Trials@uspto.gov
`571-272-7822
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` Paper No. 17
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`Entered: January 31, 2017
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`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 IPR2016-01564
`Patent 8,846,695 B2
`____________
`
`
`Before TONI R. SCHEINER, BRIAN P. MURPHY, and
`ZHENYU YANG, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
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`571-272-7822
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` Paper No. 17
`
`Entered: January 31, 2017
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`
`
`
`
`
`
`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 IPR2016-01564
`Patent 8,846,695 B2
`____________
`
`
`Before TONI R. SCHEINER, BRIAN P. MURPHY, and
`ZHENYU YANG, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`
`
`IPR2016-01564
`Patent 8,846,695 B2
`
`
`INTRODUCTION
`Mylan Pharmaceuticals Inc. (“Petitioner”) filed a Petition for an inter
`partes review of claims 1–4 of U.S. Patent No. 8,846,695 B2 (“the ’695
`patent,” Ex. 1001). Paper 2 (“Pet.”). Boehringer Ingelheim International
`GmbH (“Patent Owner”) timely filed a Preliminary Response. Paper 11
`(“Prelim. Resp.”). We review the Petition under 35 U.S.C. § 314.
`For the reasons provided below, we determine Petitioner has satisfied
`the threshold requirement set forth in 35 U.S.C. § 314(a). Because
`Petitioner has established a reasonable likelihood that it would prevail in
`showing the unpatentability of claims 1–4, we institute an inter partes
`review of the challenged claims.
`Related Proceedings
`Patent Owner informs us that it has asserted the ’695 patent against
`Petitioner in Boehringer Ingelheim Pharm. Inc. v. Mylan Pharm. Inc., Case
`No. 1:15-cv-00145 (N.D.W.Va.), which is currently inactive. Paper 7, 3.
`According to the parties, the ’695 patent is the subject of several other
`cases in district courts, which have been consolidated into Boehringer
`Ingelheim Pharm. Inc. v. HEC Pharm Group, Case No. 3:15-cv-05982
`(D.N.J.). Pet. 5; Paper 7, 2–3. In that case, Patent Owner also asserted U.S.
`Patent Nos. 8,673,927, 8,853,156, and 9,173,859. Pet. 5. Petitioner has
`concurrently filed IPR2016-01563, IPR2016-01565, and IPR2016-01566,
`challenging those patents respectively. Id.
`
`
`2
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`IPR2016-01564
`Patent 8,846,695 B2
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`
`The ’695 Patent
`The ’695 patent is directed to “certain DPP-4 [dipeptidyl peptidase 4]
`inhibitors for improving glycemic control, such as e.g. improving
`hemoglobin A1c (HbA1c) and/or fasting plasma glucose (FPG), in type 2
`diabetes patients with inadequate glycemic control despite therapy with
`metformin, as well as to the use of these DPP-4 inhibitors in antidiabetic
`therapy.” Ex. 1001, 1:6–11.
`The ’695 patent states that metformin is the drug of choice for
`beginning or first-line antidiabetic therapy. Id. at 2:1–7. It is, however,
`associated with a high secondary failure rate, that is, some diabetic patients
`may fail to achieve or maintain glycemic control over time. Id. at 1:26,
`2:10–12.
`“DPP-4 inhibitors interfere with the plasma level of bioactive peptides
`including the peptide GLP-1 and are considered to be promising drugs for
`the treatment of diabetes mellitus.” Id. at 3:67–4:3. According to the ’695
`patent, the inventor surprisingly found that certain DPP-4 inhibitors had
`“unexpected and particularly advantageous properties, which make them
`particularly suitable for improving glycemic control in patients with type 2
`diabetes mellitus inadequately controlled on metformin alone.” Id. at 9:9–
`14. Specifically, the ’695 patent identifies DPP-4 inhibitor 1-[(4-methyl-
`quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-
`piperidin-1-yl)-xanthine, also known as BI 1356 or linagliptin, as
`particularly preferred. Id. at 17:33–37, 21:4–7.
