IPR2017-01648
`U.S. Patent No. 6,866,866
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________________________
`Aurobindo Pharma USA Inc.
`Petitioners,
`v.
`Andrx Labs, LLC
`Patent Owner
`____________________________________________
`Case IPR2017-01648
`U.S. Patent No. 6,866,866
`____________________________________________
`
`
`
`PATENT OWNER’S RESPONSE
`
`

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`IPR2017-01648
`U.S. Patent No. 6,866,866
`
`TABLE OF CONTENTS
`
`
`
`I.
`II.
`
`V.
`
`INTRODUCTION ........................................................................................... 1
`FACTUAL STATEMENT .............................................................................. 5
`A. State of the Art in November 2000 .......................................................... 5
`B. Fortamet® ................................................................................................ 6
`C. The ’866 Patent ........................................................................................ 6
`D. Alleged Prior Art ...................................................................................... 7
`E. Examination of the ’866 Patent ............................................................... 9
`III. THE INSTITUTION DECISION .................................................................. 12
`IV. OPINIONS FROM PETITIONER’S DECLARANT SHOULD BE GIVEN
`MINIMAL OR NO WEIGHT ....................................................................... 13
`THE CHALLENGED CLAIMS WOULD NOT HAVE BEEN OBVIOUS
`OVER CHENG IN VIEW OF TIMMINS .................................................... 17
`A. A POSA Would Not Target a Mean Tmax Based on Timmins Absent
`the Benefit of Hindsight ......................................................................... 17
`B. A POSA Would Not Combine the Disclosures of Timmins and Cheng20
`C. A POSA Would Not Have Had A Reasonable Expectation Of Success
`In Combining Timmins and Cheng To Achieve The Claimed
`Compositions ......................................................................................... 23
`D. The Petitioner Fails To Demonstrate That A Combination of Timmins
`and Cheng Would Have Produced A Mean Tmax In The Claimed Ranges
`of 5.5-7.5 Hours, 6.0 to 7.0 Hours, or 5.5 to 7.0 Hours ......................... 27
`E. The Arguments Advanced By Petitioner and Dr. Akhlaghi
`Impermissibly Rely On the Use of Hindsight ........................................ 40
`F. Petitioner Has Failed to Demonstrate That Dependent Claims 2-25 are
`Obvious Over Cheng and Timmins ....................................................... 43
`G. Objective Indicia Demonstrate the Non-Obviousness of the Challenged
`Claims .................................................................................................... 50
`VI. REQUEST FOR ADDITIONAL DISCOVERY .......................................... 55
`VII. CONCLUSION .............................................................................................. 56
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`IPR2017-01648
`U.S. Patent No. 6,866,866
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Federal Cases
`ActiveVideo Networks, Inc. v. Verizon Commc’ns, Inc.,
`694 F.3d 1312 (Fed. Cir. 2012) .......................................................................... 25
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) .......................................................................... 32
`Amgen Inc. v. F. Hoffman-La Roche Ltd,
`580 F.3d 1340 (Fed. Cir. 2009) .......................................................................... 23
`Arendi S.A.R.L. v. Apple Inc.,
`832 F.3d 1355 (Fed. Cir. 2016) .......................................................................... 38
`In re Brandt,
`886 F.3d 1171 (Fed. Cir. 2018) .......................................................................... 31
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 19
`Ecolochem, Inc. v. S. California Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000) .......................................................................... 42
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) .......................................................................... 32
`In re Gordon,
`733 F.2d 900 (Fed. Cir. 1984) ............................................................................ 21
`Grain Processing Corp. v. American Maize-Prods. Co.,
`840 F.2d 902 (Fed. Cir. 1988) ............................................................................ 41
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 20
`MEHL/Biophile Int’l Corp. v. Milgraum,
`192 F.3d 1362 (Fed. Cir. 1999) .......................................................................... 44
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`IPR2017-01648
`U.S. Patent No. 6,866,866
`
