`the controlled release oral dosage form of the present invention is a tablet comprising
`
`(a) a core comprising: (i) the antihyperglycemic drug; (ii) optionally a binding agent,
`
`and (iii) optionally an absorption enhancer; (b) a membrane coating surrounding the
`
`5
`
`AUROBINDO EX. 1009, 6
`
`AUROBINDO EX. 1009, 6
`
`
`
`core, and (c) at least one passageway in the membrane. 3:36-44.
`
`I note the same
`
`controlled release oral dosage form being disclosed in Cheng et al., WOl999/047125
`
`(Ex. 1002), which having an international publication date of September 23, 1999,
`
`qualifies as prior art to the '459 patent ("Cheng et al. ").
`
`14.
`
`The "Summary of Invention" also notes that "[w]hen the drug is
`
`metformin or a pharmaceutically acceptable salt thereof is administered on a once-a-
`
`day basis the daily dose may vary, e.g. from about 500 mg to about 2500 mg."3 :45-48.
`
`I note that the reference WO 00/28989A1 to Lewis et al. ("Lewis et 61].", Ex. 1003),
`
`which having published on May 25 2000 is prior art to the '459 patent, indicates in
`
`relation to a controlled release preparation of metforrnin that a suitable dose of
`
`metformin is between 100 to 2000 mg, substantially overlapping the daily dose range
`
`recited in the '459 patent.
`
`15.
`
`The specification also emphasizes that
`
`it was advantageous for the
`
`method claimed to approximate certain pharmacokinetic parameters seen upon
`
`administration of GLUCOPHAGE® twice a day:
`
`"In certain embodiments of the
`
`invention,
`
`the administration of the antihyperglycemic drug, e.g. at
`
`least one
`
`metformin dosage form, provides a mean AUC0-24h from at least 80%, preferably at
`
`least 90% of the mean AUC0-24h provided by administration of the reference standard
`
`(GLUCOPHAGE) twice a day ..." 4:29-34, and that it may when "administered
`
`immediately after either breakfast or dinner" provide "a relative bioavailability
`
`to
`
`GLUCOPHAGE [which] is approximately 100%. 17:19-22.
`
`6
`
`AUROBINDO EX. 1009, 7
`
`AUROBINDO EX. 1009, 7
`
`
`
`16. However, it notes "[t]he controlled release dosage form of the present
`
`invention provides a delayed TmX as compare to the Tmax provided by GLUCOPHAGE,
`
`the delayed Tmax occurs from 5.5 to 7.5 hours after administration." 5:28-31. The
`
`delayed Tmax is said to have been selected such that after its administration at dinner
`
`time "the Tmax would occur during the time when gluconeogenesis is usually at its
`
`highest (e.g., around 2 am). 5: 32-35.
`
`I note, however, that the desirability of such a
`
`Tmx in a controlled release formulation of metformin HCl was already taught in WO
`
`99/47128 to Timmins et a]. (Ex. 1013), which having published on September 23, 1999
`
`qualifies as prior art to the '459 patent.
`
`17.
`
`It also noted in the specification of the '459 patent that the tablets used in
`
`the method provide a higher mean fluctuation index in plasma (Cmax - Cmin/Cavg) than
`
`GLUCOPHAGE administered in two equal divided doses. 18: 19—24. However, I note
`
`that the controlled release formulation of Cheng et a]. would be understood by a POSA
`
`to disclose the same upon review of Figs. 7 and 8 of the Cheng et al. reference.
`
`18.
`
`Importantly it is taught in the specification that the pharmacokinetic
`
`parameters recited in the methods of the patent are not dependent on the particular
`
`controlled release formulation recited in the specification as " [o]ther controlled release
`
`technologies known to those skilled in the art can be used in order to achieve the
`
`controlled release formulations of the present invention,
`
`i.e., formulations which
`
`provide a mean Tmax of the drug and/or other pharmacokinetic parameters described
`
`herein when orally administered to human patients." Col 12, 11. 42-47.