`
`3
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`IPR2016-01564
`Patent 8,846,695 B2
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`Illustrative Claims
`Among the challenged claims, claims 1 and 2 are independent. Claim
`1 is representative and it reads as follows:
`1.
`A method for treating type 2 diabetes mellitus in a patient
`with
`inadequate glycemic control despite
`therapy with
`metformin, said method comprising orally administering 1-[(4-
`methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
`(3-(R)-amino-piperidin-1-yl)-xanthine to said patient in an
`amount of 5 mg per day in combination with metformin.
`Claim 2 is similar to claim 1, except it recites administering linagliptin
`“as add-on combination with metformin.”
`Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds, each of which challenges the
`patentability of claims 1–4:
`Ground
`Basis
`1
`§ 103
`
`References
`Charbonnel1 or Hughes2
`in view of the ’940 Publication3
`
`
`1 Charbonnel et al., Efficacy and Safety of the Dipeptidyl Peptidase-4
`Inhibitor Sitagliptin Added to Ongoing Metformin Therapy in Patients With
`Type 2 Diabetes Inadequately Controlled with Metformin Alone, 29
`DIABETES CARE 2638–43 (2006) (Ex. 1004).
`2 Hughes, Int’l Pub. No. WO 2005/117861, published December 15, 2005
`(Ex. 1005).
`3 Dugi et al., U.S. Patent Publication No. 2007/0281940, published
`December 6, 2007 (Ex. 1003).
`
`4
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`IPR2016-01564
`Patent 8,846,695 B2
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`
`Basis
`§ 103
`
`Ground
`2
`
`References
`Janumet,4 Nauck,5 or Ahrén 20086
`in view of the ’940 Publication
`In support of its patentability challenge, Petitioner relies on the
`Declaration of Dr. Mayer B. Davidson. Ex. 1002.
`ANALYSIS
`Claim Construction
`In an inter partes review, the Board interprets a claim term in an
`unexpired patent according to its broadest reasonable construction in light of
`the specification of the patent in which it appears. 37 C.F.R. § 42.100(b);
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016). Under
`that standard, and absent any special definitions, we assign claim terms their
`ordinary and customary meaning, as would be understood by one of ordinary
`skill in the art at the time of the invention, in the context of the entire patent
`disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir.
`2007).
`
`
`4 Janumet™ (sitagliptin/metformin HCL) tablets Prescribing Information
`(Ex. 1007).
`5 Nauck et al., Efficacy and Safety of the Dipeptidyl Peptidase-4 Inhibitor,
`Sitagliptin, Compared with the Sulfonylurea, Glipizide, in Patients with Type
`2 Diabetes Inadequately Controlled on Metformin Alone: A Randomized,
`Double-Blind, Non-Inferiority Trial, 9 DIABETES, OBESITY AND
`METABOLISM 194–205 (2007) (Ex. 1006).
`6 Ahrén, Novel Combination Treatment of Type 2 Diabetes DPP-4 Inhibition
`+ Metformin, 4 VASCULAR HEALTH AND RISK MANAGEMENT 383–94 (2008)
`(Ex. 1022).
`
`5
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`IPR2016-01564
`Patent 8,846,695 B2
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`Claim terms need only be construed to the extent necessary to resolve
`the controversy. Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361
`(Fed. Cir. 2011). On this record and for purposes of this Decision, we see no
`need to construe any term expressly.
`Grounds 1 and 2
`For Ground 1, Petitioner argues that claims 1–4 would have been
`obvious over Charbonnel or Hughes in view of the ’940 Publication. Pet.
`16–25. For Ground 2, Petitioner argues that claims 1–4 would have been
`obvious over Janumet, Nauck, or Ahrén 2008 in view of the ’940
`Publication. Pet. 26–35. Patent Owner contends that Petitioner has not
`shown that Janumet is a printed publication as defined under 35 U.S.C.