`Mylan Institutional LLC v. Aurobindo Pharma Ltd.,
`857 F.3d 858 (Fed. Cir. 2017) ............................................................................ 53
`In re Nuvasive, Inc.,
`842 F.3d 1376 (Fed. Cir. 2016) .......................................................................... 44
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 50
`PAR Pharm., Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .............................................................. 44, 46-47
`In re Patel,
`566 F. App’x 1005 (Fed. Cir. 2014) ................................................................... 31
`Personal Web Techs., LLC v. Apple, Inc.,
`848 F.3d 987 (Fed. Cir. 2017) ............................................................................ 20
`PharmaStem Therapeutics, Inc. v. Viacell, Inc.,
`491 F.3d 1342 (Fed. Cir. 2007) .......................................................................... 23
`Plas-Pak Indus., Inc. v. Sulzer Mixpac AG,
`600 F. App’x 755 (Fed. Cir. 2015) ............................................................... 21, 22
`In re Rijckaert,
`9 F.3d 1531 (Fed. Cir. 1993) .............................................................................. 47
`Rolls–Royce PLC v. United Techs. Corp.,
`603 F.3d 1325 (Fed. Cir. 2010) .......................................................................... 33
`SAS Institute, Inc. v. Iancu, 138 S. Ct. 1348 (2018) ................................................ 12
`Sciele Pharma, Inc. v. Lupin Ltd.,
`684 F.3d 1253 (Fed. Cir. 2012) (“the Federal Circuit opinion) ..................passim
`Securus Techs., Inc.,
`IPR2016-00267, 2016 WL 7047972 (Sept. 12, 2016) ........................................ 42
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983) .......................................................................... 50
`Titanium Metals Corp. v. Banner,
`778 F.2d 775 (Fed. Cir. 1985) ............................................................................ 31
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`IPR2017-01648
`U.S. Patent No. 6,866,866
`
`Federal Statutes
`35 U.S.C. § 102 .......................................................................................................... 9
`35 U.S.C. § 103 .................................................................................................... 9, 12
`Other Authorities
`FDA Approval Letter (Ex. 2001) ............................................................................... 6
`U.S. Patent No. 3,845,770 ........................................................................................ 10
`U.S. Patent No. 6,866,866 .................................................................................passim
`
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`IPR2017-01648
`U.S. Patent No. 6,866,866
`
`I.
`
`INTRODUCTION
`
`This inter partes review of U.S. Patent No. 6,866,866 (the “’866 patent”)
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`involves a single ground that claims 1-25 would have been obvious over a
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`combination of Cheng (Ex. 1002) and Timmins (Ex. 1003). Petitioner’s argument
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`relies almost entirely on hindsight analysis and an incorrect interpretation of the
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`prior art, notably by a purported expert declarant whose experience and sworn
`
`testimony establish a lack of basic understanding of the relevant field that an
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`ordinary skilled artisan would possess. Furthermore, Petitioner and its declarant
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`misapply the doctrine of inherency in relation to certain dependent claims of the
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`’866 patent, and provide no alternative rationale for their invalidity. Finally, even
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`if Petitioner’s declarant is to be believed, claims 2 and 23 cannot as a legal matter
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`be rendered obvious by the asserted combination of prior art, which would fail to
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`teach or suggest every limitation of those claims. As a result, the evidence now
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`before the Board demonstrates that the Petitioner has not carried its burden of
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`showing by a preponderance of the evidence that claims 1-25 would have been
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`obvious. This deficiency can be illustrated by four reasons why the Petitioner has
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`failed to properly make its case, which are detailed below.
