Petition for Inter Partes Review of United States Patent No. 6,866,866
`IPR2017-00___
`
`Paper No.: ____
`June 22, 2017
`
`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 Ltd.
`Patent Owner(s)
`_______________
`U.S. Patent No. 6,866,866 to Chen
`Issue Date: March 15, 2005
`Title: Controlled Release Metformin Compositions
`________________
`
`PETITION FOR INTER PARTES REVIEWOF U.S. PATENT NO. 6,866,866
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. §§ 42.1-.80, 42.100-.123
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O Box 1450
`Alexandria, VA 22313-1450
`
`

`

`IPR2017-00
`
`TABLE OF CONTENTS
`
`Petitioners' Exhibit List.........................................................................................v
`
`I.
`
`II.
`
`PAYMENT OF FEES ................................................................................1
`
`INTRODUCTION ......................................................................................1
`
`A. Brief Overview Of The '866 Patent..........................................................1
`
`B. Critical Date..............................................................................................6
`
`III.
`
`STANDING (37 C.F.R. 42.104(A)); PROCEDURAL STATEMENTS...7
`
`IV. MANDATORY NOTICES (37 C.F.R. 42.8(A)(1))...................................7
`
`A. Each Real Party In Interest (37 c.f.r. § 42.8 (b)(1)) ................................7
`
`B. Notice Of Related Matters (37 c.f.r. § 42.8(b)(2)) ..................................7
`
`1. Judicial Matters Involving The '866 Patent..................................7
`
`2. Administrative Matters.................................................................8
`
`C. Designation Of Lead And Back-Up Counsel (37 c.f.r. §
`42.8(b)(3) .................................................................................................8
`
`D. Notice Of Service Information (37 c.f.r. § 42.8(b)(4).............................9
`
`V.
`VI.
`
`INDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))........ 10
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND
`THE REASONS THEREFOR IN RESPECT OF EACH
`CHALLENGED CLAIMS (37 C.F.R. § 42.22(a)) ................................. 10
`VII. PERSON OF ORDINARY SKILL IN THE ART IN RESPECT
`OF '866 PATENT .................................................................................... 11
`
`i
`
`

`

`VIII. BACKGROUND OF TECHNOLOGY AND PRIOR ART................... 12
`
`A. Claims 1-25 of the '866 Patent are Unpatentable Under 35 U.S.C.
`102(a) Over Chen, WO 00/12097 (EX1007)........................................ 15
`B. At Least Claims 1-3 of the '866 patent Are Unpatentable As
`Anticipated Under 102(a) Over Timmins, WO 99/47128
`(EX1003)............................................................................................... 18
`C. Claims 1-25 Of The '866 Patent Are Unpatentable As Obvious
`Under 103 Over Cheng WO 99/47125 (EX1002) In Light Of
`Timmins WO 99/47128 (EX1003) ....................................................... 20
`IX. CLAIM CONSTRUCTION IN LIGHT OF A POSA............................. 24
`
`A. Claim Construction Standard................................................................ 23
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`12.
`
`13.
`
`"metformin"................................................................................... 24
`
`"dosage form"................................................................................ 24
`
`"dinner time" ................................................................................. 24
`
`"bed time"...................................................................................... 25
`
`"therapeutically effective reduction"............................................. 25
`
`"sustained release"......................................................................... 26
`
`"Cmax"............................................................................................. 25
`
`"Cmin" ............................................................................................. 26
`
`"Cavg" ............................................................................................. 26
`
`"Tmax"............................................................................................. 26
`
`"t1/2".............................................................................................. 26
`
`"AUC" ........................................................................................... 27
`
`"steady state" ................................................................................. 27
`
`ii
`
`