`§ 102(b). Prelim. Resp. 9–13. For purposes of this Decision, we do not
`need to resolve this issue. Because Petitioner presents the arguments under
`Ground 2 in the alternative—obviousness over Janumet, Nauck, or Ahrén
`2008 in view of the ’940 Publication, we do not consider Janumet in our
`analysis.
`Patent Owner counters that Petitioner has failed to show a reason for
`an ordinary artisan to combine the teachings of the asserted prior art and a
`reasonable expectation of success in combining and modifying the prior-art
`teachings to arrive at the claimed invention. Prelim. Resp. 13–27.
`Based on the current record, we determine Petitioner has established a
`reasonable likelihood that it would prevail in showing that claims 1–4 would
`have been obvious over Charbonnel or Hughes in view of the ’940
`Publication, and over Nauck or Ahrén 2008 in view of the ’940 Publication.
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`6
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`IPR2016-01564
`Patent 8,846,695 B2
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`
`Petitioner refers to Charbonnel and Nauck for teaching that sitagliptin,
`a DPP-4 inhibitor, was effective in treating type II diabetes when added to
`ongoing metformin therapy for patients with inadequate glycemic control
`with metformin alone. Pet. 22 (citing Ex. 1004, 2638, 2642–43), 31 (citing
`Ex. 1006, 201–03). Similarly, Petitioner refers to Hughes for teaching that
`LAF237, another DPP-4 inhibitor, also known as vildagliptin, was effective
`in treating type II diabetes when added to ongoing metformin therapy for
`patients with inadequate glycemic control with metformin alone. Id. at 22
`(citing Ex. 1005, 2–3, 13). In addition, Petitioner points to Ahrén 2008 for
`teaching that either sitagliptin or vildagliptin is effective in treating type II
`diabetes both as add-on therapy to metformin and as initial combination
`therapy with metformin. Id. at 31–32 (citing Ex. 1022, 385–90).
`Petitioner relies on the ’940 Publication for teaching a method of
`treating type II diabetes by administering a DPP-4 inhibitor, including
`linagliptin, and metformin. Id. at 22 (citing Ex. 1003 ¶¶ 25, 31, 32, 46), 32
`(citing Ex. 1003 ¶¶ 25, 31, 32, 44, 46, 60, 61, 68, and 91). According to
`Petitioner, linagliptin is listed as “particularly preferred” in the ’940
`Publication and having “unexpected therapeutic advantages and
`improvement” when combined with other pharmaceuticals, including
`metformin. Id. at 22, 32. Furthermore, Petitioner contends that the ’940
`Publication teaches orally administering a DPP-4 inhibitor, such as
`ligagliptin, in the amount of 5 mg, as recited in claims 1 and 2. Id. at 23
`(citing Ex. 1003 ¶ 88), 32 (citing Ex. 1003 ¶ 88).
`According to Petitioner, an ordinary artisan would have had a reason
`to substitute the DPP-4 inhibitor sitagliptin or vildagliptin with linagliptin,
`7
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`IPR2016-01564
`Patent 8,846,695 B2
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`“a longer-lasting and particularly preferred” DPP-4 inhibitor, in combination
`with or as an add-on to metformin treatment to treat a diabetic patient, who
`is unable to maintain adequate glycemic control with metformin treatment
`alone. Id. at 23–24, 33. In addition, Petitioner asserts that there would have
`been a reasonable expectation of success in administering 5 mg linagliptin in
`combination with or as an add-on to metformin to treat a diabetic patient,
`who is unable to maintain adequate glycemic control with metformin
`treatment alone. Id. at 24, 33–34. As a result, Petitioner concludes that
`claims 1 and 2 would have been obvious over Charbonnel or Hughes in view
`of the ’940 Publication, or over Nauck or Ahrén 2008 in view of the ’940
`Publication.