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`First, Petitioner and Petitioner’s declarant misunderstand the disclosure of
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`Timmins and accordingly fail to make out a prima facie case of obviousness. For
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`example, there is no dispute between Petitioner and Patent Owner that Timmins
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`IPR2017-01648
`U.S. Patent No. 6,866,866
`does not teach a range of mean Tmax values or identify where the single “true”
`
`mean Tmax obtained by Example 5 of Timmins falls. To quote Petitioner’s
`
`declarant, in attempting to determine where the single mean Tmax value in Timmins
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`actually falls, “everybody is guessing here.” Petitioner and its declarant offer
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`absolutely no explanation of why a person of ordinary skill in the art (“POSA”) in
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`November 2000 reading Timmins would target a mean Tmax value in the claimed
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`ranges of 5.5 to 7.5 hours, 6.0 to 7.0 hours, or 5.5 to 7.0 hours, as opposed to a
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`mean Tmax value that falls outside the claimed ranges. In fact, despite inconsistent
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`and confused testimony from Petitioner’s declarant, her most credible, non-
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`conclusory testimony shows that a POSA would understand that the mean Tmax
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`value of Timmins would be based on a normal distribution of individual patient
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`Tmax values and would thus likely fall below the claimed ranges.
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`Furthermore, Petitioner and Petitioner’s declarant disregard the principal
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`teaching in Timmins that the location of release of the disclosed metformin dosage
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`forms in the gastrointestinal tract is what is critical to obtaining the disclosed
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`advantages. Instead, the Petition focuses on a median Tmax value reported by
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`Timmins, which a POSA would understand to be incidental to Timmins’ main
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`purpose, and which, in any event, would provide insufficient information for such
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`a person to determine the mean Tmax of Timmins, let alone design a dosage form of
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`metformin producing such a mean Tmax value.
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`IPR2017-01648
`U.S. Patent No. 6,866,866
`Second, a POSA would not have been motivated to combine Cheng and
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`Timmins because they respectively teach different and mutually exclusive dosage
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`forms and mean Tmax values. Cheng seeks to provide a dosage form without any
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`expanding polymer, while Timmins teaches that one or more expanding, swelling
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`hydrophilic polymers are required to provide the disclosed advantages.
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`Furthermore, Cheng is directed to a dosage form of metformin that provides a
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`mean Tmax value of 8-12 hours, which is mathematically excluded by the dosage
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`form of Timmins (because the highest individual Tmax value achieved in Timmins
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`was 8 hours). Thus, the purported combination would render Cheng inoperative
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`for its intended purpose, eliminating the possibility of a motivation for a POSA to
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`combine these references with any reasonable expectation of success.
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`Third, Petitioner’s obviousness arguments are fraught with hindsight bias.
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`Hindsight is the only explanation for why Petitioner assumes that a POSA would
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`seek to target a mean Tmax value at all based on Timmins, and Petitioner fails to
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`offer any other explanation of why a POSA reading Timmins would choose a mean
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`Tmax value falling within the ’866 patent’s claimed ranges. This failure is even
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`more transparent given Petitioner’s declarant’s admissions that the likely
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`distribution of individual Tmax values from Timmins produces a mean Tmax below
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`the claimed ranges. Evidence of hindsight is further confirmed by testimony by
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`Petitioner’s declarant, who admitted that her search for prior art and motivation to
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`IPR2017-01648
`U.S. Patent No. 6,866,866
`combine relied on the ’866 patent itself as a blueprint. This is a quintessential
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`example of improper hindsight bias.
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`Finally, Petitioner’s only arguments as to the obviousness of dependent
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`claims 2-25 rely on the doctrine of inherent obviousness, which doctrine is
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`inapplicable in the present case based on sworn testimony from Petitioner’s own
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`declarant. As the Federal Circuit has made clear, inherency must be carefully
`
`circumscribed in the obviousness context—such a finding is only appropriate
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`where the prior art necessarily functions in accordance with, or includes, the
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`claimed limitations, and the mere fact that a given claim limitation may result from
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`the prior art is insufficient. That is particularly the case here, as Petitioner’s
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`declarant admitted that, even assuming the combination of Cheng and Timmins
`
`provided a dosage form of metformin with a mean Tmax value in the claimed
`
`ranges, that dosage form “might or might not” demonstrate the other
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`pharmacokinetic parameters recited in the dependent claims. Again, to quote
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`Petitioner’s declarant, “[i]t’s like lots of uncertainty here.” With Petitioner’s
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`inherency argument being dispatched, Petitioner advances no other evidence or
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`argument for the asserted obviousness of the dependent claims, which accordingly
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`must survive this review.
