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`Paper No. ____
`Filed: January 24, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`AUROBINDO PHARMA USA INC.,
`Petitioner,
`
`v.
`Andrx Corporation,
`Andrx Labs, LLC
`Andrx Laboratories, Inc.
`Andrx Laboratories (NJ), Inc.
` Andrx EU Ltd.
`Andrx Pharmaceuticals, LLC,
` Teva Pharmaceutical Industries Inc.
`Patent Owner(s).
`_____________________________
`Case No. IPR 2018-______
`Patent No. 6,790,459
`_____________________________
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 6,790,459
`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
`
`
`
`
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`GW00911/0068-US-6114551/4
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`

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`I.
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`II.
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`Table of Contents
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`
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`Page
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`PAYMENT OF FEES ......................................................................................................... 1
`
`INTRODUCTION............................................................................................................... 1
`A.
`Commercial Product Said to Be Covered by the '459 Patent ............................1
`B.
`Brief Overview of the '459 Patent. ........................................................................2
`C.
`Brief Overview of the Prosecution History. .........................................................3
`D.
`Critical Date .........................................................................................................10
`
`III. STANDING (37 C.F.R. 42.104(A)); PROCEDURAL STATEMENTS ....................... 10
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`IV. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ................................................... 10
`A.
`Designation of Lead and Back-up Counsel (37 C.F.R. § 42.8(b)(3) and
`(b)(4). .....................................................................................................................12
`Notice of Service Information (37 C.F.R. § 42.8(b)(4)) .....................................13
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`B.
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`V.
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`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(B)) ................................ 13
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`VI. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR IN RESPECT OF EACH CHALLENGED CLAIM
`(37 C.F.R. § 42.22(A)) ..................................................................................................... 14
`
`VII. PERSON OF ORDINARY SKILL IN THE ART IN RESPECT OF U.S.
`PATENT NO. 6,790,459 B1 ............................................................................................ 15
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`VIII. BACKGROUND OF TECHNOLOGY AND PRIOR ART ......................................... 16
`
`IX. CLAIM CONSTRUCTION ............................................................................................. 17
`A.
`“metformin” .........................................................................................................18
`B.
`“therapeutically effective reduction” .................................................................18
`C.
`“Cmax” ....................................................................................................................18
`D.
`“Tmax” ....................................................................................................................18
`E.
`“T1/2” .....................................................................................................................19
`F.
`“AUC” ...................................................................................................................19
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`i
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`“a patient”.............................................................................................................19
`“mean”, .................................................................................................................20
`“controlled release carrier” ................................................................................20
`"passageway" .......................................................................................................20
`
`G.
`H.
`I.
`J.
`
`X. DETAILED ANALYSIS OF GROUNDS FOR TRIAL ................................................ 21
`A.
`Brief Summary of the Prior Art Cited Herein ..................................................21
`B.
`Grounds for Unpatentability ..............................................................................29
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`XI. NO OBJECTIVE INDICIA OF NON-OBVIOUSNESS ............................................... 60
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`XII. CONCLUSION ................................................................................................................. 60
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`XIII. CERTIFICATE OF COMPLIANCE ............................................................................. 62
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`XIV. APPENDIX - LIST OF EXHIBITS ................................................................................ 63
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`ii
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`I.
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`PAYMENT OF FEES
`Pursuant to 37 C.F.R. §§ 42.15(A) AND 42.103 the fee paid at the time of
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`filing this petition, is charged to Deposit Account 506744. Should any further fees
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`be required by the present Petition, the Patent Trial and Appeal Board (“PTAB”) is
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`hereby authorized to charge the above referenced Deposit Account.
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`II.
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`INTRODUCTION
`Pursuant to the provisions of 35 U.S.C. § 311 and § 6 of the Leahy-Smith
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`America Invents Act (“AIA”), and to 37 C.F.R. Part 42, Aurobindo Pharma Inc.,
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`(“Petitioner”) hereby requests inter partes review of United States Patent No.
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`6,790,459 to Xiu Cheng et al., (“the '459 patent,” Ex. 1001), which issued on Sept.
`
`14, 2004, and is currently assigned to Andrx Labs LLC., which is owned by Teva
`
`Pharmaceutical Industries Inc. (collectively “Patent Owner(s)”).
