Trials@uspto.gov
`Tel. 571-272-7822
`
`
`
`
`
`Paper 16
`Entered: February 3, 2017
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`BOEHRINGER INGELHEIM INTERNATIONAL GMBH,
`Patent Owner.
`_____________
`
`Case IPR2016-01563
`Patent 8,673,927 B2
`______________
`
`
`
`
`
`
`
`Before TONI R. SCHEINER, BRIAN P. MURPHY, and
`ZHENYU YANG, Administrative Patent Judges.
`
`
`MURPHY, Administrative Patent Judge.
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`

`

`IPR2016-01563
`Patent 8,673,927 B2
`
`
`
`INTRODUCTION
`
`I.
`
`Mylan Pharmaceuticals Inc. (“Petitioner”) filed a Petition requesting an inter
`
`partes review of claims 1–26 of U.S. Patent No. 8,673,927 B2 (Ex. 1001, “the ’927
`
`patent”). Paper 2 (“Pet.”). Boehringer Ingelheim International GmbH (“Patent
`
`Owner”) filed a Preliminary Response to the Petition. Paper 10 (“Prelim. Resp.”).
`
`We have statutory authority under 35 U.S.C. § 314(a), which provides that an inter
`
`partes review may not be instituted “unless . . . there is a reasonable likelihood that
`
`the petitioner would prevail with respect to at least 1 of the claims challenged in
`
`the petition.”
`
`Based on the arguments and evidence presented in the Petition and
`
`Preliminary Response, we determine there is a reasonable likelihood Petitioner
`
`would prevail with respect to claims 1 and 10 of the ’927 patent challenged in the
`
`Petition. Therefore, we institute an inter partes review.
`
`A. Related Proceedings
`
`Petitioner and Patent Owner identify the following as related district court
`
`proceedings in the District of New Jersey regarding the ’927 patent: Boehringer
`
`Ingelheim Pharmaceuticals Inc. v. HEC Pharm. Group, Civ. Action No. 3:15-cv-
`
`05982-PGS-TJB (consolidated); Boehringer Ingelheim Pharmaceuticals Inc., v.
`
`Accord Healthcare, Inc., Case No. 3:16-cv- 00852-PGS-TJB; Boehringer
`
`Ingelheim Pharmaceuticals Inc. v. Dr. Reddy’s Laboratories, Ltd., Case No. 3:16-
`
`cv-02394-PGS-TJB; Boehringer Ingelheim Pharmaceuticals Inc. v. Prinston
`
`Pharmaceutical Inc., Case No. 3:16- cv-00851-PGS-TJB; Boehringer Ingelheim
`
`Pharmaceuticals Inc. v. Sun Pharmaceutical Industries Ltd., Case No. 3:16-cv-
`
`01727-PGS-TJB. Pet. 3; Paper 7, 2–3.
`
`
`
`2
`
`

`

`IPR2016-01563
`Patent 8,673,927 B2
`
`Patent Owner identifies the following inactive district court cases: in the
`
`U.S. District Court for the Middle District of North Carolina, Boehringer
`
`Ingelheim Pharmaceuticals Inc. v. Intas Pharmaceuticals Ltd., Case No. 1:15-cv-
`
`00664-CCE-LPA; in the U.S. District Court for the Northern District of West
`
`Virginia, Boehringer Ingelheim Pharmaceuticals Inc. v. Mylan Pharmaceuticals
`
`Inc., Case No. 1:15-cv-00145-JPB. Paper 7, 3.
`
`Petitioner identifies requests for inter partes review of related U.S. Patent
`
`Nos. 8,846,695 (IPR2016-01564), 8,853,156 (IPR2016-01565), and 9,173,859
`
`(IPR2016-01566), which also are asserted in Boehringer Ingelheim
`
`Pharmaceuticals Inc. v. HEC Pharm. Group, Civ. Action No. 3:15-cv-05982-PGS-
`
`TJB (D.N.J.) (consolidated). Pet. 3.
`
`B. Proposed Grounds of Unpatentability
`
`Petitioner advances three grounds of unpatentability under 35 U.S.C. §§ 102
`
`and 103 in relation to the challenged claims in the ’927 patent:
`
`
`
`Reference[s]
`
`’510 Publication (Ex. 1003)1
`
`Statutory
`Basis
`§ 102
`
`Challenged
`Claims
`18–26
`
`’510 Publication and Glucophage Label
`(Ex. 1004)2
`
`§ 103
`
`1–26
`
`
`1 Himmelsbach et al., U.S. Patent Publication No. 2004/0097510, published May
`20, 2004 (“the ’510 Publication”). Ex. 1003.
`2 Glucophage® (metformin hydrochloride tablets) and Glucophage®
`XR (metformin hydrochloride extended-release tablets) prescribing
`information (“Glucophage Label”). Ex. 1004.
`
`
`
`3
`
`