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`IPR2017-01648
`U.S. Patent No. 6,866,866
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`II.
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`FACTUAL STATEMENT
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`A.
`
`State of the Art in November 2000
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`Metformin is a short-acting drug used to treat non-insulin-dependent
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`diabetes mellitus (“NIDDM”). ’866 patent, col. 1, ll. 56-58. At the time of filing
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`of the ’866 patent in November 2000, metformin hydrochloride was marketed as
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`Glucophage® by Bristol-Myers Squibb in the United States. Id. col. 1, ll. 61-63.
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`At the time, there was no fixed dosage regimen for Glucophage® to manage
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`hyperglycemia in patients with diabetes mellitus—instead, dosages were
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`individualized to each patient using 500 mg, 850 mg, or 1,000 mg tablets based on
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`both effectiveness and tolerance, while not exceeding the maximum recommended
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`dose of 2,550 mg per day. Id. col. 1, l. 63–col. 2, l. 2. However, because
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`metformin is a short-acting drug, patients had to take the medication two or three
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`times each day. Id. col. 2, ll. 4-6. Such frequent dosing routinely led to reduced
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`patient compliance and increased adverse events. See id. col. 1, ll. 14-18; col. 2, ll.
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`4-6. In the case of metformin, such adverse events include the potentially
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`dangerous side-effects of anorexia, nausea, and vomiting. Id. col. 2, ll. 6-8; col.
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`20, ll. 16-18.
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`At the time of the ’866 patent, there was thus a need in the art for a safe and
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`effective dosage form of metformin that would enable patients with type 2 diabetes
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`IPR2017-01648
`U.S. Patent No. 6,866,866
`(also known as “NIDDM”) to take their medication only once-a-day, thereby
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`improving patient compliance and reducing adverse events.
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`B.
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`Fortamet®
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`To address these shortcomings in the prior art treatments for type 2 diabetes,
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`the inventors of the ’866 patent developed Fortamet®, a novel extended release
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`dosage form of metformin. Results from clinical studies demonstrated that
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`Fortamet® was comparable to immediate-release metformin in terms of efficacy
`
`and safety, while providing for a more convenient once-daily dosage regimen. See
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`Apr. 27, 2004 Letter from the FDA Approving NDA 21-574 (hereinafter “the
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`Fortamet® FDA Approval Letter”) (Ex. 2001); Fortamet® FDA Label (Rev.
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`02/10) at 8-12, 28 (Ex. 2002). The FDA approved Fortamet® for use in managing
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`type 2 diabetes on April 27, 2004. See Fortamet® FDA Approval Letter (Ex.
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`2001).
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`C. The ’866 Patent
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`The ’866 patent, entitled “Controlled Release Metformin Compositions,”
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`issued from U.S. Patent Application No. 09/705,630, which was filed on
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`November 3, 2000 (“the ’630 application”). The named inventors are Chih-Ming
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`Chen, Xiu-Xiu Cheng, Steve Jan, and Joseph Chou. The invention relates to
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`“controlled release unit dose formulations containing an antihyperglycemic drug”
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`IPR2017-01648
`U.S. Patent No. 6,866,866
`such as metformin hydrochloride, ’866 patent, col. 1, ll. 5-11, which are used as
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`treatments for type 2 diabetes.
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`D. Alleged Prior Art
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`The remaining invalidity ground is based on two references alleged to be
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`prior art to the ’866 patent, both of which were before the Patent Office during
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`prosecution of the ’866 patent.
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`1.