`

`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`"single dose".................................................................................. 27
`
`"multiple dose".............................................................................. 27
`
`"a patient" ...................................................................................... 28
`
`"mean" ........................................................................................... 28
`
`"median"........................................................................................ 28
`
`"Degree of Fluctuation"................................................................. 29
`
`"controlled release carrier"............................................................ 29
`
`"the membrane"............................................................................. 29
`
`"passageway"................................................................................. 29
`
`X.
`
`DETAILED ANALYSIS OF GROUNDS FOR TRIAL ........................ 30
`
`A. Ground 1: Claims 1-25 Are Unpatentable Under 35 U.S.C. § 102
`Over Chen WO 00/12097 (EX1007) As Being Anticipated ................ 30
`B. Ground 2: At Least Claims 1-3 Are Unpatentable Under 35
`U.S.C. § 102 Over Timmins WO 00/47128 (EX1003) As Being
`Anticipated ............................................................................................ 42
`C. Ground 3: Claims 1-25 Are Unpatentable Under 35 U.S.C. §
`103(a) as Being Obvious Over Cheng WO 99/47125 (EX1002) In
`View Of WO Timmins 99/47128 (EX1003) ........................................ 45
`D. Objective Indicia Of Non-Obviousness................................................ 59
`XI. CONCLUSION........................................................................................ 60
`
`iii
`
`

`

`PETITIONERS’ EXHIBIT LIST
`
`Description
`
`U.S. Patent 6,866,866
`WO 99/47125 ("Cheng et al.")
`WO 99/47128 ("Timmins et al.")
`U.S. Patent 6,099,859
`Prosecution File History of U.S. Patent 6,866,866 (Application No.
`09/705,630)
`Fed. Cir. [2012-1228] (July 2, 2012)
`WO 00/12097 ("Chen et al.")
`Lupin Settlement
`Mylan Settlement
`Amendment Under 37 C.F.R. 1.111 (dated February 24, 2003),
`Application No. 09/705,630.
`U.S. Patent No. 6,475,521
`Labelling NDA 21202 (GLUCOPHAGE® and GLUCOPHAGE
`XR®)
`U.S. Patent 5,955,106 ("Moeckel")
`WO 00/28989 ("Lewis et al.")
`U.S. Patent 6,284,275
`U.S. Patent 6,099,862
`U.S. Patent 3,845,770
`Remington, 1995 ("Chiao")
`Declaration of Dr. Fatemeh Akhlaghi
`CV of Dr. Fatemeh Akhlaghi
`
`Exhibit No.
`1001
`1002
`1003
`1004
`
`1005
`
`1006
`1007
`1008
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`1014
`1015
`1016
`1017
`1018
`1019
`1020
`
`iv
`
`

`

`Pursuant to 35 U.S.C. § 311 and 37 C.F.R. Part 42, Aurobindo Pharma USA
`
`Inc. (“Petitioner”) respectfully petitions for Inter Partes Review of U.S. Patent No.
`
`6,866,866 (“the ’866 Patent”) (EX1001) which is co-assigned to Andrx Corporation
`
`et al., subsidiaries of Teva Pharmaceutical Industries Ltd. (“Patent Owner”), seeking
`
`cancellation of claims 1-25 thereof.
`
`I.
`
`PAYMENT OF FEES
`
`Pursuant to 37 C.F.R. section 42.103, these fees are being paid at the time
`
`of filing this petition, charged to Deposit Account 506744. Should any further
`
`fees be required by the present Petition, the Patent Trial and Appeal Board
`
`(“PTAB”) is hereby authorized to charge the above referenced Deposit Account.
`
`II.
`
`INTRODUCTION
`
`A.
`
`Brief Overview of The ‘866 Patent
`
`The '866 patent is titled “Controlled Release Metformin Compositions,” with
`
`first inventor Chih-Ming Chen. The ’866 patent issued on March 15, 2005 claiming
`
`priority through U.S. Application No. 09/705,630 to a filing date of November 3,
`
`2000.
`
`The Abstract of '866 patent discloses: "[a] composition 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
`
`1
`
`