`
`7
`
`AUROBINDO EX. 1009, 8
`
`AUROBINDO EX. 1009, 8
`
`
`
`19.
`
`Thus, the inventors and applicant admit that it was within the skill of a
`
`POSA to produce the pharmacokinetic parameters recited in the '459 patent using other
`
`controlled release preparations.
`
`20.
`
`I note that the specification of US. Patent No. 6,790,459 ("459 patent")
`
`is identical to the specification of US. Patent No. 6,866,866 ("the '866 patent", Ex.
`
`1016) (except for some minor errors being corrected). The application leading to the
`
`'866 patent being filed on the same day that the application leading to the '459 patent
`
`was filed. Both applications list the same applicant (Aner Labs, LLC) and the four
`
`same inventors.
`
`21.
`
`As noted in the prosecution history of the '459 patent (Ex. 1006), the
`
`applicant and inventors admitted that a POSA would understand that controlled release
`
`formulations could be easily altered to produce particular pharmacokinetic parameters
`
`specified in the mutual specifications, such as TmaX ranges:
`
`filed,
`the time the application was
`In addition, at
`numerous controlled release technologies were well
`within the knowledge of pharmaceutical
`formulators
`having ordinary skill
`in the art. Such pharmaceutical
`formulators know that controlled release technologies can
`be manipulated. . .to provide a formulation which upon in-
`vivo testing will provide the Tmax range of the present
`invention. This fact is supported, e.g., by a simple review
`of patents discussed in the specification concerning
`formulation technologies, which patents provide ranges of
`ingredients. These ranges represent the acknowledgement
`of those skilled in the art
`that a certain amount of
`
`be necessary to
`considered to
`experimentation is
`manipulate a controlled release technology to obtain a
`desired release pattern of the drug. Such release patterns
`
`8
`
`AUROBINDO EX. 1009, 9
`
`AUROBINDO EX. 1009, 9
`
`
`
`are demonstrated by the (well-known) use of in-vitro
`dissolution testing, which is considered by pharmaceutical
`formulators of ordinary skill in the art to provide guidance
`as to which particular formulations might provide the desired
`in-vivo performance.
`Ex.
`1006,
`(US. Patent No.
`Amendment March 4, 2003)1
`
`6,790,459 file history:
`
`22.
`
`Thus the applicant (Andrx Labs) and the four inventors of the '459 patent
`
`acknowledged that a POSA could easily manipulate with less than extensive
`
`experimentation any controlled oral dosage form which had a similar in-vitro
`
`dissolution profile to achieve the pharmacokinetic parameters recited in the '459 patent.
`
`23.
`
`As I note below, certain controlled release pharmaceutical oral dosage
`
`forms were known that had nearly an identical release rate to that recited in the '459
`
`patent. Thus, the only patentability that might be associated with the method claims
`
`set forth in the '459 patent would be with respect to the non—obviousness of the
`
`pharmacokinetic parameters recited in the claims.
`
`As such pharmacokinetic
`
`parameters were associated with other controlled release dosage forms, such could not
`
`be said to be non-obvious.
`
`24.
`
`Furthermore I note that there is no mention anywhere in the specification
`
`or in the file history of any unexpected result or special advantage associated with any
`
`of the pharmacokinetic parameters recited in the claims of the '459 patent. Thus, none
`
`of the claims rise to a level of patentability.
`
`1 Amendment Under 37 CPR. § 1.111, filed March 4, 2003 (From file history of
`Application Serial No. 09/705,625, Ex. 1006, pp. 215-216)
`
`9
`
`AUROBINDO EX. 1009, 10
`
`AUROBINDO EX. 1009, 10
`
`
`
`25.