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`Timmins
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`International Patent Application Publication No. WO 99/47128 (hereinafter
`
`“Timmins”) (Ex. 1003) is titled “Biphasic Controlled Release Delivery System for
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`High Solubility Pharmaceuticals and Method.” Timmins discloses a “biphasic
`
`controlled release delivery system for pharmaceuticals which have high water
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`solubility, such as the antidiabetic metformin [hydrochloride] salt, … which
`
`provides a dosage form that has prolonged gastric residence.” Ex. 1003 at
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`Abstract. The stated goal of Timmins is to achieve “prolonged gastric residence,”
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`to maximize contact between released drug and the site of the absorption for
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`metformin, which Timmins indicates is primarily in the upper small intestine. Ex.
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`1003 at 11, ll. 13-14; Declaration of Dr. Jennifer Dressman, Ph.D. (Ex. 2010) ¶37.
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`Timmins does not disclose a single mean Tmax value for the disclosed
`
`compositions. Ex. 2010 ¶¶73-74; Akhlaghi Deposition (Ex. 2011) at 77:17-81:1.
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`Instead, Timmins in Example 5 discloses administration to a group of patients
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`IPR2017-01648
`U.S. Patent No. 6,866,866
`either a dosage form of metformin hydrochloride prepared according to Example 3
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`(i.e., a dosage form that includes an expanding polymer) or Glucophage®. Ex.
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`2010 ¶40. Timmins does report that the median Tmax value obtained for the patient
`
`group dosed with Example 3 was 5 hours, with the lowest individual Tmax value
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`observed at 4 hours and the highest individual Tmax value observed at 8 hours. Ex.
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`2010 ¶40. Timmins does not provide the individual Tmax values for the other
`
`patients receiving the Example 3 dosage form, and thus a mean Tmax value cannot
`
`be calculated from the data presented in Example 5. Ex. 2010 ¶41.
`
`2.
`
`Cheng
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`International Patent Application Publication No. WO 99/47125 (“Cheng”)
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`(Ex. 1002) is titled “Controlled Release Oral Tablet Having a Unitary Core.”
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`Cheng discloses a “controlled release antihyperglycemic tablet … comprising a
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`core containing the antihyperglycemic drug, a semipermeable membrane coating
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`the core and at least one passageway in the membrane.” Cheng at Abstract. It was
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`published on the same day as Timmins.
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`One of the stated goals of Cheng is “to provide a controlled or sustained
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`release formulation for an antihyperglycemic drug that does not employ an
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`expanding polymer.” Ex. 1002 at 3, ll. 3-6 (emphasis added). Cheng also teaches
`
`that another key feature of its tablet is that it “provide[s] therapeutic levels of the
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`drug throughout the day with peak plasma levels [(i.e., Tmax)] being obtained
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`IPR2017-01648
`U.S. Patent No. 6,866,866
`between 8-12 hours after administration” following dinner. Ex. 1002 at 4, ll. 3-9.
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`Cheng states that its disclosure is directed to “a controlled or sustained release
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`formulation for an antihyperglycemic drug that obtains peak plasma levels
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`approximately 8-12 hours after administration;” and that “a controlled or sustained
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`release formulation for an antihyperglycemic drug that can provide continuous and
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`non-pulsating therapeutic levels of an antihyperglycemic drug to an animal or
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`human in need of such treatment over a twelve hour to twenty-four hour period.”
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`Ex. 1002 at 3, ll. 7-17 (emphasis added).
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`E.
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`Examination of the ’866 Patent
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`During prosecution of the ’630 application, the Patent Office was aware of,
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`and specifically considered, the disclosures of both Cheng and Timmins, on which
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`Petitioner now relies. As an initial matter, Applicant discussed both Timmins and
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`Cheng in the Background of the Invention section of the ’866 patent specification.