`

`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."
`
`It is further stated that: "[i]n 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 core, and (c) at least one
`
`passageway in the membrane. (col. 3, lines 34-42)
`
`The specification of the '866 patent states "[t]he controlled release dosage form
`
`of the present invention provides a delayed Tmax as compared to the Tmax provided by
`
`GLUCOPHAGE®. The delayed Tmax occurs from 5.5 to 7.5 hours after administration.
`
`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)." Col 5, lines 26-32.
`
`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
`
`2
`
`

`

`administered to human patients." Col 12, lines 42-46.
`
`Thereby the inventors and applicant admitted that it was within the skill of a
`
`person of ordinary skill in the art ("POSA") to produce the pharmacokinetic parameters
`
`recited in the '866 patent using other controlled release preparations.
`
`Further, during the prosecution of the application for the '866 patent the
`
`inventors admitted directly to the Examiner that a POSA would easily alter the
`
`controlled release formulations of the prior art to produce the in vivo Tmax range
`
`specified in the '866 patent. It was understood the POSA would be guided by drug
`
`release rate, measured by in vitro dissolution testing, to establish desired in vivo
`
`performance:1
`
`the time the application was filed, numerous
`"In addition, at
`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
`
`1 Amendment Under 37 C.F.R. 1.111, February 24, 2003, Application No.
`09/705,630 (EX1010).
`
`3
`
`

`

`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 in-vivo performance."2 [Emphasis added]
`
`Thus, the applicant (Andrx Labs, LLC), and the four inventors of the '866
`
`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 '866
`
`patent.
`
`There is no mention anywhere in the specification or in the file history of an
`
`unexpected result or special advantage associated with any of these pharmacokinetic
`
`parameters recited in the dependent claims of the '866 patent.
`
`Claim 1 is the only independent claim in the '866 patent. Thus all other
`
`claims, 2 –25, depend upon claim 1 and by dependency assert each of the limitations
`
`of claim 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
`
`2File history of U.S. Patent No. 6,866,866 (EX1010), Amendment Under 37 C.F.R.
`1.111, February 24, 2003, p. 8-p. 9.
`
`4
`
`

`

`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.
`
`Dr. Akhlaghi, in her declaration states (EX1019, ¶ 26) "With respect to
`
`claim 1 and its dependent claims… I find each of the pharmacokinetic parameters
`
`recited to be obvious or inherently anticipated by the prior art, in particular by
`
`WO 99/47125, WO 99/47128 and WO 00/12097, alone or in combination, all of
`
`which by my calculations teach the same composition of the dosage form claimed
`
`in the '866 patent."
`
`As claims 2 –25 are either directly or indirectly dependent on claim 1, the
`
`only patentability that might be associated with the dependent composition claims
`
`set forth in the '866 patent would be with respect to the non-obviousness of the
`
`pharmacokinetic parameters recited in the claims. Because the pharmacokinetic
`
`parameters were already associated with or inherent in other known controlled
`
`release dosage forms, such could not be said to be non-obvious.
`
`Claims 2 and 3 recite mean Tmax times ranging from 6.0-7.0 hours and 5.5-7.0
`
`hours, respectively. Claims 4 and 5 recite dissolution profile limitations for the
`
`controlled release oral dosage form of claim 1, using a USP type 2 paddle apparatus
`
`5
`
`

`

`operated at 75 rpm, wherein the dissolution medium comprises 900 ml of simulated
`
`intestinal fluid (pH 7.5 phosphate buffer) maintained at a temperature of 37 oC.
`
`Claims 6-25 recite various pharmacokinetic functional limitations related to
`
`pharmaceutical performance of the dosage form that are dependent on dose and
`
`inherent to the in vitro release characteristics of metformin from the dosage form of
`
`claim 1. These limitations include mean Cmax, mean AUC0-24, AUC0-∞ and t1/2 (the
`
`drug clearance half-life).
`
`Claims 11-12, 15-17 and 19-21 are additionally directed to the oral
`
`administration of a 2000 mg once-a-day controlled release formulation of metformin
`
`of claim 1. Claim 18 is directed to a 1700 mg once-a-day dose of metformin,
`
`administered after an evening meal.
`
`With regard to these additional pharmacokinetic parameters as recited in the
`
`dependent claims, Dr. Akhlaghi states (EX1019, ¶31): "I stress, in regard to all of
`
`these claims, a POSA would expect the claimed pharmacokinetic parameters to be
`
`found inherently in the prior art, for example, as in the controlled release tablets of
`
`Chen et al., WO 00/12097. By my analysis, those tablets comprise the same
`
`formulation and structure found in the tablets of the '866 patent. The Chen et al.
`
`tablets also exemplify the same in vitro release rate as the claimed tablets."
`
`B.
`
`Critical Date
`
`6
`
`