`Claims 3 and 4 depend from claim 1 and recite administering
`linagliptin in the amount of 5 mg once daily and 2.5 mg twice daily,
`respectively. According to Petitioner, the ’940 Publication teaches these
`additional limitations. Pet. 25, 34–35. Petitioner further argues that
`“optimizing the dosing amount and frequency of dosing would have been a
`matter of routine experimentation.” Id. at 25, 35. Thus, Petitioner contends
`that claims 3 and 4 are also unpatentable.
`At this stage of the proceeding, we find Petitioner’s argument and
`evidence sufficient to satisfy the reasonable likelihood standard of 35 U.S.C.
`§ 314(a). It is undisputed that at the time of the ’695 invention, an ordinary
`artisan recognized the limitations of metformin monotherapy in maintaining
`glycemic control in diabetic patients. See, e.g., Ex. 1004, 2638; Ex. 1005,
`2–3; Ex. 1006, 195; Ex. 1022, 384. An ordinary artisan also recognized that
`because DPP-4 inhibitors and metformin “target potentially complementary
`8
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`IPR2016-01564
`Patent 8,846,695 B2
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`pathways, the addition of [a DPP-4 inhibitor] for patients with type 2
`diabetes who do not have adequate glycemic control with metformin
`monotherapy may provide improved glycemic control.” Ex. 1004, 2638.
`Indeed, it was known that
`metformin acts primarily by reducing hepatic glucose output and
`improving insulin sensitivity in liver and muscle[,] whereas
`DPP-4 inhibitors act by increasing GLP-1 levels and thereby
`stimulating insulin secretion and inhibiting glucagon secretion.
`The two strategies therefore have the potential to improve
`different mechanisms, which are defective in type 2 diabetes and
`therefore an additive or synergistic action when used in
`combination is anticipated.
`Ex. 1022, 385 (citations omitted). Each of Charbonnel, Hughes, Nauck and
`Ahrén 2008 teaches treating diabetic patients with a DPP-4 inhibitor in
`combination with or as add-on to metformin when metformin alone provides
`inadequate glycemic control. Ex. 1004, 2638; Ex. 1005, 2–3, 13; Ex. 1006,
`203; Ex. 1022, 383.
`The ’940 Publication also teaches using DPP-4 inhibitors in
`conjunction with other antidiabetic agents, including metformin. Ex. 1003
`¶¶ 60, 61, 91. It specifically identifies linagliptin as one of 12 “particularly
`preferred” DPP-4 inhibitors. Id. ¶¶ 31, 32. According to the ’940
`Publication, these DPP-4 inhibitors, including linagliptin, “are distinguished
`from structurally comparable DPP-4 inhibitors, as they combine exceptional
`potency and a long-lasting effect with favourable pharmacological
`properties, receptor selectivity and a favourable side-effect profile or bring
`about unexpected therapeutic advantages or improvements when combined
`with other pharmaceutical active substances,” including metformin. Id. ¶ 44.
`
`9
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`IPR2016-01564
`Patent 8,846,695 B2
`
`
`Patent Owner presents several arguments. For example, according to
`Patent Owner, the structure of linagliptin is “unrelated and distinct from”
`those of sitagliptin or vildagliptin. Prelim. Resp. 20. As a result, Patent
`Owner contends there would have been “substantial uncertainty as to
`whether these prior art compounds and linagliptin would behave similarly in
`combination therapy.” Id. This is merely attorney argument unsupported by
`persuasive evidence at this stage of the proceeding.
`Patent Owner does not dispute Petitioner’s assertion that “linagliptin
`has the same mechanism of action as vildagliptin and sitagliptin.” Pet. 24
`(citing Ex. 1002 ¶ 57), 34 (citing Ex. 1002 ¶ 79). Thus, based on the current
`record, we are persuaded that an ordinary artisan, at the time of the ’695
`patent invention, would have had a reason to substitute sitagliptin or
`vildagliptin with linagliptin, in combination with or as an add-on to
`metformin treatment to treat a diabetic patient, who is unable to maintain
`adequate glycemic control with metformin treatment alone. See Novo
`Nordisk A/S v. Caraco Pharm. Labs., Ltd., 719 F.3d 1346, 1354–55 (Fed.