`
`Claim 1 is the only independent claim in the '459 patent. Thus all other
`
`claims, 2 — 21, depend upon claim 1 and by dependency assert each of the limitations
`
`of claim 1:
`
`1. A method for lowering blood glucose levels in human patients
`
`needing treatment
`
`for non-insulin—dependent diabetes mellitus
`
`(NIDDM), comprising orally administering to human patients on a
`
`once-a-day basis at
`
`least one oral controlled release dosage form
`
`comprising an effective dose of metformin or a pharmaceutically
`
`acceptable salt thereof and an effective amount of a controlled release
`
`carrier to control the release of said metformin or pharmaceutically
`
`acceptable salt thereof from said dosage form, wherein following oral
`
`administration of a single dose, the dosage form provides a mean time
`
`to maximum plasma concentration (Tmax) of metformin at from 5.5 to
`
`7.5 hours after administration following dinner; and the administration
`
`of the at least one metformin dosage form provides a mean AUC0-24 of
`
`2259028626 ng-hr/ml and a mean Cmax of 2435i630 ng/ml on the first
`
`day of administration and a mean AUC0-24 of 24136i7996 ng'hr/ml and
`
`a mean Cmx of 2288i736 np/ml on the 14th day of administration, for
`
`administration of a 2000 mg once-a-day dose of metformin.
`
`26. With respect to claim 1, as expanded more below, I find each of the
`
`pharmacokinetic parameters recited to be obvious or anticipated by the prior art, in
`
`particular Cheng et al. which would suggest the claimed AUC0-24 and the Cmax at day 1
`
`to a POSA, and the Tucker et 611., (EX. 1005) reference that would suggest the mean
`
`Cmax and AUC0-24 at day 14.
`
`10
`
`AUROBINDO EX. 1009, 11
`
`AUROBINDO EX. 1009, 11
`
`
`
`27. Dependent claims 2 and 3 differ from claim 1 only in reciting mean time
`
`to maximum plasma concentration (Tmax) being within the range of Tmax recited in
`
`claim 1, that is, 5.5 to 7.5 hours (claim 2 reciting a Tmax range of 6.0 to 7.0 hours, with
`
`claim 3 reciting a Tmax of from 5.5 to 7.0 hours). As each of these ranges is within the
`
`fall of the Tmax range of Cheng et al. prior art, I find neither of these claims adding to
`
`patentability, as both claims 4 and 5 add a requirement that the width at 50% of the
`
`height of a mean plasma concentration/time curve of metformin be either about 4.5 to
`
`about 13 hours (claim 4) or 5.5 to 10 hours (claim 5). However Fig. 8 of Cheng et al.,
`
`which discloses the exact same preferred controlled release formulation, teaches a
`
`width at 50% of the height of a mean plasma concentration/time curve of metformin
`
`of about 4.5 to 13 hours, covering both ranges. There is no indication in the file
`
`wrapper or specification that the narrower range of 5.5 to 10 hours proffers any
`
`unexpected result.
`
`28.
`
`Claims 6-8 assert administration of at least one metformin dosage form
`
`that provides a Cmax of metformin which is more than about 7 to about 14 times the
`
`mean plasma level of metformin at about 24 hours after administration (claim 6 — more
`
`than 7, claim 7 — from about 7 times to about 14 times, claim 8 from about 8 times to
`
`about 12 times). Fig. 8 of Cheng et al. teaches administration of at least one metformin
`
`dosage form that provides a Cmax of metformin which is more than about 7 or 8 times
`
`the mean plasma level of the metformin at about 24 hours after administration. This
`
`11
`
`AUROBINDO EX. 1009, 12
`
`AUROBINDO EX. 1009, 12
`
`
`
`more than about 7 or 8 clearly fits within the ranges recited in claims 6 -8, and thus
`
`such ranges are obvious as encompassing a known range.
`
`29.
`
`Claim 9 — 10 add the limitation that the at least one metformin dosage
`
`form provides a mean AUC0.24hr from at least 80% of the mean AUC0-24 (claim 9) or at
`
`least one metformin dosage form provides a mean AUCo.z4hr that is from at least 90%
`
`(claim 10) provided by administration of an immediate release reference standard
`
`twice a day, wherein the daily dose of the reference standard is substantially equal to
`
`the once-a—day dose of metformin administered in the controlled release oral dosage
`
`form. However, a POSA would understand from Figs. 7 and 8 of Cheng et a]. that the
`
`parameters asserted in claim 9 and 10 would eventuate upon administration of two 500
`
`mg tablets of the immediate release reference, and would be motivated to do the same
`
`to match then gold standard pharmacokinetic parameters of GLUCOPHAGE®.