`

`The ‘866 patent derives from U.S. Patent Application Serial No. 09/705,630,
`
`filed on November 3, 2000. Thus, the critical date for the ‘866 patent is November
`
`3, 2000.
`
`III.
`
`STANDING (37 C.F.R. 42.104(a)); PROCEDURAL STATEMENTS
`
`Petitioner certifies that (1) the ‘866 patent is available for IPR; and (2)
`
`Petitioners are not barred or estopped from requesting IPR of any claim of the ‘866
`
`patent on the grounds identified herein. The required fee is paid through the Patent
`
`Review Processing System, as set forth above.
`
`IV. MANDATORY NOTICES (37 C.F.R. 42.8(a)(1))
`
`A.
`
`Each Real Party in Interest (37 C.F.R. § 42.8 (b)(1))
`
`The real parties-in-interest for Petitioner are Aurobindo Pharma USA Inc.
`
`and Aurobindo Pharma Ltd.
`
`B.
`
`Notice of Related Matters (37 C.F.R. § 42.8(b)(2))
`
`1.
`
`Judicial Matters Involving the ‘866 Patent
`
`On January 25, 2017, Patent Owner filed a complaint against Aurobindo in
`
`the District of Delaware (EX1007) asserting infringement of the ‘866 patent in the
`
`action Shionogi Inc. and Andrx Labs. L.L.C. v. Aurobindo Pharma Ltd. et al., Civ.
`
`Act. No. 1:17-cv-00072-UNA (D. Del. 1-25-17).
`
`The '866 patent has been the subject of extensive previous litigation, both
`
`in the District of Delaware, the Federal Circuit (EX1006), and in the District of
`
`7
`
`

`

`New Jersey, all of which has settled. Sciele Pharma Inc. et al. v. Lupin Ltd, et
`
`al., D. Del. 1:09-cv-00037; Shionogi Pharma Inc. et al. v. Mylan Inc., et al., D.
`
`Del. 1:10-cv-00135; Shionogi Inc. et al. v. Nostrum Laboratories, Inc., et al.,
`
`D.N.J. 1:12-cv-04402. The Federal Circuit ruled, in 2012, regarding the asserted
`
`claims of the '866 patent that "Cheng in view of Timmins [r]aises a [s]ubstantial
`
`[q]uestion of [v]alidity" (EX1006, p. 12) and remanded the case back to the
`
`District of Delaware for reconsideration. Plaintiffs Sciele Pharma Inc. (now
`
`Shionogi Pharma Inc.) and Andrx et al. subsequently settled with Defendants
`
`Lupin et al. (EX1008) and Mylan et al. (EX1009), Defendant Lupin being
`
`allowed by settlement to market its generic Fortamet drug as of September 1,
`
`2011 and Mylan being allowed by settlement to market its generic Fortamet drug
`
`as of August 1, 2013.
`
`2.
`
`Administrative Matters
`
`Petitioner Aurobindo is not aware of any other pending administrative
`
`matters regarding IPR petitions for U.S. Patent No. 6,866,866.
`
`C.
`
`Designation of Lead and Back-up Counsel (37 C.F.R. § 42.8(b)(3)
`and (b)(4).
`Petitioner provides the following designation and service information.
`
`Petitioner respectfully requests that all correspondence related to this proceeding be
`
`sent to lead and back up counsel at the email addresses listed below. (37 C.F.R. §
`
`42.8(b)(4)):
`
`8
`
`