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`A. Commercial Product Said to Be Covered by the '459 Patent
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`FORTAMET® (metformin hydrochloride) Extended-Release Tablets contain
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`an oral antihyperglycemic drug used in the management of type 2 diabetes.
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`Metformin
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`hydrochloride
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`(N,N-dimethylimidodicarbonimidicdiamide
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`hydrochloride) is a member of the biguanide class of oral antihyperglycemics and is
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`not chemically or pharmacologically related
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`to any other class of oral
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`GW00911/0068-US-6114551/4
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`1
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`

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`antihyperglycemic agents. The empirical formula of metformin hydrochloride is
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`C4H11N5•HCl and its molecular weight is 165.63. Its structural formula is:
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`B.
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`Brief Overview of the '459 Patent.
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`U.S. Patent No. 6,790,459 (the '459 patent") issued with 21 claims of which
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`claim 1 is the sole independent claim. Claim 1 of the '459 patent is directed to a
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`method for lowering blood glucose levels in human patients needing treatment for
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`non-insulin-dependent diabetes mellitus (NIDDM), comprising orally administering
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`to human patients on a once-a-day basis at least one oral controlled release dosage
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`form comprising an effective dose of metformin, or a pharmaceutically acceptable
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`salt thereof, and an effective amount of a controlled release carrier to control the
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`release of said metformin, or pharmaceutically acceptable salt thereof, from the
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`dosage
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`form within specified pharmacokinetic
`
`(PK) parameters.
`
` The
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`pharmacokinetic parameters of the once a day dosage include a mean time to
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`maximum plasma concentration (Tmax) of metformin at from 5.5 to 7.5 hours after
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`administration following dinner; a mean AUC0-24 of 22590±3626 ng·hr/ml and a
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`2
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`mean Cmax of 2435±630 ng/ml on the first day of administration, a mean AUC0-24 of
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`24136±7996 ng·hr/ml, a mean Cmax of 2288±736 ng/ml on the 14th day of
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`administration, for administration of a 2000 mg once-a-day dose of metformin. The
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`dependent claims assert more limiting.
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`U.S. Patent No. 6,790,459 issued from U.S. Application Serial No.
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`09/705,625 filed on Nov. 3, 2000. No earlier priority date is asserted. As shown at
`
`Exhibit 1001 the specification of U.S. Patent No. 6,790,459 is, except for some very
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`minor corrections, identical to the specification of U.S. Patent No. 6,866,866
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`(Exhibit 1007) the application of which was filed on the same day as U.S.
`
`Application Serial No. 09/705,625 (which led to U.S. Patent No. 6,790,459).
`
`C. Brief Overview of the Prosecution History.1
`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
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`Application Serial No. 09/705,625 was filed with 34 claims (Ex. 1006, '459 File
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`History).
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`A first Office Action on the merits of the Application was mailed to
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`Applicants on Dec. 31, 2001, (Ex. 1006, 251-262). All claims 1-34 were rejected
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`with no position taken regarding the drawings. Claims 2 and 3 were objected to
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`1 See, also, Declaration of Professor Akhlaghi, Ex. 1010, ¶¶ 38-55.
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`3
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`under 37 CFR 1.75 (c) as being in improper dependent form for failing to further
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`limit the subject matter of previous claim. Claims 4-31 were rejected under 35
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`U.S.C. 112, second paragraph, as being indefinite -- the claims reciting the method
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`of claim 3, was found to be in contradiction to the composition claim of claim 3.
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`Further claims 22-26 were rejected under 35 U.S.C. §112, second paragraph on the
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`basis that these claims were omnibus-type claims.
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`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), and under 35 USC
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`102(b) over WO 99/47125 to Cheng et al. ('125), and US Patent No. 5,955,106 to
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`Moeckel et al. ('106).
`
`Claims 1-34 were also rejected as obvious under 35 U.S.C. 103 (a) over Lewis
`
`et al. '989 or Cheng et al. '125 or Moeckel et al. '106 each alone or each in
`
`combination with Drug Facts and Comparisons, pg. 635-642 (1999). The Examiner
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`stated that the '989, '125 and '106 references all teach controlled release metformin
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`compositions, and that because the formulations of the references are substantially
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`the same, "the instant claimed functional limitations are inherent." Claims 1-34 were
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`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).