`

`IPR2016-01563
`Patent 8,673,927 B2
`
`Reference[s]
`
`’510 Publication, Ahrén (Ex. 1005),3
`Hughes (1006),4 and/or Brazg (1007)5
`
`Statutory
`Basis
`§ 103
`
`Challenged
`Claims
`1–26
`
`Pet. 9. Petitioner supports its challenge with a Declaration by Dr. Mayer B.
`
`Davidson (“Davidson Declaration”). Ex. 1002.
`
`C. The ’927 Patent
`
`The ’927 patent, titled “Uses of DPP-IV Inhibitors,” issued March 18, 2014,
`
`from an application filed November 15, 2010. Ex. 1001. The ’927 claims priority,
`
`through a continuation application, to EP application 06009203, filed May 4, 2006.
`
`Id. at (30), 1:3–4. The ’927 patent is assigned to Patent Owner. Id. at (73).
`
`The Dipeptidyl Peptidase (“DPP”)-IV enzyme breaks down bioactive
`
`peptides, including the peptide GLP-1. Id. at 1:18–23. GLP-1 is a naturally
`
`occurring peptide “that helps reduce blood glucose by stimulating the pancreas to
`
`produce insulin and by inhibiting the release of glucagon, a substance that causes
`
`the liver to release glucose.” Ex. 1002 ¶ 28 (citing Ex. 1011, 149–150; Ex. 1014,
`
`708); see also Prelim. Resp. 10. DPP-IV enzymes deactivate GLP-1 (and related
`
`hormones), thereby depressing the level of insulin in the body. Id. DPP-IV
`
`inhibitors are used to inhibit the DPP-IV enzyme, thereby preventing the
`
`breakdown of GLP-1 and helping to regulate blood glucose levels. Id. The ’927
`
`
`3 Ahrén et al., Twelve and 52-Week Efficacy of the Dipeptidase IV
`Inhibitor LAF237 in Metformin-Treated Patients with Type 2
`Diabetes, 27 DIABETES CARE 2874–880 (2004) (“Ahrén”). Ex. 1005.
`4 Hughes, International Patent No. WO 2005/117861, published December 15,
`2005 (“Hughes”). Ex. 1006.
`5 Brazg, et al., Effect of Adding MK-0431 to On-going Metformin
`Therapy in Type 2 Diabetic Patients Who Have Inadequate
`Glycemic Control on Metformin, 54 DIABETES (Suppl. 1):A3
`(2005) (“Brazg”). Ex. 1007.
`
`
`
`4
`
`

`

`IPR2016-01563
`Patent 8,673,927 B2
`
`patent states that DPP-IV inhibitors “are highly promising molecules for the
`
`treatment of diabetes mellitus.” Ex. 1001, 1:21–23.
`
`The ’927 patent describes a genus of DPPV-IV inhibitor compounds
`
`according to formula I (id. at 4:54–5:22), but the claims at issue are directed to
`
`methods of treating type II diabetes using one species of DPP-IV inhibitor known
`
`as “linagliptin.” 6 Id. at 5:25–35 (“1-[(4 -methyl-quinazolin-2 -yl)methyl]-3-
`
`methy1-7-(2-butyn-1-y1)-8-(3-(R)-amino-piperidin-l-y1)-xanthine (cf.
`
`WO2004/018468, Example 2 (142)”). The ’927 patent identifies linagliptin as one
`
`of twelve “particularly preferred DPP-IV inhibitors” that may “bring about
`
`unexpected therapeutic advantages or improvements when combined with other
`
`pharmaceutical active substances.” Id. at 5:23–27, 8:15–17. Metformin is
`
`identified as a “particularly preferred example of an antidiabetic combination
`
`partner” for the DPP-IV inhibitors. Id. at 14:32–33. The ’927 patent describes an
`
`orally administered dose of “the DPP IV inhibitors” as “0.5 mg to 100 mg,
`
`preferably 2.5 mg to 50 mg, in each case 1 to 4 times a day” (id. at 8:32–33), and it
`
`further describes oral tablet dosage forms containing 0.5, 1.0, 2.5, 5.0, and 10.0 mg
`
`of DPP-IV inhibitor (id. at 20:4–24).
`
`The ’927 patent includes a series of prophetic treatment examples. Id. at
`
`16:20–23:44. Prophetic Example 13 describes a “Combined Treatment with DPP
`
`IV Inhibitor–Metformin” used for treating type II diabetes or pre-diabetes. Id. at
`
`20:52–57. The combined treatment method is described as follows: “a DPP IV
`
`inhibitor according to the invention may be combined with the anti-diabetically
`
`active substance metformin . . . in a tablet.” Id. at 20:57–60. The ’927 patent
`
`further states:
`
`
`6 “Type 2 diabetes mellitus . . . manifests itself in a fasting blood sugar level
`exceeding 125 mg of glucose per dl of plasma.” Ex. 1001, 1:30–32.
`
`
`
`5
`
`