`
`30.
`
`Claim 11 asserts use of two controlled release dosage forms containing
`
`1000 mg once a day. However, the Lewis et al. ‘989 publication, clearly discloses a
`
`metformin suitable sustained release dosage form between 100 to 3000 mg. (Page 5,
`
`11. 13-14). A person of ordinary skill in the art would have taken two tablets of 1000
`
`mg each to attain 2000 mg strength, as single 2000 mg tablet cannot be administered
`
`to patient because of the size of the tablet.
`
`31.
`
`Claim 12 asserts the administration of the at least one metformin dosage
`
`form provides a mean AUC0-24 of 1827712961 ng-hr/ml and a mean Cmax of 1929i333
`
`ng/ml, for administration of a 1700 mg once—a—day dose of metformin. A POSA would
`
`12
`
`AUROBINDO EX. 1009, 13
`
`AUROBINDO EX. 1009, 13
`
`
`
`understand from Table 3 of the Tucker et al. reference that the pharmacokinetic
`
`parameter AUC0-24 is linear in relation to doses of metformin between 500 mg and 1500
`
`mg. Therefore the POSA would expect that the administration of a 1700 mg once-a-
`
`day dose of metformin would match AUC0-24 of two 850 mg tablets formulated in the
`
`same manner. As Cheng et a1. teaches a mean AUC value obtained from one 850 mg
`
`tablet of the same preferred formulation of the '459 patent, a POSA knowing of linear
`
`kinetics would expect that two 850 mg tablets would provide the same AUC as a single
`
`tablets. This is the case. Furthermore, the POSA would expect the Cmax to be
`
`approximately twice that of a single 850 mg tablet, as the concentration of drug would
`
`be doubled Therefore the recitations of claim 12 are obvious.
`
`32.
`
`Claim 13 recites the method of claim 1 wherein the administration of the
`
`at least one metformin dosage form provides a mean half-life 0%) from 2.8 to 4.4.
`
`Half—life is a pharmacokinetic parameter that is inherent to the molecule and is
`
`independent of release rate.
`
`I note that there is nothing unobvious in such a range, as
`
`Cheng et a1. teaches in same preferred controlled release formulation a mean t1/2 from
`
`3 to 5.5 (see Figs. 7 and 8).
`
`33.
`
`Claim 14 asserts the method of claim 1 which further comprises
`
`administering to said human patients at least one additional pharmaceutically active
`
`ingredient for treatment of NIDDM. Claim 15 recites that the pharmaceutically active
`
`ingredient for treatment of NIDDM is selected from the group of drugs consisting of a
`
`sulfonylurea, a glitazone, or a second biguanide. However, Lewis et al. teaches a
`
`13
`
`AUROBINDO EX. 1009, 14
`
`AUROBINDO EX. 1009, 14
`
`
`
`metformin controlled release preparation in accord with the preferred embodiment of
`
`the '459 patent which also includes an insulin sensitizer which may be a glitazone (page
`
`20: Claim 15). Therefore, both claims 14 and 15 are made obvious by such teaching
`
`of Lewis et al.
`
`34.
`
`Claim 16 recites the method of claim 1 in which the dose of metformin
`
`comprises metformin hydrochloride. However, as noted above Cheng et a1. discloses
`
`the
`
`same preferred controlled release
`
`formulation can contain metformin
`
`hydrochloride (1 : 1-8). Therefore claim 16 is obvious in light of the prior art.
`
`35.