`
`The Examiner rejected claims 1-34 under the judicially created doctrine of
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`obviousness-type double patenting, as being unpatentable over U.S. Patent No.
`
`4
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`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-
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`species relationship.
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`Claims 1-34 were also rejected under a provisional obviousness-type double
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`patenting rejection based on co-pending application Nos. 09/705,630, 09/726,193
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`and 09/594,637.
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`In response to the Examiner’s comments, Applicants filed an Amendment to
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`the Application on July 08, 2002. Therein, with claims 1-34 pending, claims 1-3
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`and 22-26 were amended and submitted for examination. Claim 1, the only
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`independent claim, read as follows:
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`1. (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 anti hyperglycemic agent or a
`pharmaceutically acceptable salt thereof and a controlled release carrier,
`wherein the dosage form provides a mean time to maximum plasma
`concentration (Tmax) of [metformin] the agent at from 5.5 to 7.5 hours
`after administration.
`
`5
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`On Oct. 22, 2002 the Examiner once more rejected the claims again stating
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`that applicant’s arguments were not persuasive, and that claims 1-31 remained
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`rejected under 35 U.S.C. § 112 and claims 32-34 rejected under 35 U.S.C. § 102(b).
`
`In response to the Examiner’s comments, Applicants made further arguments
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`and filed an Amendment to the Application on March 3, 2003. Therein, claims 2-3,
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`6, 16-17 and 32-34 were cancelled; and claims 1, 4-5, 7-15 and 19-29 were amended
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`(“without prejudice”). After such amendments, claims 1, 4-5, 7-15, and 18-31
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`remained pending. Claim 1, the only independent claim read as follows:
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`l. (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 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 [agent] metformin at from
`5.5 to 7.5 hours after administration following dinner.
`
`In response to the Examiner's section 112, first paragraph rejections of claim
`
`1, applicants amended the claim in part to specifically recite "metformin" in place of
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`6
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`"antihyperglycemic agent." Applicants stated that, in any event, Applicants were
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`not required to exemplify every formulation, as it would be inefficient and unethical,
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`and admitted that at the time of the application there were numerous controlled
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`release technologies in the art, and that testing for drug-plasma levels was routine.
`
`Applicants 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."
`In support of this statement, reference was made to the pending application on
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`Page 19, line 21 to Page 20, line 14. Applicants made the following, supplemental
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`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 specification concerning
`formulation
`technologies, which patents provide
`ranges of
`ingredients. These ranges represent the acknowledgement of those
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`7
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`
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`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 in-vivo performance."
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`On July 14, 2003, the Examiner rejected all claims in a non-final office action,
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`except claim 25 which was objected to, stating that applicant arguments were not
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`persuasive. Claims 1, 4-5, 7-15, 18-24 and 26-31 were rejected. Claim 18 was
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`rejected under 35 U.S.C. § 112. Claims 1, 4-5, 7-15, 18-24 and 26-31 were rejected
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`as obvious under 35 USC 103(a) over WO 00/28989, Chiao (Remington, 1995) and
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`further in combination with Drug Facts and Comparisons (1999) or U.S. 5,955,106
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`in combination with Chiao (Remington, 1995) and further in combination with Drug
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`Facts and Comparisons (1999).
`
`Claims 1, 4-5, 7-15, 18-24 and 26 -31 were further rejected under 35 USC
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`103(a) as unpatentable over WO 99/47125 in view of Drug Facts and Comparisons
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`(1999) and U.S. Patent No. 3,845,770.
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`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
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`8
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`U.S. 6,099,859, 6,284,275 and 6,099,862, in view of U.S. Patent No. 3,845,770 and
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`also over copending application 09/726,193.
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`The Examiner noted that claim 25 would be allowable if re-written in
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`independent form including all the limitations of the base claim and any intervening
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`claims.
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`In their response of Oct, 14, 2003, Applicants argued that the patentability of
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`the pending claims, while rewriting the claims to address the examiner’s previous
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`rejections. Claim 1 was amended to incorporate claim 25 and now read as follows:
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`Claim 1. (currently amended) 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 meformin 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
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`9
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`administration for administration of a 2,000 mg onc e-a-day dose of
`metformin .