`

`IPR2016-01563
`Patent 8,673,927 B2
`
`A therapeutically effective dose of the DPP IV inhibitor (e.g. a
`dose of between 0.1 and 100 mg) may be combined with different
`doses of metformin, e.g. with 500 mg, 850 mg or 1000 mg
`metformin as a single dose with a total daily dose of metformin
`of 500-2850 mg, or with 500 mg, 1000 mg, 1500 mg, or 2000 mg
`metformin in delayed-release form.
`Id. at 20:60–66. Example 13 provides that clinical efficacy can be found if the
`
`combination therapy “leads to a significantly greater reduction in the fasting
`
`glucose and/or non-fasting glucose and/or the HbAlc value7 than either the DPP IV
`
`inhibitor alone or metformin alone.” Id. at 21:7–10.
`
`D. Challenged Claims
`
`Petitioner challenges claims 1–26 of the ’927 patent. Independent claims 1
`
`and 18 are illustrative and reproduced below:
`
`1.
`A method of treating type II diabetes mellitus comprising
`administering to a patient in need thereof a pharmaceutically
`effective oral amount of 1-[(4-methyl-quinazolin-2-y1)- methyl]-
`3-methy1-7-(2-butyn-l-y1)-8-(3-(R)-amino-piperidin-1-y1)-
`xanthine, and a pharmaceutically effective amount of metformin,
`which is from 300 mg to 1000 mg once or twice a day, or
`delayed-release metformin in a dose of 500 mg to 1000 mg once
`or twice a day or 500 mg to 2000 mg once a day.
`
`18. A method of treating type II diabetes mellitus comprising
`administering to a patient in need thereof a pharmaceutically
`effective oral amount of 1-[(4-methyl-quinazolin-2-y1)- methyl]
`-3-methy1-7-(2-butyn-l-y1)-8-(3-(R)-amino-piperidin-1-y1)-
`xanthine which is an oral daily dose of from 2.5 mg to 10 mg,
`and a pharmaceutically effective amount of metformin.
`
`
`
`
`
`
`
`7 HbA1c value refers to a patient’s glycated hemoglobin level, which “reflects the
`average blood sugar level of the preceding 4-12 weeks.” Ex. 1001, 1:59–62; see
`also Ex. 1002 ¶ 65.
`
`
`
`6
`
`

`

`IPR2016-01563
`Patent 8,673,927 B2
`
`A. Claim Construction
`
`II. ANALYSIS
`
`Petitioner relies on the ordinary and customary meaning of the claim terms
`
`in the ’927 patent. Pet. 6. Patent Owner does not address claim construction in its
`
`Preliminary Response. Therefore, we determine that claim construction is not
`
`necessary for any of the claim terms at this stage of the proceedings. See, e.g.,
`
`Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011)
`
`(“[C]laim terms need only be construed ‘to the extent necessary to resolve the
`
`controversy.’”) (citation omitted).
`
`B. Ground 1: Asserted Anticipation of Claims 18–26
`
`Petitioner asserts that the ’510 Publication anticipates claims 18–26. Pet.
`
`16–21. Patent Owner opposes, relying primarily on the assertion that the ’510
`
`Publication discloses a much broader dosage range for linagliptin than the broadest
`
`dosage range of 0.5 mg to 50 mg recited in independent claim 20. Prelim. Resp.
`
`18–19. We address the evidence and the parties’ arguments below.
`
`1. The ’510 Publication
`
`The ’510 Publication, assigned to Patent Owner, published on May 20, 2004
`
`and is a prior art printed publication under 35 U.S.C. § 102(b). Ex. 1003; Pet. 16.
`
`The ’510 Publication discloses a genus of substituted xanthine compounds that act
`
`as DPP-IV inhibitors, particularly for the prevention and treatment of type II
`
`diabetes. Id. at Abstract, ¶¶ 3–4. The ’510 Publication discloses linagliptin as one
`
`in a series of 30 “[m]ost particularly preferred” substituted xanthine compounds.
`
`Id. ¶¶ 232, 245. The ’510 Publication also lists the IC50 values of nearly 50 DPP-
`
`IV inhibitor compounds, including linagliptin. Id. ¶ 295 (linagliptin is Example 2
`
`
`
`7
`
`