`
`Claims 17 — 21 recite different metformin or metformin salt dose ranges
`
`(claim 17 — about 1000 mg to about 2500 mg of metformin hydrochloride; claim 18
`
`2000 mg to about 2500 mg metformin hydrochloride) or specific doses of metformin
`
`or metformin salts (claim 19 — 2000 mg metformin or pharmaceutically acceptable salt
`
`thereof; claim 20 — 1000 ng metformin or pharmaceutically acceptable salt thereof; 21
`
`— 500 mg of metformin or pharmaceutically acceptable salt thereof). However, none
`
`of these claims asserts any unobvious dose or dose range of metformin or salt of
`
`metformin, as the Lewis et a]. reference teaches "a suitable dosage of metformin is
`
`between 100 to 3000 mg" (Page 5, 11. 13-14).
`
`36.
`
`In regard to all of the claims, a POSA would also expect the exact same
`
`pharmacokinetic parameters for metformin to be found in the prior art controlled
`
`release tablets of Chen et 61]., W0 00/ 12097, (Ex. 1011), as such tablet has the exact
`
`14
`
`AUROBINDO EX. 1009, 15
`
`AUROBINDO EX. 1009, 15
`
`
`
`same formulation and structure and meets the preferred and most preferred in Vitro
`
`release rates for metformin as found in the tablets of the '459 patent.
`
`37.
`
`I also note in my review of the file history of the '459 patent (Ex. 1006),
`
`the specification of the '459 patent, and the general searches I performed in respect of
`
`this declaration, I did not uncover any evidence of objective indicia of non-obviousness
`
`of any the claims of the '459 patent.
`
`IV. BRIEF SUMMARY OF THE FILE HISTORY OF THE ’459 PATENT
`
`38. US. Patent No. 6,790,459 matured to issue on Sept. 14, 2004 from US.
`
`Patent Application Serial No. 09/705,625 filed on Nov. 3, 2000, (Ex. 1001). US.
`
`Patent Application Serial No. 09/705,625 was filed with 34 claims on Nov. 3, 2000
`
`(Ex. 1006, '459 File History).
`
`39. A first Office Action on the merits of the Application was mailed to
`
`Applicants on Dec. 31, 2001, (Ex. 1006, 251-262). All claims 1-34 were rejected with
`
`no position taken regarding the drawings. Claims 2 and 3 were objected to under 37
`
`CFR 1.75 (c), as being improper dependent form for failing to filrther limit the subject
`
`matter of previous claim. Claims 4-31 were rejected under 35 U S C. 112, second
`
`paragraph, as being indefinite;
`
`the claims requiring the method of claim 3,
`
`in
`
`contradiction to the composition claim of claim 3. Further claims 22-26 were rejected
`
`under 35 U.S.C. §112, second paragraph on the basis that these claims were omnibus-
`
`type claims.
`
`15
`
`AUROBINDO EX. 1009, 16
`
`AUROBINDO EX. 1009, 16
`
`
`
`40.
`
`Further, the examiner rejected claims 1-15 and 19-34 under 35 U.S.C. 102
`
`(a) and as being anticipated over WO 00/28989 to Lewis et al. ('989), under 35 USC
`
`102(b) over WO 99/47125 to Cheng et al. ('125), and US Patent No. 5,955,106 to
`
`Moeckel et a1. (' 106).
`
`41.
`
`Claims 1-34 were also rejected as obvious under 35 U.S.C. 103 (a) over
`
`'989 or '125 or '106 each alone or each in combination with Drug facts and
`
`Comparisons, pg. 635-642 (1999),
`
`the Examiner stating the '989,
`
`'125 and '106
`
`references
`
`all
`
`teach controlled release metformin compositions. Because the
`
`formulations of the references are substantially the same, "the instant claimed
`
`functional limitations are inheren ." Claims 1-34 were further rejected as obvious
`
`under U.S.C. 103(a) based on US. Patent No. 6,270,805 to Chen et al. ('805), in view
`
`of Drug facts and Comparisons, pg. 635-642 (1999)
`
`42.