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`’866 patent, col. 2, ll. 34-47. In addition, in the first Office Action, the Examiner
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`rejected the pending claims over Cheng under pre-AIA 35 U.S.C. §§ 102 and 103,
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`stating that Cheng “discloses controlled metformin compositions” including those
`
`having “a semi-permeable membrane coating surrounding the core.” Office Action
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`mailed Dec. 31, 2001 for the ’630 application at 4, 6 (Ex. 1005 at 92, 94). The
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`Examiner again rejected the claims as allegedly anticipated by Cheng in the second
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`Office Action, reiterating that Cheng “discloses controlled release
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`IPR2017-01648
`U.S. Patent No. 6,866,866
`antihyperglycemic dosage form[s] that has the same composition taught by the
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`specification as providing the instant mean fluctuation indexes.” Office Action
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`mailed Oct. 22, 2002 for the ’630 application at 5 (Ex. 1005 at 126). Finally, in a
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`third Office Action, the Examiner rejected the claims as allegedly obvious over
`
`Cheng, stating that “it would have been obvious to one skilled in the art at the time
`
`of the invention to manipulate the release profile of [Cheng] in accordance with the
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`teachings in [U.S. Patent No. 3,845,770] with the motivation of providing
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`controlled delivery of metformin over a desired period of time.” Office Action
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`mailed May 21, 2003 for the ’630 application at 4 (Ex. 1005 at 152). The rationale
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`underlying these rejections was the same as Petitioner’s argument to the Board –
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`that Cheng taught or suggested the claimed dosage forms, and that therefore the
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`recited Tmax was inherently disclosed, or that a POSA would have modified those
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`teachings to arrive at the recited Tmax.
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`In response to these rejections, Applicant explained that Cheng and the other
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`cited references failed to teach or suggest the claimed ranges of mean Tmax values
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`or to provide any motivation that would lead the skilled person to dosage forms
`
`providing those values. After considering Applicant’s arguments and amendments,
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`the Examiner eventually withdrew the rejections based on Cheng. Notice of
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`Allowance mailed Dec. 19, 2003 for the ’630 application at 1 (Ex. 1005 at 178);
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`Form PTO-1449 dated Dec. 12, 2003 for the ’630 application (Ex. 1005 at 177);
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`IPR2017-01648
`U.S. Patent No. 6,866,866
`Supplemental Notice of Allowability dated Nov. 30, 2004 at 1-2 (Ex. 1005 at 198-
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`99); see the ’866 patent.
`
`The Patent Office also considered United States Patent No. 6,475,521
`
`(hereinafter “the ’521 patent”), which the Applicant cited in an IDS, and which
`
`accordingly appears as a Reference Cited on the face of the ’866 patent. Notice of
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`Allowance mailed Dec. 19, 2003 for the ’630 application at 1 (Ex. 1005 at 178);
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`Form PTO-1449 dated Dec. 12, 2003 for the ’630 application (Ex. 1005 at 177);
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`Supplemental Notice of Allowability dated Nov. 30, 2004 at 1-2 (Ex. 1005 at 198-
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`99). The ’521 patent is a continuation-in-part of United States Patent Application
`
`No. 09/044,446 to which Timmins also claims priority. Thus, the ’521 patent has
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`essentially the same disclosure as Timmins, plus additional disclosure.1 The
`
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`1 For purposes of this dispute, the only meaningful difference in the disclosures of
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`the ’521 patent and Timmins is that Timmins discloses a method “for treating
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`hyperglycemia including Type II diabetes (NIDDM) and/or Type I diabetes
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`(IDDM) wherein a therapeutically effective amount of the biphasic formulati[o]n
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`of the invention containing metformin or a salt thereof, optionally in combination
`
`with another antihyperglycemic agent, is administered to a patient in need of
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`treatment,” while the ’521 patent lacks this specific disclosure. See Ex. 1003 at 22,
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`ll. 14-21; cf. ’521 patent.
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`IPR2017-01648
`U.S. Patent No. 6,866,866
`disclosure related to mean Tmax values in the ’521 patent is the same as that in
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`Timmins.