`

`LEAD COUNSEL
`Steven J. Moore, Esq. (Reg. # 35,959)
`Email:
`steven.moore@withersworldwide.com
`Withers Bergman LLP
`Suite 400
`1700 East Putnam Avenue
`Greenwich, CT 06870
`Tel.: (203) 302-4069
`Fax: (203) 302-6609
`
`BACK-UP COUNSEL
`John Winterle (Reg. # 57,276)
`Email:
`john.winterle@withersworldwide.com
`Withers Bergman LLP
`Suite 400
`1700 East Putnam Avenue
`Old Greenwich, CT 06870
`Tel.: (203) 328-2225
`Fax: (203) 285-1652
`Hans Peter Hoffmann (Reg. # 37,352)
`Email:
`peter.hoffmann@withersworldwide.com
`Withers Bergman
`Suite 400
`1700 East Putnam Avenue
`Old Greenwich, CT 06870
`Tel.: (203) 302-4076
`Fax: (203) 302-6609
`Alan Gardner (Reg. # 69,495)
`Email:
`alan.gardner@withersworldwide.com
`Withers Bergman
`Suite 400
`1700 East Putnam Avenue
`Old Greenwich, CT 06870
`Tel.: (203) 302-4085
`Fax: (203) 302-6609
`Notice of Service Information (37 C.F.R. § 42.8(b)(4))
`
`D.
`
`Petitioner hereby consents to electronic service. Service should be made to
`
`the lead counsel and back-up counsel as noted above, as well
`
`to IPG-
`
`AUR@withersworldwide.com.
`
`Correspondence can be sent by mail to lead counsel at the above address.
`
`9
`
`

`

`V.
`
`INDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))
`
`IPR of claims 1-25 of the ‘866 patent is requested on the grounds of
`
`unpatentability listed below. Per 37 C.F.R. § 42.6(d), copies of references are filed
`
`herewith.
`
`In support of the proposed grounds for unpatentability, this Petition
`
`includes the declaration of a technical expert, Dr. Akhlaghi (EX1019), explaining
`
`what the art would have conveyed to a POSA. Professor Akhlaghi is an expert in
`
`the field of pharmaceutical formulations and pharmacokinetics.
`
`VI.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND
`THE REASONS THEREFOR IN RESPECT OF EACH
`CHALLENGED CLAIM (37 C.F.R. § 42.22(a))
`Petitioner requests IPR of all of claims 1 –25 of the ‘866 patent, and
`
`cancellation of the same, under 35 U.S.C. § 311 and AIA §6, on the following
`
`grounds:
`
`References
`Ground 1: Claims 1-25 Are
`Unpatentable Under 35 U.S.C.
`§ 102 Over WO 00/12097
`(EX1007) As Being
`Anticipated.
`Ground 2: Claims 1-3 Are
`Unpatentable Under 35 U.S.C.
`§ 102 Over View of WO
`99/47128 (EX1003) As Being
`Anticipated.
`Ground 3: Claims 1-25 Are
`Unpatentable Under 35 U.S.C.
`§ 103(a) As Being Obvious
`Over WO 99/47125 (EX1002)
`
`Basis
`35 U.S.C. § 102
`
`Claims Challenged
`All challenged claims
`
`35 U.S.C. § 102
`
`Claims 1-3
`
`35 U.S.C. § 103
`
`All challenged claims.
`
`10
`
`