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`
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`Subsequent to submission of the response, Applicant requested and held on
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`November 20, 2003, an interview with the Examiner. The Examiner in response to
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`the interview issued a notice allowance on Feb. 11, 2004 and allowed the amended
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`claims 1, 4, 5, 7-11, 14, 15, 18, 22, 26-24 and 35-37, as set forth in present form of
`
`U.S. Patent No. 6,790,459. The file wrapper is devoid of any reasons for notice of
`
`allowance.
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`D. Critical Date
`The ‘459 patent derives from U.S. Patent Application Serial No. 09/705,625,
`
`
`
`filed on November 3, 2000. Thus, the critical date for the ‘459 patent is November
`
`3, 2000.
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`III. STANDING (37 C.F.R. 42.104(A)); PROCEDURAL STATEMENTS
`
`Petitioner certifies that (1) the ‘459 patent is available for IPR; and (2)
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`Petitioners are not barred or estopped from requesting IPR of any claim of the ‘459
`
`patent on the grounds identified herein. The required fee is paid through the Patent
`
`Review Processing System, as set forth above.
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`IV. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`Real Party-in-Interest (37 C.F.R. § 42.8(b)(1)):
`
`10
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`
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`The following real parties-in-interest are identified: Aurobindo Pharma Ltd.
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`and Aurobindo Pharma USA Inc.
`
`Related Matters (37 C.F.R. § 42.8(b)(2)):
`
`
`
`On January 25, 2017, Patent Owner Andrx Corporation (a Delaware entity)
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`filed a complaint, in conjunction with NDA holder Shionogi, Inc., in the District of
`
`Delaware in Shionogi Inc. et al. v. Aurobindo Pharma Ltd. et al., Case No. 1.17-cv-
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`00072-UNA (D.Del. Jan. 25, 2017). This case alleges infringement of U.S. Patent
`
`No. 6,790,459 by Aurobindo Pharma Ltd. and Aurobindo Pharma USA Inc. and
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`remains pending.
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`2.
`
`Administrative Matters
`
`Petitioner notes that the PTAB panel (Susan L.C. Mitchell, Tina E. Hulse and
`
`Devon Zastro Newman) denied its first IPR filing in respect of U.S. Patent No.
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`6,790,459 (IPR2017-01673) in a decision issued on December 29, 2017. This filing
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`is an attempt to address the deficiencies noted by the panel in such decision, and
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`entails new references in the obviousness assertion to address the concerns of the
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`panel in respect of the Tucker reference (Ex. 1009 in IPR2017-01673). Aurobindo
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`is not aware of any other pending administrative matters regarding IPR petitions for
`
`U.S. Patent No. 6,790,459.
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`11
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`
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`A. 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)):
`
`LEAD COUNSEL
`
`BACK-UP 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
`
`
`
`
`John Winterle (Reg. # 57,276)
`Email:
`john.winterle@withersworldwide.com
`
`Withers Bergman LLP
`Suite 400
`1700 East Putnam Avenue
`Greenwich, CT 06870
`Tel.: (203) 328-2225
`Fax: (203) 285-1652
`Hans Peter G. Hoffmann (Reg. # 37,352)
`Email: hans-
`peter.hoffmann@withersworldwide.com
`
`Withers Bergman
`Suite 400
`1700 East Putnam Avenue
`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
`
`12
`
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`
`

`

`
`
`
`1700 East Putnam Avenue
`Greenwich, CT 06870
`Tel.: (203) 302-4085
`Fax: (203) 302-6609
`
`B. Notice of Service Information (37 C.F.R. § 42.8(b)(4))
`Petitioner hereby consents to electronic service. Service should be made to
`
`the lead counsel and back-up counsel as noted above, as well as to IPG-
`
`AUR@withersworldwide.com.
`
`Correspondence can be sent by mail to lead counsel at the above address.
`
`V.
`
`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(B))
`
`IPR of claims 1-21 of the ‘459 patent is requested on the grounds for
`
`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 a revised (from IPR2017-0163) declaration of a technical expert, Dr.
`
`Akhlaghi (Ex. 1009), explaining what the art would have conveyed to a POSA and
`
`addressing the concerns of the panel in IPR2017-0163. Dr. Akhlaghi is an expert in
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`the field of pharmacokinetics of biguanides such as metformin (Id. ¶¶ 1-7).
`
`
`
`13
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`
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`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 – 21 of the ‘459 patent, and
`
`cancellation of the same, under 35 U.S.C. § 311 and AIA §6.