`Cir. 2013).
`We are also persuaded that the prior art teaches the orally
`administered 5 mg per day dosage for linagliptin. The ’940 Publication
`teaches administering the exemplified DPP-4 inhibitors orally in the amount
`of “0.5 mg to 100 mg, preferably 2.5 mg to 50 mg, in each case 1 to 4 times
`a day.” Ex. 1003, ¶ 46. Specifically, Example 11 teaches tablets comprising
`DPP-4 inhibitor in oral dosage forms of 0.500 mg, 1.000 mg, 2.500 mg,
`5.000 mg, and 10.000 mg. Id. ¶ 88. More specifically, Petitioner refers to
`
`10
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`IPR2016-01564
`Patent 8,846,695 B2
`
`Exhibit 10207 for “disclosing 5 mg as an effective dose” of linagliptin. Pet.
`15 (citing Ex. 1020). The Dugi Reference, coauthored by the inventor of the
`’695 patent, reports a Phase I clinical study for orally administered
`linagliptin. Ex. 1020. It concludes that linagliptin “has a wide therapeutic
`window of >100-fold based on a therapeutic dose of 5 mg,” and that “[t]he
`pharmacokinetic profile is consistent with a once daily dosing regimen.” Id.
`Thus, we determine that, at this stage of the proceeding, Petitioner has
`provided sufficient evidence to show that prior art suggests the recited orally
`administered linagliptin dosage of 5 mg per day (claim 1), administered in
`the amount of 5 mg once daily (claim 3), or 2.5 mg twice daily (claim 4).
`CONCLUSION
`For the foregoing reasons, the information presented in the Petition
`and accompanying evidence establishes a reasonable likelihood that
`Petitioner would prevail in showing the unpatentability of claims 1–4 of the
`’695 patent.
`
`ORDER
`
`Accordingly, it is
`ORDERED that pursuant to 35 U.S.C. § 314, an inter partes review is
`hereby instituted on the following grounds:
`1. claims 1–4 as obvious over Charbonnel or Hughes in view of the
`’940 Publication;
`
`
`7 Dugi et al., Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics
`of BI 1356, a Novel DPP-IV Inhibitor with a Wide Therapeutic Window,
`DIABETIC MEDICINE P821 (2006) (Ex. 1020, “the Dugi Reference”).
`11
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`IPR2016-01564
`Patent 8,846,695 B2
`
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`2. claims 1–4 as obvious over Nauck or Ahrén 2008 in view of the
`’940 Publication;
`FURTHER ORDERED that no other ground of unpatentability is
`authorized in this inter partes review; and
`FURTHER ORDERED that pursuant to 35 U.S.C. § 314(a), inter
`partes review of the ’270 patent is hereby instituted commencing on the
`entry date of this Order, and pursuant to 35 U.S.C. § 314(c) and 37 C.F.R.
`§ 42.4, notice is hereby given of the institution of a trial.
`
`
`
`PETITIONER:
`Thomas J. Parker
`Ellen Y. Cheong
`Christopher L. McArdle
`Charles A. Naggar
`ALSTON & BIRD LLP
`thomas.parker@alston.com
`ellen.cheong@alston.com
`chris.mcardle@alston.com
`charles.naggar@alston.com
`
`PATENT OWNER:
`
`Leora Ben-Ami
`Eugene Goryunov
`Mira Mulvaney
`KIRKLAND & ELLIS LLP
`leora.benami@kirkland.com
`eugene.goryunov@kirkland.com
`mira.mulvaney@kirkland.com
`
`
`12
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