`
`After considering Cheng, the ’521 patent, and the other prior art before the
`
`Patent Office, the Examiner allowed the claims of the ’630 application. The ’866
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`patent then issued on March 15, 2005. See ’866 patent. The Patent Office thus
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`concluded that the claims were patentable over Cheng, Timmins, and a
`
`combination of prior art because the references failed to teach or suggest key
`
`limitations (e.g., a mean Tmax of 5.5 hours to 7.5 hours) recited in the claims of the
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`’866 patent.
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`III. THE INSTITUTION DECISION
`
`The Board initially instituted inter partes review of claims 1-25 of the ’866
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`patent limited to the combination of Cheng and Timmins (Ground III) under 35
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`U.S.C. § 103. Paper No. 12. Following SAS Institute, Inc. v. Iancu, 138 S. Ct.
`
`1348 (2018), the Board instituted on all challenged claims and all challenged
`
`grounds in the Petition. Paper No. 20. However, this inter partes review was once
`
`again limited to Ground III after the Board granted the parties’ voluntary and joint
`
`withdrawal of the remaining grounds. Paper No. 23.
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`In its Decision on Institution, the Board did not resolve any differences in
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`the parties’ definitions of a person of ordinary skill in the art (“POSA”). Paper No.
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`12 at 5. However, the Board acknowledged that Patent Owner asserted that a
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`U.S. Patent No. 6,866,866
`person of ordinary skill in the art at the time of the invention would have “held a
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`degree in pharmacy, chemistry, chemical engineering, or a related field with at
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`least three to five years of pharmacokinetics, biopharmaceutics, medicinal
`
`chemistry, pre-formulation, or formulation experience, research, or training [and
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`would have been familiar] with the methods used in formulating oral dosage forms,
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`modified release dosage forms, and osmotic delivery, and [understand]
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`fundamental principles as to how osmotic dosage forms behave and function.”
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`Prelim. Resp. 15–16 (alterations added); Paper No. 12 at 5-6. The Board found
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`that “[b]oth parties contend that a person of ordinary skill in the art would have had
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`experience with and knowledge of the development of pharmaceuticals and the
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`ability to analyze pharmacokinetic data including the relationship between oral
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`dosage forms and osmotic delivery.” Paper No. 12 at 6.
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`IV. OPINIONS FROM PETITIONER’S DECLARANT SHOULD BE
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`GIVEN MINIMAL OR NO WEIGHT
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`During her deposition, Dr. Akhlaghi gave varying, inconsistent, and
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`unsupported testimony regarding the disclosure of Timmins. Ex. 2010 ¶¶41-49.
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`For at least the reasons below, Dr. Akhlaghi’s conclusions as to whether the ’866
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`patent would have been obvious to a POSA in November 2000 should be given
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`minimal, if any, weight.
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`First, Dr. Akhlaghi conceded that she is not an expert in formulation
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`development. Ex. 2011 at 24:5-9; 37:18-38:5. In particular, she admitted that she
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`has never developed the dosage forms relevant to the two prior art references at
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`issue in this proceeding; Timmins (i.e., expanding polymer-based dosage forms)
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`and Cheng (i.e., osmotic pump dosage forms). Ex. 2011 at 33:16-22 (“Q: Your CV
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`doesn’t indicate that you’ve ever designed or developed an osmotic pump dosage
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`form. Correct? A: I did not develop an osmotic pump dosage form. Q: And your
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`CV doesn’t indicate that you’ve ever designed an expanding polymer dosage form?
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`A: I have not done it”). Because the problem with which a POSA in November
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`2000 was faced was the development of a solid dosage form of metformin, Dr.
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`Akhlaghi’s lack of expertise in this area undercuts the value of her opinions.
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`Second, Dr. Akhlaghi evinced a lack of understanding of the subject matter
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`of the claims of the ’866 patent. Ex. 2010 ¶¶44-45. For example, Dr. Akhlaghi
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`initially stated that the subject matter of the ’866 patent relates only to
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`pharmacokinetic parameters, not formulation development. Ex. 2011 at 24:5-16,
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`32:20-34:12. However, Dr. Akhlaghi subsequently stated that her conclusion that
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`a motivation existed for a POSA to combine Timmins and Cheng to arrive at the
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`’866 patent’s claims was based on the development of a dosage form of metformin,
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`contradicting her earlier statement. Ex. 2011 at 86:2-22. Dr. Akhlaghi’s shifting
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`U.S. Patent No. 6,866,866
`opinion can possibly be explained by her lack of expertise in formulation
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`development.