`

`In View of WO 99/47128
`(EX1003)
`VII. PERSON OF ORDINARY SKILL IN THE ART IN RESPECT OF
`U.S. PATENT NO. 6,866,866
`
`As explained in the Declaration of Professor Akhlaghi (EX1019, ¶¶ 91-96),
`
`a POSA with respect to the ‘866 patent in the relevant field as of November 3, 2000
`
`a POSA would typically have experience in the research or development of
`
`pharmaceuticals and have the ability to gather and interpret pharmacokinetic data
`
`and the relationship between drug release from a dosage form and its effect on
`
`pharmacokinetic parameters. The POSA would understand the references discussed
`
`in this Petition.
`
`The POSA would include an individual with a Pharm.D. and/or Ph.D. with
`
`experience in pharmaceutical sciences, dosage forms, clinical pharmacology or
`
`related fields, such as pharmacology. As part of a team, the POSA might have
`
`access to a person having experience in endocrinology with specific experience in
`
`metformin therapies for T2DM.
`
`The POSA would understand work published in the field, including the
`
`publications discussed in this declaration.
`
`In addition, as pharmaceutical development is an inherently collaborative
`
`process, the POSA could have access to, or be part of a team including, other skilled
`
`individuals, such as an M.D. with experience in the field of diabetes treatment.
`
`In
`
`11
`
`

`

`particular, one of ordinary skill in the art would likely have some combination of
`
`the following skills and experience: (i) experience with the research or development
`
`of pharmaceuticals; (ii) the ability to gather and interpret pharmacokinetic and
`
`pharmacodynamics data including dose-response curves; and (iii) the ability to
`
`understand results and findings presented or published by others in the field,
`
`including the publications discussed in this declaration.
`
`This Petition is supported by the declaration of Professor Akhlaghi who
`
`received her Ph.D. from the University of Sydney. (EX1019)
`
`VIII. BACKGROUND OF TECHNOLOGY AND PRIOR ART
`
`Type 2 diabetes ("T2DM"), or "NIDDM," is a chronic metabolic condition
`
`that affects glucose homeostasis, whereby the body demonstrates insulin resistance
`
`and increased levels of blood glucose (hyperglycemia). Metformin is an
`
`antihyperglycemic (glucose-lowering) agent which improves glucose tolerance in
`
`patients with type 2 diabetes.
`
`Before November 3, 2000, it was known by the POSA that type 2 diabetes
`
`("T2DM"), or "NIDDM," is a chronic metabolic condition that affects glucose
`
`homeostasis, whereby the body demonstrates insulin resistance and increased levels
`
`of blood glucose (hyperglycemia). It was also known that metformin is an
`
`antihyperglycemic (glucose-lowering) agent which improves glucose tolerance in
`
`patients with T2DM, and that metformin lowers both basal and postprandial plasma
`
`12
`
`

`

`glucose. It was also recognized generally by the POSA that metformin decreases
`
`hepatic glucose production, decreases intestinal absorption of glucose, and improves
`
`insulin sensitivity by increasing peripheral glucose uptake and utilization.
`
`Further, it was well known to the artisan at the time the application leading
`
`to the patent was filed that during extended fasting after the evening meal, and
`
`during sleep,
`
`the liver newly synthesizes glucose from non-carbohydrate
`
`physiologic sources ("gluconeogenesis") and that such peak occurs, according to
`
`the '866 patent near 2 AM.3 As such the POSA would have been aware of the
`
`advantages of evening administration of an antihyperglycemic drug, with extended
`
`drug release, such that the maximum drug concentration (Cmax) is reached at a time
`
`(Tmax) when gluconeogenesis peaks.
`
`At least one immediate release dosage form "GLUCOPHAGE®" and at
`
`least one controlled release dosage form for metformin, "GLUCOPHAGE XR®,"
`
`a competitor product
`
`to FORTAMET® (covered by the '866 patent) with
`
`overlapping release and pharmacokinetic characteristics to those claimed in the
`
`'866 patent, had already been approved for marketing by Bristol-Myers Squibb
`
`in the United States by October 2000. 4 GLUCOPHAGE® is referenced in the '866
`
`3 Id., col. 5, lines31-32.
`4 NDA 021202 for Glucophage XR was approved on October 13, 2000:
`https://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N
`&Appl_No=021202
`
`13
`
`

