`
`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).
` _______________
`U.S. Patent No. 6,790,459 to Cheng et al.
`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.
`
`
`
`
`
`
`
`
`
`_________________
`
`TABLE OF CONTENTS
`
`QUALIFICATIONS
`I.
`SCOPE OF WORK
`II.
`III. OVERVIEW OF THE '459 PATENT
`IV. BRIEF SUMMARY OF THE FILE HISTORY OF THE
`’459 PATENT
`LEGAL STANDARDS
`V.
`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 TOEVENTUATE
`IN THE SUBJECT MATTER OF THE '459 PATENT
`X. DETAILED ANALYSIS OF THE CLAIMS AND GROUNDS FOR
`UNPATENTABILITY
`XI. SUMMARY OF INVALIDITY DUE TO ANTICIPATION AND
`OBVIOUSNESS
`XII. CONCLUDING STATEMENTS
`
`2
`3
`4
`
`12
`28
`31
`33
`40
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`42
`
`49
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`71
`82
`
`
`
`
`
`
`
`i
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`
`
`
`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 80 peer-reviewed articles, I
`
`have published at least 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, College 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, U.K. until January 2001.
`
`2
`
`
`
`
`
`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 pharmacokinetic and pharmacodynamics,
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`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 U.S.
`
`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
`
`U.S.A. 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
`3
`
`
`
`
`
`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 XIII.
`
`10.
`
`I am being compensated by the petitioner at the rate of $450/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 U.S. 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 noninsulin-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 consisting
`
`of (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
`4
`
`
`
`
`
`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., WO1999/047125
`
`(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 al.", 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 metformin that a suitable dose of
`
`metformin is between 100 to 2,000 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.
`5
`
`
`
`
`
`16. However, it notes "[t]he controlled release dosage form of the present
`
`invention provides a delayed Tmax 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
`
`Tmax in a controlled release formulation of metformin HCl was already taught in WO
`
`99/47128 to Timmins et al. (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 al. 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, ll. 42-47.
`6
`
`
`
`
`
`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 U.S. Patent No. 6,790,459 ("459 patent")
`
`is identical to the specification of U.S. 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 (Andrx 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:
`
`In addition, at the time the application was filed,
`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
`experimentation
`is considered
`to be necessary
`to
`manipulate a controlled release technology to obtain a
`desired release pattern of the drug. Such release patterns
`7
`
`
`
`
`
`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, (U.S. Patent No. 6,790,459 file history:
`Amendment March 4, 2003)1
`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 C.F.R. § 1.111, filed March 4, 2003 (From file history of
`Application Serial No. 09/705,625, Ex. 1006, pp. 215-216)
`8
`
`
`
`
`
`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 noninsulin-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
`22,590±3,626 ng·hr/ml and a mean Cmax of 2,435±630 ng/ml on the
`first day of administration and a mean AUC0-24 of 24,136±7,996
`ng·hr/ml and a mean Cmax of 2,288±736 ng/ml on the 14th day of
`administration, for administration of a 2,000 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 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, from
`
`which the AUC0-24 and the Cmax at day 14 could be determined.
`
`9
`
`
`
`
`
`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). For the reasons set forth below, I find
`
`these obvious.
`
`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). For the reasons set forth below, I find these obvious.
`
`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 AUC0-24hr 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. For the reasons set forth below, I find these obvious.
`
`30. Claim 11 asserts use of two controlled release dosage forms, each
`
`containing 1,000 mg, once a day. For the reasons set forth below, I find this obvious.
`
`31. Claim 12 asserts the administration of the at least one metformin dosage
`
`form provides a mean AUC0-24 of 18,277±2,961 ng·hr/ml and a mean Cmax of
`10
`
`
`
`
`
`1,929±333 ng/ml, for administration of a 1,700 mg once-a-day dose of metformin. For
`
`the reasons set forth below, I find this 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 (t½) from 2.8 to 4.4,
`
`independent of release rate. I note that there is no evidence of non-obviousness in such
`
`a range, as noted below.
`
`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. For the reasons set forth below, I find
`
`this obvious.
`
`34. Claim 16 recites the method of claim 1 in which the dose of metformin
`
`comprises metformin hydrochloride. However, as noted above Cheng et al. 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 1,000 mg to about 2,500 mg of metformin hydrochloride; claim 18
`
`2,000 mg to about 2,500 mg metformin hydrochloride) or specific doses of metformin
`
`or metformin salts (claim 19 – 2,000 mg metformin or pharmaceutically acceptable
`
`11
`
`
`
`
`
`salt thereof; claim 20 – 1,000 ng metformin or pharmaceutically acceptable salt
`
`thereof; claim 21 – 500 mg of metformin or pharmaceutically acceptable salt thereof).