`

`IPR2016-01563
`Patent 8,673,927 B2
`(142)8). Linagliptin is one of six compounds listed as having the highest potency
`
`in the group, with the lowest IC50 value of 1 nM. Id.
`
`The ’510 Publication discloses that “the compounds of general formula I
`
`according to the invention,” due to their “ability to inhibit DPP-IV activity,” are
`
`“expected . . . [to] be suitable for the prevention or treatment of diseases or
`
`conditions such as type 1 and type 2 diabetes mellitus.” Id. ¶ 297. The ’510
`
`Publication discloses that “[t]he compounds according to the invention may also be
`
`used in conjunction with other active substances . . ., for example, antidiabetics,
`
`such as me[t]formin.” Id. ¶ 298. The ’510 Publication further discloses an oral
`
`dosage, delivered by conventional tablet dosage form, of “1 to 1000 mg, preferably
`
`1 to 100 mg, in each case 1 to 4 times a day” for “the compounds of formula I
`
`prepared according to the invention, optionally combined with other active
`
`substances.” Id. ¶¶ 300, 2899–2910.
`
`2. Analysis
`
`Independent claims 18 and 19 of the ’927 patent each recite “A method of
`
`treating type II diabetes mellitus comprising administering to a patient in need
`
`thereof a pharmaceutically effective oral amount of [linagliptin] which is an oral
`
`daily dose of [specific linagliptin dose or range of doses], and a pharmaceutically
`
`effective amount of metformin.” Ex. 1001, 24:58–25:3. Claim 18 specifies an oral
`
`daily linagliptin dose of “from 2.5 mg to 10 mg.” Claim 19 specifies an oral daily
`
`linagliptin dose of “5 mg.”
`
`Petitioner, in a single sentence of its claim 18 chart that is duplicated in Dr.
`
`Davidson’s Declaration, argues that the ’510 Publication discloses the recited oral
`
`
`8 The ’510 Publication contains numerous examples for preparing compounds of
`the general formula, including the preparation of linagliptin in Example 2 (142).
`Ex. 1003 ¶¶ 1933–37, 2400. The ’927 patent also identifies linagliptin as Example
`2 (142) from WO 2004/018468. Ex. 1001, 5:27–28.
`
`
`
`8
`
`

`

`IPR2016-01563
`Patent 8,673,927 B2
`
`daily linagliptin dosages because “the most preferable oral dosage range for
`
`linagliptin encompasses and thus anticipates the claimed dose recited in claim 18
`
`[and claim 19].” Pet. 18–19 (citing Ex. 1002 ¶ 35; Ex. 1003 ¶ 300). Petitioner also
`
`cites Perricone v. Medicis Pharma. Corp., 432 F.3d 1368, 1376 (Fed. Cir. 2005).
`
`Id. at 19. The Petition, however, does not contain any further analysis of the issue.
`
`Id.
`
`The ’510 Publication does not expressly disclose the oral daily linagliptin
`
`doses recited in claims 18 and 19. The ’510 Publication discloses a preferred oral
`
`dose of 1 to 100 mg “1 to 4 times a day . . . [of] the compounds of formula I
`
`prepared according to the invention, optionally combined with other active
`
`substances.” Ex. 1003 ¶ 300. Disclosure of an oral dose of linagliptin in the range
`
`of 1 to 100 mg, 1 to 4 times daily, is insufficient to satisfy the test for anticipation.
`
`To anticipate a claim, a single prior art reference must disclose all limitations
`
`“arranged as in the claim,” either expressly or inherently. Connell v. Sears,
`
`Roebuck & Co., 722 F.2d 1542, 1548 (Fed. Cir. 1983). To be “arranged as in the
`
`claim,” the anticipatory reference must “show all of the limitations of the claims
`
`arranged or combined in the same way as recited in the claims, not merely in a
`
`particular order.” NetMoneyIn, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1369 (Fed.
`
`Cir. 2008). Petitioner’s conclusory argument that the ’510 Publication discloses an
`
`oral daily dosage range that “encompasses” the recited dosages in claims 18 and 19
`
`does not satisfy the standard for anticipation.
`
`The ’510 Publication discloses a preferred oral dosage range from 1 to 100
`
`mg, 1 to 4 times daily, for a total range of 1 to 400 mg daily. Prelim. Resp. 16.
`
`Although disclosure of such a relatively broad dosage range “encompasses” the
`
`specific linagliptin dosages recited in claims 18 (2.5–10 mg) and 19 (5 mg), prior
`
`disclosure of such a range of values, without more, is not sufficient to anticipate
`
`the specific dosages recited in claims 18 and 19. While Petitioner’s assertion is
`
`
`
`9
`
`