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`Third, Dr. Akhlaghi was unable to provide clear and consistent testimony
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`regarding the purported disclosure of a mean Tmax value in Timmins that is
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`supported by the limited data presented therein. Ex. 2010 ¶¶46-47. For example,
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`Dr. Akhlaghi alternately testified that Timmins’s Example 5 describes a mean Tmax
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`value (1) that must fall in the range of 4.67 to 6.33 hours, (2) that could be 8 hours,
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`(3) that could be anywhere between 4 to 8 hours, (4) that cannot be 5 hours, (5)
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`that cannot be less than 5 hours, (6) that could be 4 hours, (7) that could be 6 hours,
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`(8) that cannot be calculated absent the undisclosed underlying raw data, and (9)
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`that she was able to calculate to be “around 5.75 [hours], or something like that.”
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`Ex. 1019 at 190 (“Such prolonged release, however, accompanied with a
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`lengthened Tmax, was already known to the artisan, as Timmins (WO 99/47128)
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`disclosed a median Tmax of 5 hours (range 4-8 hours), from which the artisan would
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`calculate a mean Tmax of between 4.67 and 6.33 hours.”); Ex. 2011 at 70:8-71:21
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`(“Q: In general, a person skilled in the art would understand how to calculate a
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`mean Tmax value based on administration of a single daily dose. Right? A: If you
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`have the raw data, yes. . . Q: You don't have the raw data for Timmins? A: I don’t.
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`No. Q: And Timmins does not report the Tmax data for each patient from
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`Example 5? A: No, it does not.”); 72:8-12 (“Q: So what is the single mean Tmax
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`value you calculated from the data presented in Timmins? A: It was around 5.75,
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`or something like that.”); 77:13-20; 79:9-15 (Q: And a single mean Tmax from
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`Timmins could fall anywhere between 4.6 and 6.33 hours. Right? A: It can fall
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`between 4 to 8 hours. We are assuming it is falling between 4.67 based on the
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`median data. But honestly, the range is 4 to 8. Maybe they had everybody in 8.
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`Maybe they had everybody at 4. Maybe they had everybody at 6.”); 79:19-80:4
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`(“Q: Right. So the single mean Tmax value from Timmins could be 5 hours.
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`Right? . . . A: It cannot be 5 hours because of the fact that we also have 8-hour
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`people.”); 81:5-8 (“Q: As you said, the single mean Tmax value could be just
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`below 5. Right? A: No, it cannot be below 5, because we have the 8 people that
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`have 8 hours.”); 81:9-16 (“Q: So the single Tmax value from Timmins could be
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`just greater than 5 hours. Right? A: I'm not sure. You know, I'm -- you know, this
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`is kind of -- I cannot speculate. Q: Right. You don't know where it falls? . . . A: I
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`know it probably falls between 4.67 to 6.33.”).
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`Not only are a number of these values inconsistent with one another, several
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`are outside the range of possibilities of 4.67 to 6.33 hours calculated by the Federal
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`Circuit opinion and relied on by Dr. Akhlaghi. See Sciele Pharma, Inc. v. Lupin
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`Ltd., 684 F.3d 1253 (Fed. Cir. 2012) (hereinafter “the Federal Circuit opinion”).
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`Moreover, several are also inconsistent with the plain reading of Timmins, which
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`reports a median Tmax value of 5 hours, with at least one patient having an
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`individual Tmax of 8 hours and at least one patient having an individual Tmax of 4
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`hours. Ex. 1003 at 36.
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`Finally, Dr. Akhlaghi contradicted her own testimony that sh