`
`The Examiner rejected 1-34 claims under the judicially created doctrine
`
`of obviousness—type double patenting, as being unpatentable over US. Patent No.
`
`6,099,859, US. Patent No. 6,284,275 and US. Patent No. 6,099,862, as it was asserted
`
`that they were not patentable distinct from each other as they were in genus-species
`
`relationship.
`
`43.
`
`Claims 1-34 were also rejected under a provisional obviousness-type
`
`double patenting rejection based on co-pending application Nos. 09/705,630,
`
`09/726, 193 and US. Patent Application No. 09/594,637.
`
`16
`
`AUROBINDO EX. 1009, 17
`
`AUROBINDO EX. 1009, 17
`
`
`
`44.
`
`In response to the Examiner’s comments, Applicants filed an Amendment
`
`to the Application on July 08, 2002. Therein, with claims 1-34 pending, claims 1-3
`
`and 22—26 were amended and submitted for examination. The amended claims read as
`
`follows:
`
`The following claim has been amended as follows:
`
`I.
`
`(Amended) A method for lowering blood glucose levels in human patients needing
`
`treatment for non-insulin-dependent diabetes mellitus (NIDDM). comprising orally
`
`administering to human patients on a once-a-day basis at least one oral controlled release
`
`dosage form comprising an effective dose of at least one suitable antihyperglycemic agent
`
`or a pharmaceutical ly acceptable salt thereof and a controlled release carrier. wherein the
`
`dosage form provides a mean time to maximum plasma concentration (Tm) of
`
`[metfonninl the agent at from 5.5 to 7.5 hours after administration.
`
`2.
`
`(Amended) The [controlled release dosage fomtl method of claim 1 wherein said at least
`
`one antihyperglyeemic agent is a biguanide.
`
`3.
`
`(Amended) The [controlled release dosage form) method of claim 2 wherein said
`
`biguanide is metfonnin or a pharmacautically acceptable salt thereof
`
`22.
`
`(Amended) The method of claim 3, in which the administration of the at least one
`
`metiormin dosage form provides a mean 511;; pt ]§2?? a 296i ng-hn‘ml and a mean
`
`gm of 102‘} e 33} tight) [at mean plasma concentration-time profiles of metformin
`
`substantially as set forth in FIG. I]. based on administration eta 1700 mg once-a-day
`
`dose ofmetfomtin after an gvgtting rttgai.
`
`23,
`
`(Amended) The method of claim 3. in which the administration of the at least one
`
`metfonnin dosage form provides a mean Aug, of29335 e 4360 ng-hn’ml and a mean
`
`gm of from 2053 a 44? nggml [a mean plasma concentration-time profiles of metformin
`
`substantially as set forth in FIG. 2|, based on administration of a 2000 mg once-a-day
`
`dose of mctfonnirt alter 3|} evening meal.
`
`17
`
`AUROBINDO EX. 1009, 18
`
`AUROBINDO EX. 1009, 18
`
`
`
`24.
`
`(Amended) The method of claim 3, in which the administration of the at least one
`
`metfonnin dosage form provides a mean we, 2, 2f 2§§l 8 i ?052 ng'hn’ml and a mean
`
`gm of 2849 :l: 727 ngfiml [a mean plasma concentration-time profiles of metfonnin
`
`substantially as set forth in FIG. 4], based on administration of a 2000 mg once-a-day
`
`dose of metfonnin after an evening meal [at dimer].
`
`25.
`
`(Amended) The method of claim 3, in which the administratiou of the at least one
`
`metfonnin dosage form provides a mean Aug,“ of 22590 i- 3626 ng-hr/ml and a mean
`
`QM f243$ :l: 63 n ml (in the frst da ofadmini tration and a mean AUC ,z.of24136
`
`:l: 792;; rig-hrfml and a mean Cm, of22§8 :I: '36 ngml on the 14'“ day of ndminislration [a
`
`mean plasma concentration-time profiles of metformin substantially as set forth in FIG.