`

`IPR2016-01563
`Patent 8,673,927 B2
`
`true, “the inquiry does not end there.” OSRAM Sylvania, Inc. v. Am. Induction
`
`Techs., Inc., 701 F.3d 698, 706 (Fed. Cir. 2012). Of “critical importance” in
`
`conducting the anticipation analysis is “how one of ordinary skill in the art would
`
`understand the relative size of a genus or species in a particular technology.” Id.
`
`Petitioner has not provided evidence to address the critical question of how one of
`
`ordinary skill would have understood the dosage range of DPP-IV inhibitors
`
`disclosed in the ’510 Publication, relative to the claimed linagliptin dosages used in
`
`a method for treating type II diabetes. The present case also is distinguishable
`
`from Perricone, where the prior art disclosure of a composition having an active
`
`ingredient concentration of “from 0.01 to 20% by weight” was determined to be
`
`sufficient to anticipate claimed ranges “up to 10% by weight” and “from about
`
`0.025% to about 10% by weight.” Perricone, 432 F.3d at 1377. Unlike Perricone,
`
`this is not a case where the prior art range “entirely encompasses, and does not
`
`significantly deviate from, [the] claimed ranges.” Id. (emphasis added).
`
`It is “Petitioner's burden to demonstrate that the claimed subject matter was
`
`disclosed in the prior art with sufficient specificity to constitute an anticipation of
`
`the challenged claims.” Dynamic Drinkware, LLC v. Nat’l Graphics, Inc., Case
`
`IPR2014-01162, 2015 WL 5578357 at *7 (PTAB Jan. 29, 2015). For example,
`
`Petitioner does not address the fact that the ’510 Publication’s preferred oral daily
`
`dosage range is many times broader than the claimed dosage range of 2.5 mg to 10
`
`mg recited in claim 18. Petitioner also does not explain why, based on the
`
`disclosure of a genus of dosage ranges for DPP-IV inhibitors, a person of skill in
`
`the art would immediately envisage administering linagliptin in the dosage
`
`amounts recited in claims 18 and 19 of the ’927 patent. See Dynamic Drinkware,
`
`2015 WL 5578357, at *7.
`
`Independent claim 20 more broadly recites “an oral dosage of from 0.5 mg
`
`to 50 mg.” Ex. 1001, 25:11–12. Claims 21–26 depend from claim 20 and recite
`
`
`
`10
`
`

`

`IPR2016-01563
`Patent 8,673,927 B2
`
`progressively narrower dosages. Id. at 25:16–26:18. Although a closer question
`
`with regard to claim 20, we note Patent Owner’s point that the ’510 Publication’s
`
`disclosure of a preferred oral daily dosage range of 1 to 400 mg is still broader than
`
`the dosage range claimed in claim 20. We do not consider such a disclosure as
`
`falling within the purview of Perricone, particularly in the absence of a substantive
`
`analysis by Petitioner. Therefore, our analysis above regarding claims 18 and 19
`
`applies equally to claims 20–26.
`
`For the reasons given above, we determine Petitioner has not shown a
`
`reasonable likelihood of prevailing in its assertion that claims 18–26 of the ’927
`
`patent are anticipated by the ’510 Publication.
`
`C. Ground 2: Asserted Obviousness of Claims 1–26 Over the ’510
`Publication and Glucophage Label
`
` Petitioner asserts that the ’510 Publication and the Glucophage Label would
`
`have rendered the subject matter of claims 1–26 obvious to a person of ordinary
`
`skill in the art (“POSA”).9 Pet. 21–29. Patent Owner opposes, relying on the
`
`assertion that Petitioner’s evidence is insufficient to establish the Glucophage
`
`Label as a “printed publication” under 35 U.S.C. § 102(b). Prelim. Resp. 19–24.
`
`We address the evidence and the parties’ arguments below.
`
`
`9 Petitioner characterizes a POSA as one having an advanced degree in the field of
`medicine, pharmaceuticals, medicinal chemistry, and/or a related discipline, at
`least 5 years of clinical experience treating type II diabetes and related disorders,
`and experience with the pharmaceutical and clinical properties of DPP-IV
`inhibitors. Pet. 8–9 (citing Ex. 1002 ¶ 11). Preferably, a POSA also would have
`some experience investigating pharmaceutical compositions for treating diabetes
`and diabetes-related disorders. Id. Patent Owner does not challenge Petitioner’s
`description. Therefore, we adopt and apply Petitioner’s definition of a POSA.
`
`
`
`11
`
`