`
`Claims Challenged
`Basis
`35 U.S.C. § 103 All challenged claims.
`
`References
`Are
`1-21
`Claims
`35
`Unpatentable Under
`U.S.C. § 103(a) As Being
`Obvious Over Cheng et al.,
`WO 99/47125 (Ex. 1002) In
`View of Timmins et al,. WO
`99/47128
`(Ex.
`1013),
`Wagner, Fundamentals of
`Clinical Pharmacokinetics,
`Drug
`Intelligence
`Publications, Inc. Hamilton,
`Illinois, pp. 133-145 (First
`Edition 1975)(Ex. 1019),
`Lewis
`al., WO
`et
`2000028989 A1 (Ex. 1003),
`as
`further supported by
`Gibaldi
`et
`al.:
`Pharmacokinetics, Second
`Edition
`(Drugs
`and
`Pharmaceutical Sciences) 2nd
`Edition,
`1982, Marcel
`Dekker Inc., NY, NY (Ex.
`1018), and DeFranzo et al.,
`Efficacy of Metformin
`in
`Patients with Non-Insulin
`Dependent
`Diabetes
`Mellitus, 333 N.E.J.M.. No.
`9, 541-549, (August 31,
`1995)(Ex. 1020).
`
`14
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`VII. PERSON OF ORDINARY SKILL IN THE ART IN RESPECT OF U.S.
`PATENT NO. 6,790,459 B1
`As explained in the Declaration of Professor Akhlaghi (EX1009, ¶¶ 67-73), a
`
`POSA as of November 3, 2000, would typically have experience in the research or
`
`development of pharmaceuticals and have the ability to gather and interpret
`
`pharmacokinetic data, as well as understand the relationship between drug release
`
`from a dosage form and its effect on pharmacokinetic parameters. The POSA would
`
`include an individual with a Pharm.D. and/or Ph.D. with experience in
`
`pharmaceutical sciences, dosage form design, clinical pharmacology or related
`
`fields, such as pharmacology.
`
`Additionally, 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.
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`In 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 pharmacokinetics and
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`pharmacodynamics data including dose-response curves; and (iii) the ability
`
`understand results and findings presented or published by others in the field,
`
`including the publications discussed in this declaration.
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`VIII. BACKGROUND OF TECHNOLOGY AND PRIOR ART
`
`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
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`glucose. It was also recognized generally by the POSA that metformin decreases
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`hepatic glucose production, decreases intestinal absorption of glucose, and improves
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`insulin sensitivity by increasing peripheral glucose uptake and utilization.
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`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 (also known as "gluconeogenesis") and that such peak occurs, according to
`
`the '459 patent near 2 AM.2
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`At least one immediate release dosage form "GLUCOPHAGE®," and at
`
`least one controlled release dosage form for metformin, " GLUCOPHAGE® XR,"3
`
`
`2 Id., col. 5, lines 33-34.
`3 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 (See also, Ex. 1015)
`
`16
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`

`a competitor product with overlapping
`
`
`
`release and pharmacokinetic
`
`characteristics as claimed in the '459 patent, had already been approved for
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`marketing by Bristol-Myers Squibb in the United States by October 2000, that is,
`
`before the critical date.
`
`IX. CLAIM CONSTRUCTION
`
`In an inter partes review, a claim in an unexpired patent is given its broadest
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`reasonable construction in light of the specification. 37 C.F.R. § 42.100(b);
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`Cuozzo Speed Techs., LLC v. Lee, 579 U.S. ---, 136 S. Ct. 2131, 2146 (2016).
`
`Reasonableness implies that the claim terms and phrases are to be given an
`
`interpretation that is reasonable in terms of the disclosure in the specification to a
`
`POSA at the time of the invention. Claims terms are also “generally given their
`
`ordinary and customary meaning,” which is the meaning that the term would have
`
`to a person of ordinary skill in the art at the time of the invention in view of the
`
`specification. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007).
`
`Under either standard, there is a reasonable likelihood that Petitioner will prevail
`
`with respect to the challenged claims. A few terms are discussed below that are
`
`supported by the Declaration of Akhlaghi, Ex. 1009 ¶¶ 74-97.
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`17
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`
`
`A.