`

`patent (and elsewhere) in the prior art as a comparator product. Andrx would have
`
`been alerted to the release characteristics of the GLUCOPHAGE XR® product
`
`because of their competition for the same NIDDM market.
`
`The POSA would have also been aware of the art published prior to November
`
`3, 2000 including at least: WO 00/12097 to Chen et al. ("Chen," EX1007) published
`
`on March 9, 2000; WO 1999/047125 to Cheng et al. ("Cheng", EX1002) with an
`
`international publication date of Sept. 23, 1999, and WO 99/47128 to Timmins et al.
`
`("Timmins", EX1003) which published on September 23, 1999. These three
`
`references are discussed in detail below. The additional prior art references listed in
`
`Appendix XIII of Dr. Akhlaghi's declaration (EX1019) would also have been known
`
`to the POSA.
`
`Chen et al., WO 00/12097 in Example 3 teaches tablets which are objectively
`
`identical to the tablets exemplified and claimed in '866 patent, including the
`
`number of passageways (holes) drilled in the sustained release membrane to allow
`
`metformin release. The tablets of WO 00/12097 are identical to those of the '866
`
`patent but for a minor amount of the sulfonylurea, glipizide (a hypoglycemic drug),
`
`in the tablet core in the WO publication. Such a minor amount of glipizide would
`
`be recognized by a POSA as not contributing to a change of the pharmaceutical
`
`parameters associated with metformin release. (Akhlaghi Declaration, EX1019, ¶
`
`135)
`
`14
`
`

`

`As for the dosage forms described in the '866 patent, the tablets of WO
`
`00/12097 and the '866 patent each comprise a core containing metformin
`
`hydrochloride (active drug), povidone (binder), sodium lauryl sulfate (absorption
`
`enhancer) and magnesium stearate (lubricant) in very similar concentrations. The
`
`core is optionally coated by a seal coat comprising "Opadry." The optionally seal
`
`coated core is coated by a sustained release membrane comprising cellulose
`
`acetate, triacetin and PEG 400 (flux enhancer) in both the WO/12097 publication
`
`and the '866 patent.
`
`WO 00/12097 notes that the disclosed tablets provide continuous therapeutic
`
`levels of an antihyperglycemic drug over a twelve or twenty four hour period,5 the
`
`same as evidenced by the '866 patent in Figures 1, 2 and 4.
`
`A.
`
`Claims 1-25 of the '866 Patent are Unpatentable under 35 U.S.C.
`§ 102(a) over Chen, WO 00/12097
`
`Dr. Akhlaghi specifically compares compositions of the 850 mg tablets of
`
`Example 1 of WO 00/12097 and Example 2 of the '866 patent. Akhlaghi
`
`Declaration, EX1019, ¶ 132). The compositions are seen to be essentially identical
`
`with respect to core and membrane composition, drug content, and excipient
`
`content and type.
`
`The tablet of Example 1 of Chen (WO 00/12097) comprises two laser drilled
`
`5 WO 00/12097, p. 4, lines 3-7.
`
`15
`
`

`

`passageways6 ("holes") as does the device claimed the '866 patent.7 Except for a
`
`small amount of glipizide, the Dr. Akhlaghi notes that tablets are objectively
`
`identical to Example 2 of the '866 patent, also an 850 mg tablet, differing slightly
`
`only in that the core of the latter comprises a small fraction, about 0.5%,8 of the
`
`sulfonylurea drug, glipizide, while the patented device of the '866 patent lacks
`
`glipizide. In Dr. Akhlaghi's opinion (EX1019, ¶ 135), this additional, very minor
`
`core component has no significant effect on the function of the tablet of Example
`
`1 of WO 00/12097 with regards to the pharmacokinetic properties of metformin,
`
`when compared to tablets claimed in the '866 patent. Further, the presence of
`
`glipizide is not excluded from the claims of the '866 patent as "comprising"
`
`transitional language is used in the only independent claim, language which does
`
`not exclude other unnamed active components in the tablet core, such as glipizide.
`
`The release rate of metformin from Example 1 of WO 00/12097 conforms to
`
`the preferred limitations claimed in the '866 patent.
`
`The following table
`
`demonstrates that fact:
`
`6 Id., p. 14, lines 9-10.
`7 U.S. Patent No. 6,866,866, col. 15, lines 7-8.
`8 The core of Example 1 of WO 00/12097 comprises 850 mg metformin
`hydrochloride and 5 mg of glipizide, a mass ratio of 170:1.
`
`16
`
`