`

`IPR2016-01563
`Patent 8,673,927 B2
`
`1. The Glucophage Label
`
`The Glucophage Label provided by Petitioner as Exhibit 1004 includes a
`
`cover page stating it is the “FINAL PRINTED LABELING” for application
`
`number 20-357/S019 at the Food and Drug Administration (“FDA”) Center for
`
`Drug Evaluation and Research. Ex. 1004, 1. Glucophage® is described in the
`
`document as metformin hydrochloride tablets and Glucophage® XR is described
`
`as metformin hydrochloride extended release tablets, both indicated for the
`
`treatment of type II diabetes. Id. at 2 (col. 1 ¶ 2). The Glucophage Label identifies
`
`Bristol-Myers Squibb as the drug sponsor and contains a date indicated as
`
`“Revised January 2001.” Id. at 7. The Glucophage Label does not contain a
`
`copyright date or other indicia of a publication date.
`
`2. Analysis of Glucophage Label as a Printed Publication
`
` Under 35 U.S.C. § 311(b), a petitioner in an inter partes review may only
`
`challenge the claims of a patent based on “prior art consisting of patents or printed
`
`publications.” 35 U.S.C. § 311(b). Petitioner has the ultimate burden of
`
`persuasion to prove unpatentability by a preponderance of the evidence. Dynamic
`
`Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d 1375, 1378–79 (Fed. Cir. 2015).
`
`Petitioner also bears the initial burden of production to establish the existence of
`
`prior art that renders the claims unpatentable. Id. To satisfy the initial burden of
`
`production, we have often required a petitioner to make a threshold showing that
`
`the reference relied upon was publicly accessible as a printed publication prior to
`
`the effective filing date of a challenged patent. See, e.g., Frontier Therapeutics,
`
`LLC v. Medac Gesellschaft Für Klinische Spezialpraparate MBH, Case IPR2016-
`
`00649, slip op. at 22 (PTAB September 1, 2016) (Paper 10) (finding that an alleged
`
`“printed package insert” was not a printed publication); Symantec Corp. v. Trs. of
`
`Columbia Univ., Case IPR2015-00371, slip op. at 5–9 (PTAB June 17, 2015)
`
`(Paper 13); Temporal Power, Ltd. v. Beacon Power, LLC, Case IPR2015-00146,
`
`
`
`12
`
`