`
`6], based on administration of a 2000 mg once-a-day dose of metformin after an evening
`
`meal [at breakfast].
`
`26.
`
`(Amended) The method of claim 3 [3], in which the administration of the at least one
`
`metforrnin dosage fOnn provides a mean '1'”2 from 3.3 to 44 [about mean plasma glucose
`
`concentration-time profiles substantially as set forth in FIG. 5, based on administration of
`
`a 2000 mg once-a-day dose of metformin at dinner].
`
`45.
`
`On Oct. 22, 2002 the Examiner once more rejected the claims again
`
`stating that applicant’s arguments were not persuasive, and that claims 1-31 remained
`
`rejected under 35 U.S.C. § 112 and claims 32-34 rejected under 35 U.S.C. § 102(b).
`
`46.
`
`In response to the Examiner’s comments, Applicants made further
`
`arguments and filed an Amendment to the Application on March 3, 2003. Therein,
`
`claims 2-3, 6, 16-17 and 32-34 were cancelled; and claims 1, 4-5, 7-15 and 19-29 were
`
`amended (“without prejudice”). After such amendments, claims 1, 4-5, 7-15, and 18—
`
`31 remained pending and the claims read as follows:
`
`18
`
`AUROBINDO EX. 1009, 19
`
`AUROBINDO EX. 1009, 19
`
`
`
`The claims have been amended as follows:
`
`1. (Twice Amended) A method for lowering blood glucose levels in human patients
`
`needing treatment for non-insulin—dependent diabetes mellitus (NIDDM). comprising orally
`
`administering to human patients on a once-a-day basis at least one oral controlled release dosage
`
`form comprising an effective dose of [at least one suitable antibyperglycemic agent]
`
`metformin or a pharmaceutically acceptable salt thereof and an effective amount of a
`
`controlled release carrier to control the release of said mett‘ormin or pharmaceuticallx
`
`acceptable salt thereof from said dosage form, wherein following oral administration of a
`
`single dose, the dosage form provides a mean time to maximum plasma concentration (Tm) of
`
`[agent] mett‘ormin at from 5.5 to 7.5 hours alter administration following dinner.
`
`4. (Amended) The method of claim [3] i, in which the administration of the at least one
`
`metformin dosage form provides a mean time to maximum plasma concentration (Em) of
`
`metfonnin at from 6.0 to 7.0 hours after administration.
`
`5. (Amended) The method of claim [3] l. in which the administration of the at least one
`
`metformin dosage form occurs at dimer time and provides a mean time to maximum plasma
`
`concentration (Tmm) of metformin at from [about] 5.5 to 7.0 hours after the administration.
`
`7. (Amended) The method of claim [3] l, in which the administration of the at least one
`
`metformin dosage form provides a width at 50% of the height of a mean plasma
`
`19
`
`AUROBINDO EX. 1009, 20
`
`AUROBINDO EX. 1009, 20
`
`
`
`concentration/time curve of [the drug] metformin from about 4.5 to about 13 hours.
`
`8. (Amended) The method of claim [3] l, in which the administration of the at least one
`
`metformin dosage form provides a width at 50% of the height of a mean plasma
`
`concentration/time curve of [the drug] metformin from about 5.5 to about 10 hours.
`
`9.(Amended) The method of claim [3] 1, in which the administration of the at least one
`
`metformin dosage form provides a mean maximum plasma concentration (me) of metformin
`
`which is more than about 7 times the mean plasma level of said metformin at about 24 hours
`
`after administration.
`
`10. (Amended) The method of claim [3] l, in which the administration of the at least one
`
`metformin dosage form provides a mean maximum plasma concentration (Cum) of metformin
`
`which is from about 7 times to about 14 times the plasma level of said metformin at about 24
`
`hours after administration.
`
`11. (Amended) The method of claim [3] l, in which the administration of the at least one
`
`metformin dosage form provides a mean maximum plasma concentration (Cmax) of metformin
`
`which is lirom about 8 times to about 12 times the plasma level of said metformin at abou
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