`

`Time
`(hours)
`
`% Metformin Released,
`WO 00/12097,
`'866 Patent
`EX1, 850 mg9
`Preferred Release
`Limit10
`0
`0
`0
`0-30
`17
`2
`10-45
`32
`4
`30-90
`56
`8
`NLT 50
`76
`12
`NLT 60
`89
`16
`NLT 70
`-11
`20
`Further, the release rate of metformin from Example 1 of WO 00/12097 also
`
`conforms to the most preferred limitations claimed in the '866 patent. The
`
`following table once again demonstrates that fact:
`
`Time
`(hours)
`
`0
`2
`4
`8
`12
`16
`
`% Metformin Released,
`WO 00/12097,
`'866 Patent
`EX1, 850 mg12
`Most Preferred
`Release Limit13
`0
`0-25
`20-40
`45-90
`NLT 60
`NLT 70
`
`0
`17
`32
`56
`76
`89
`
`9WO 00/12097, p. 14, lines 11-22.
`10 U.S. Patent No. 6,866,866, col. 12, lines 24-32. Also see, claim 4.
`11 Not reported, but 76% drug was released at the 12 hour test point, a value which
`also meets the required 16 and 20-hour release values of NLT (not less than) 60%
`and 70%, respectively.
`12 WO 00/12097, p. 14, lines 11-22.
`13 U.S. Patent No. 6,866,866, col. 12, lines 24-32. Also see, claim 5.
`
`17
`
`

`

`20
`
`-14
`
`NLT 80
`
`Thus, the preferred and most preferred release limitations are met in every case.
`
`As Dr. Akhlaghi concludes (EX1019, ¶ 144) "… as would the POSA, that the
`
`tablets disclosed in WO 00/12097 in Example 1 and the tablets claimed in the '866
`
`patent are functionally and structurally identical and will behave identically in
`
`vivo… [and thus the POSA]… would expect the other pharmacokinetic parameters
`
`recited in the dependent claims of the '866 patent to be the same when the same
`
`dosage of metformin was administered by either tablet."
`
`B.
`
`Claims 1-3 Of The '866 Patent Are Unpatentable As Anticipated
`Under 35 U.S.C §102(a) Over Timmins, WO 99/47128 (EX1003)
`
`Timmins et al., WO 99/47128 is prior art. Timmins teaches among
`
`embodiments a biphasic controlled release delivery system for metformin HCL salt
`
`comprising an inner solid particulate phase with one or more hydrophilic polymers,
`
`and hydrophobic material, and an outer solid continuous phase in which the granules
`
`are embedded and dispersed throughout. The Timmins disclosure covers Bristol-
`
`Myers Squibb's product, GLUCOPHAGE XR®, which was approved for marketing
`
`(October 13, 2000) before the priority date of the '866 patent. Timmins teaches a
`
`Tmax range of 4-8 hours, with a median (not mean) Tmax of 5 hours for a single dose
`
`14 Not reported, but 89% drug was released at the 16 hour test point, a value which
`also meets the 20 hour test value.
`
`18
`
`

`

`after dinner administration.15
`
`Example 3 of Timmins WO 99/47128 teaches a controlled release, 500 mg
`
`metformin hydrochloride oral dosage form for the once-a-day administration of an
`
`effective dose of metformin or a salt thereof,16 wherein with oral administration
`
`after dinner provides a Tmax in the range of 4-8 hours, with median Tmax of 5 hours.17
`
`From the data of Timmins, the POSA would understand that a mean Tmax of
`
`between 4.67 and 6.33 hours is taught, according to the Federal Circu