`

`IPR2016-01563
`Patent 8,673,927 B2
`
`slip op. at 8–11 (PTAB Apr. 27, 2015) (Paper 10); Dell, Inc. v. Selene Comm’n
`
`Techs., LLC, Case IPR2014-01411, slip op. at 21–22 (PTAB Feb. 26, 2015) (Paper
`
`23). “A given reference is “publicly accessible” upon a satisfactory showing that
`
`such document has been disseminated or otherwise made available to the extent
`
`that persons interested and ordinarily skilled in the subject matter or art exercising
`
`reasonable diligence, can locate it.” Bruckelmyer v. Ground Heaters, Inc., 445
`
`F.3d 1374, 1378 (Fed. Cir. 2006) (citing In re Wyer, 655 F.2d 221, 226 (CCPA
`
`1981)); see also Voter Verified, Inc. v. Premier Election Solutions, Inc., 698 F.3d
`
`1374, 1380 (Fed. Cir. 2012). With these principles in mind, we consider the
`
`parties’ arguments below.
`
`Petitioner relies on Dr. Davidson for the assertion that the Glucophage Label
`
`was approved and published by the FDA for the treatment of type II diabetes in
`
`February 2001. Pet. 21–22 (citing Ex. 1002 ¶ 43). Dr. Davidson’s background
`
`indicates he is an expert in the field of diagnosing and treating type II diabetes,
`
`having received his medical degree from Harvard Medical School in 1961 and later
`
`his board certification in the subspecialty of Diabetes, Endocrinology, and
`
`Metabolism. Ex. 1002 ¶¶ 5–8. Dr. Davidson states that metformin “was first
`
`approved by the U.S. Food & Drug Administration for the therapeutic treatment of
`
`diabetes in 1994,” but he cites the January 2001 revision of the Glucophage Label
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`in support. Id. at ¶ 27. Dr. Davidson further states that a long-acting extended-
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`release form of metformin, Glucophage XR®, was available in the year 2000, but
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`again cites to the January 2001 revision of the Glucophage Label in support. Id.
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`With regard to the Glucophage Label itself, Dr. Davidson’s Declaration contains
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`the same conclusory sentence contained in the Petition asserting, without
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`explanation or other supporting evidence, that the Glucophage Label was approved
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`and published by the FDA for treating type II diabetes in February 2001. Id. ¶ 43.
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`
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`IPR2016-01563
`Patent 8,673,927 B2
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`We agree with Patent Owner that the Glucophage Label does not contain
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`any source identifying information, e.g. as an FDA-approved label, or other indicia
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`of when the document became publicly available. Prelim. Resp. 22. For example,
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`the Glucophage Label submitted by Petitioner contains no indicia that it (i) is a
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`certified copy of a public record, (ii) is copied from an official 2001 publication
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`such as the United States Pharmacopoeia–National Formulary, (iii) is copied from
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`a recognized periodical published in 2001 such as the Physicians’ Desk Reference,
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`or (iv) otherwise bears the hallmarks of a self-authenticating document published
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`in 2001. See Fed. R. Evid. 902 (4)–(7), (11). The Glucophage Label indicates
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`Bristol-Myers Squibb is the drug sponsor and the label was revised in January
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`2001, but it bears no source identifying information from the FDA, copyright
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`notice or publication date. Ex. 1004, 7. Moreover, although Dr. Davidson is an
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`unquestioned expert in the diagnosis and treatment of type 2 diabetes, his
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`Declaration does not provide a sufficient explanation or foundation to establish his
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`personal knowledge of the Glucophage Label’s alleged publication in February
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`2001. Dr. Davidson’s statements that Glucophage® was approved by the FDA in
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`1994 and Glucophage® XR in 2000 are insufficient, by themselves, as a threshold
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`showing that the Glucophage Label was a publicly available printed publication as
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`of February 2001. Earlier FDA approval of the Glucophage® drug products is not
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`co-extensive with a February 2001 publication date of the revised Glucophage
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`Label, on which Petitioner relies for proof of the specific metformin doses recited
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`in claims 1–17 and the “pharmaceutically effective amount” and “therapeutically
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`effective dose” of metformin recited in claims 18–26. Pet. 23–26, 28–29.
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`For the reasons given above, we determine Petitioner has not satisfied its
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`initial burden of production to show that the Glucophage Label was available as a
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`prior art printed publication. Therefore, we determine Petitioner has not shown a
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`reasonable likelihood of prevailing on its assertion that the subject matter of claims
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`
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`IPR2016-01563
`Patent 8,673,927 B2
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`1–26 of the ’927 patent would have been obvious over the ’510 Publication and the
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`Glucophage Label.
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`D. Ground 3: Asserted Obviousness of Claims 1–26 Over the ’510
`Publication, Ahrén, Hughes, and/or Brazg
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`Petitioner asserts that the ’510 Publication, Ahrén, Hughes, and/or Brazg
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`would have rendered the subject matter of claims 1–26 obvious to a POSA. Pet.
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`29–41. Patent Owner opposes. Prelim. Resp. 24–40. A claimed invention is
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`unpatentable if the differences between the claimed subject matter and the prior art
`
`are such that the subject matter as a whole would have been obvious at the time the
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`invention was made to a person having ordinary skill in the art to which the subject
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`matter pertains. 35 U.S.C. § 103(a). Obviousness under 35 U.S.C. § 103 requires
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`an assessment of (1) the “‘level of ordinary skill in the pertinent art,’” (2) the
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`“‘scope and content of the prior art,’” (3) the “‘differences between the prior art
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`and the claims at issue,’” and (4) “‘secondary considerations’” of nonobviousness