`“metformin”
`The term “metformin” as it is used herein means metformin base or any
`
`pharmaceutically if acceptable salt e.g., metformin hydrochloride. (Id. col. 6, ll. 65-
`
`67)
`
`B.
`“therapeutically effective reduction”
`The term “therapeutically effective reduction” when used herein is meant to
`
`signify that blood glucose levels are reduced by approximately the same amount as
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`an immediate release reference standard (e.g., GLUCOPHAGE®) or more, when
`
`the controlled release dosage form is orally administered to a human patient on a
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`once-a-day basis. (Id. col. 7, ll. 25-30)
`
`C.
`“Cmax”
`The term “Cmax” is the highest plasma concentration of the drug attained
`
`within the dosing interval, i.e., about 24 hours. (Id. col. 7, ll. 43-45)
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`D.
`“Tmax”
`The term “Tmax” is the time period which elapses after administration of the
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`dosage form at which the plasma concentration of the drug attains the highest plasma
`
`concentration of drug attained within the dosing interval ( i.e., about 24 hours). (Id.
`
`col. 7, ll. 52-56)
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`18
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`
`
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`E.
`“T1/2”
`The term “T1/2” as used in the patent is the time required for the plasma
`
`concentration of metformin during the elimination phase of concentration-time
`
`curve to decrease to one half of its previous concentration. (Akhlaghi Declaration,
`
`Ex. 1009, ¶ 85). The POSA understands T1/2 is an intrinsic pharmacological property
`
`of metformin, as it interacts uniquely with various dissipative mechanisms in a body,
`
`such as kidney function, and is independent of the dosage form used to deliver
`
`metformin.
`
`F.
`“AUC”
`The term “AUC” as used herein, means area under the plasma concentration-
`
`time curve, calculated by the trapezoidal rule over the complete 24-hour interval.
`
`(Id. col. 7, ll. 57-59)
`
`G.
`“a patient”
`The term “a patient” means that the discussion (or claim) is directed to the
`
`pharmacokinetic parameters of an
`
`individual patient and/or
`
`the mean
`
`pharmacokinetic values obtained from a population of patients, unless further
`
`specified. (Id. col. 8, ll. 6-10)
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`19
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`

`
`
`
`H.
`“mean”,
`The term “mean”, when preceding a pharmacokinetic value (e.g. mean Cmax)
`
`represents the arithmetic mean value of the pharmacokinetic value taken from a
`
`population of patients unless otherwise specified (e.g. geometric mean). (Id. col. 8,
`
`ll. 11-14)
`
`I.
`“controlled release carrier”
`In either case, the controlled release dosage form may optionally include a
`
`controlled release carrier which is incorporated into a matrix along with the drug, or
`
`which is applied as a controlled release coating. (Id. col. 12, ll. 50-53)
`
`J.
`"passageway"
`As defined in the specification of the '459 patent, the term passageway
`
`includes an aperture, orifice, bore, hole, weakened area or an erodible element
`
`such as a gelatin plug that erodes to form an osmotic passageway for the release
`
`of the antihyperglycemic drug from the dosage form.4 In either case, the controlled
`
`release dosage form may optionally include a controlled release carrier which is
`
`incorporated into a matrix along with the drug, or which is applied as a controlled
`
`release coating. (Id. col. 12, ll. 50-53)
`
`
`4 Id., col. 11, lines 32-36.
`
`20
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`
`
`Having assessed the meaning of the ‘459 patent claims, we now assess the
`
`scope and content of the prior art, the differences between the prior art and the ‘459
`
`patent claims, if any, and the level of skill in the art. We then determine whether the
`
`‘459 patent claims would have been obvious to a person having ordinary skill in the
`
`art.
`
`X. DETAILED ANALYSIS OF GROUNDS FOR TRIAL
`
`A. Brief Summary of the Prior Art Cited Herein
`Cheng et al., WO1999/047125 (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)
`The Cheng ‘125 publication discloses a controlled release anti-
`
`hyperglycemic tablet (Andrx Metformin XL) that does not contain an expanding
`
`polymer and comprises a core containing an anti-hyperglycemic drug, a
`
`semipermeable membrane coasting the core, and at least one passageway in the
`
`membrane (abstract) (Akhlaghi Declaration, Ex. 1009, ¶110).
`
`The ‘125 publication discloses the in vivo plasma profile of its metformin
`
`susta