`
`36. However, I note below none of these claims asserts any unobvious dose
`
`or dose range of metformin or salt of metformin, as the Lewis et al. reference teaches
`
`"a suitable dosage of metformin is between 100 to 3,000 mg" (Page 5, ll. 13-14).
`
`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. U.S. Patent No. 6,790,459 matured to issue on Sept. 14, 2004 from U.S.
`
`Patent Application Serial No. 09/705,625 filed on Nov. 3, 2000 (Ex. 1001). U.S. 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 further 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, was found
`
`to be in contradiction to the composition claim of claim 3. Further claims 22-26 were
`12
`
`
`
`
`
`rejected under 35 U.S.C. §112, second paragraph on the basis that these claims were
`
`omnibus-type claims.
`
`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 al. ('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 inherent." Claims 1-34 were further rejected as obvious
`
`under U.S.C. 103(a) based on U.S. 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 U.S. Patent No.
`
`6,099,859, U.S. Patent No. 6,284,275 and U.S. 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.
`
`13
`
`
`
`
`
`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 U.S. Patent Application No. 09/594,637.
`
`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:
`
`14
`
`
`
`
`
`The following claim has been amended as follows:
`
`(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 pharmaceutically 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.
`
`(Amended) The [controlled release dosage form] mm ofclaim I wherein said at least
`
`one antihyperglycemic agent is a biguanide.
`
`(Amended) The [controlled release dosage fonnl method of claim 2 wherein said
`
`biguanide is metfonnin or a pharmaceutically acceptable salt thereof.
`
`22.
`
`(Amended) The method of claim 3, in which the administration of the at least one
`
`metfonnin dosage form provides _a_ mean Aug, _ of 13277 i 226i ng-hglml and a mean
`
`Cw 9f I929 i 333 nglml [a mean plasma concentration~time profiles of metfonnin
`
`substantially as set forth in FIG. ll. based on administration ofa I700 mg once-a-day
`
`dose ofmetforminWill-
`
`23.
`
`(Amended) The method of claim 3. in which the administration ofthe at least one
`
`metfonnin dosage form provides a mean AUQD of 20335 i 4360 ng-hr/ml and a mean
`
`gm of from 2053 t 447 nglml [a mean plasma concentration-time profiles of metfonnin
`
`substantially as set forth in FIG. 2|, based on administration of a 2000 mg once-a-day
`
`dose of metfonnin ails; an gvgning meal.
`
`
`
`15
`
`15
`
`
`
`
`
`
`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:
`
`16
`
`
`
`
`
`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 antihyperglycemic agent]
`
`metformin or a pharmaceutically acceptable salt thereof and an effective amount of a
`
`controlled release carrier to control the release of said metformin 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] metformin at from 5.5 to 7.5 hours afler administration following dinner.
`
`4. (Amended) The method of claim [3] l, in which the administration of the at least one
`
`metformin dosage form provides a mean time to maximum plasma concentration (Tum) of
`
`metformin 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 dinner time and provides a mean time to maximum plasma
`
`concentration (Tm) 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
`
`
`
`17
`
`17
`
`
`
`
`
`concentration/time curve of [the drug] metformin fi'om 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] l, in which the administration of the at least one
`
`metformin dosage form provides a mean maximum plasma concentration (am) 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 (Cmax) of metformin
`
`which is from about 7 times to about 14 times the plasma level of said metformin at about 24
`
`hours afier administration.
`
`1 1. (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 from about 8 times to about 12 times the plasma level of said metformin at about 24
`
`hours afler administration.
`
`12. (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 (me) of metformin
`
`from about 1500 11ng to about 3000 ng/ml, fir‘ [based on] administration of a 2000 mg once-a
`
`day dose of metformin.
`
`13. (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
`
`from about 1700 ngjml to about 2000 ng/ml, ill; [based on] administration of a 2000 mg once-
`
`
`
`18
`
`18
`
`
`
`
`
`
`
`a-day dose of metformin.
`
`14. (Amended) The method of claim [3] 1, in which the administration of the at least one
`
`metfonnin dosage form provides a mean AUCMm from at least 80% of the mean AUCM.‘
`
`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.