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`such as “‘commercial success, long-felt but unsolved needs, failure of others, etc.’”
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`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007) (quoting Graham v. John
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`Deere Co., 383 U.S. 1, 17–18 (1966)). A party who petitions the Board for a
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`determination of obviousness must show that “‘a skilled artisan would have been
`
`motivated to combine the teachings of the prior art references to achieve the
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`claimed invention, and that the skilled artisan would have had a reasonable
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`expectation of success in doing so.’” Procter & Gamble Co. v. Teva Pharms. USA,
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`Inc., 566 F.3d 989, 994 (Fed. Cir. 2009) (quoting Pfizer, Inc. v. Apotex, Inc., 480
`
`F.3d 1348, 1361 (Fed. Cir. 2007)). We assess Petitioner’s evidence and argument
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`according to this standard.
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`
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`IPR2016-01563
`Patent 8,673,927 B2
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`1. Ahrén
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`Ahrén published in December 2004 and is prior art to the ’927 patent under
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`35 U.S.C. § 102(b) (pre-AIA). Ex. 1005. Ahrén discloses the clinical effect of
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`DPP-IV inhibitor LAF237 (vildagliptin) when combined with metformin to treat
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`patients with type II diabetes. Id. at 2874–7510. Ahrén discloses a 12-week study
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`that compares two groups of type II diabetes patients treated with either metformin
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`monotherapy (1500 to 3000 mg per day), or metformin (1,500 to 3,000 mg per
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`day) and vildagliptin (50 mg once per day) combination therapy. Id. at 2874. In
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`the patients who received metformin and vildagliptin combination therapy for 12
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`weeks, the glycated hemoglobin (HbA1c) baseline level decreased by -0.6 ±0.1%.
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`Id. at 2875 (col. 3 ¶ 4). Treatment with metformin alone showed no change from
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`the baseline during the same time period. Id. In a 40-week extension of the 12-
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`week study, the difference in HbA1c level between the combination therapy group
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`and metformin monotherapy group was -1.1 ±0.2%. Id. at 2875–76.
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`The combination therapy group showed a more significant and rapid
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`reduction in HbA1c level when compared to the metformin monotherapy group, as
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`shown in Ahrén Figure 3 below. Id. at 2876–77; Ex. 1002 ¶ 65.
`
`
`10 Petitioner cites to the internal page numbers of the DIABETES CARE publication,
`rather than to the pages numbers of Exhibit 1005. For consistency, we do the
`same.
`
`
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`
`
`As shown in Ahrén Figure 3, above, mean glucose levels were significantly
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`reduced in patients who received LAF237 (vildagliptin) and metformin
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`combination therapy, when compared with metformin monotherapy patients. Ex.
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`1005, 2877–78. The overall incidence of adverse events was similar in both
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`treatment groups. Id. at 2878. The authors concluded that “when added to
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`metformin treatment, LAF237 was effective at improving glycemic control for at
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`least 1 year in patients with type 2 diabetes and appeared to be well tolerated.” Id.
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`(col. 2 ¶ 4).
`
`2. Hughes
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`Hughes published on December 15, 2005 and is prior art to the ’927 patent
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`under 35 U.S.C. § 102(b) (pre-AIA). Ex. 1006. Like Ahrén, Hughes discloses a
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`method of treating patients with type II diabetes using a combination of LAF237
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`
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`(vildagliptin) and metformin over an extended period of time. Id. at Abstract, 3–4,
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`1311. Hughes teaches that vildagliptin may be administered in an oral daily dosage
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`“between 1 and 100 mg; preferably between 10 and 100 mg e.g. 10 mg; most
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`preferably between 25 and 100 mg e.g. 25 mg or 30 or 40 or 50, 61, 70, 90, 100
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`mg.” Id. at 23. Metformin is administered at a daily dosage in the range of about
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`50 mg to about 3000 mg, preferably from about 500 mg to about 2000 mg, using
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`commercially available 500 mg tablets. Id. Hughes discloses a clinical study
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`involving the administration of vildagliptin (50 mg once daily) and metformin
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`(1500–3000 mg daily) and reports that the combination therapy achieved better
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`clinical results when compared to metformin plus placebo treatment. Id. at 25–33.
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`Hughes further discloses that vildagliptin-metformin combination therapy can
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`effectively maintain low glucose levels or low HbA1c levels in diabetes patients
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`over an extended period of time. Id. at 3–4.
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`3. Brazg
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`Brazg published in June 2005 and is prior art to the ’927 patent under 35
`
`U.S.C. § 102(b) (pre-AIA). Ex. 1007. Brazg discloses the efficacy of combining
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`the DPP-IV inhibitor MK-0431 (sitagliptin) with ongoing metformin therapy in
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`type II diabetes patients. Id. at 2 (col. 2). Brazg notes that “[m]etformin is a
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`commonly used first-line antihyperglycemic agent.” Id. Brazg states that
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`“[c]ombination treatment with MK-0431 [sitagliptin] and metformin may be useful
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`since these agents target different pathophysiologic process leading to
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`hyperglycemia in [type II diabetes].” Id. Brazg discloses clinical trial data that
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`compares