`
`15. (Amended) The method of claim [3] l, in which the administration of the at least one
`
`metformin dosage form provides a mean AUCM“Ir that is from at least 90% of the mean AUCM4
`
`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 metforrnin
`
`administered in the controlled release oral dosage form.
`
`19. (Amended) The method of claim [3] l, in which the administration of the at least one
`
`metformin dosage form provides a mean AUCom, from about 17200 ng.hr/ml to about 33900
`
`ng.hr/ml, M [based on] administration of a 2000 mg once-a-day dose of metfonnin.
`
`20. (Amended) The method of claim [3] l, in which the administration of the at least one
`
`metfonnin dosage form provides a mean AUCam, from about 17200 ng.hr/ml to about 26500
`
`ng.hr/rnl, M [based on] administration of a 2000 mg once-a-day dose of metformin.
`
`21. (Amended) The method of claim [3] 1, in which the administration of the at least one
`
`metforrnin dosage form provides a mean AUCMW from aboutl9800 ng.hr/ml to about 33900
`
`ng.hr/ml, M [based on] administration of a 2000 mg once-a-day dose of metfonnin.
`
`22. (Twice Amended) The method of claim [3] 1, in which the administration of the at least one
`
`metfonnin dosage form provides a mean AUCo. of 18277 t 2961 ng-hr/ml and a mean Cm of
`
`1929 :1: 333 ng/ml, M [based on] administration of a 1700 mg once-a-day dose of metformin
`
`
`
`19
`
`19
`
`
`
`
`
`47.
`
`In response to the Examiner's section 112, first paragraph rejections,
`
`claim 1 was amended in part to specifically recite "metformin" in place of
`
`
`
`20
`
`
`
`
`
`"antihyperglycemic agent." Applicants stated that, in any event, Applicants were not
`
`required to exemplify every formulation, as it would be inefficient and unethical, and
`
`admitted that at the time of the application there were numerous controlled release
`
`technologies in the art, and that testing for drug-plasma levels was routine.
`
`48. Applicants also stated:
`
`[t]herefore it is submitted that once the Tmax range which
`provides for a useful dosage form has been established, other
`controlled release technologies known in the prior art can be
`manipulated and tested to achieve this Tmax range without
`undue experimentation.
`
`
`49.
`
`In support of this statement, reference was made to the pending
`
`application on Page 19, line 21 to Page 20, line 14. Applicants made the following,
`
`supplemental statements regarding the adaptation of prior art dosage forms to obtain
`
`the instant invention:
`
`"In addition, at the time the application was filed,
`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, e.g., by varying the amount of controlled
`release carrier (among other things), 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
`21
`
`
`
`
`
`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 experimentation is considered to
`be necessary
`to manipulate a controlled
`release
`technology to obtain a desired release pattern of the drug.
`Such release patterns 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
`vivo
`in
`performance."
`
`50. On July 14, 2003, the Examiner rejected claims in a non-final office
`
`action, stating that applicant arguments were not persuasive. Claims 1, 4-5, 7-15, 18-
`
`24 and 26 -31 were rejected. Claim 18 was rejected under 35 U.S.C. § 112. Claims 1,
`
`4-5, 7-15, 18-24 and 26 -31 were rejected as obvious under 35 USC 103(a) over '989,
`
`Chiao (Remington, 1995) and further in combination with Drug Facts and
`
`Comparisons (1999) or '106 in combination with Chiao (Remington, 1995) and further
`
`in combination with Drug Facts and Comparisons (1999).
`
`51. Claims 1, 4-5, 7-15, 18-24 and 26 -31 were further rejected as under 35
`
`USC 103(a) as unpatentable over WO 99/47125 in view of Drug Facts and
`
`Comparisons (1999) and U.S. Patent No. 3,845,770.
`
`22
`
`
`
`
`
`52. The examiner also rejected claims 1, 4-5, 7-15 and 18-31 under the
`
`judicially created doctrine of obviousness-type double patenting, as being unpatentable
`
`over U.S. 6,099,859, 6,284,275 and 6,099,862, in view of U.S. Patent No. 3,845,770
`
`and also over copending application 09/726,193.
`
`53. The Examiner noted that claim 25 would be allowable if re-written in
`
`independent form including all the limitations of the base claim and any intervening
`
`claims.
`
`54.
`
`In their response of Oct, 14, 2003, Applicants argued that the patentability
`
`of the pending claims, while rewriting the claims to address the examiner’s rejections.
`
`The following amended claims were submitted for further examination:
`
`23
`
`
`
`
`
`Claim 1. (currently 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
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