Trials@uspto.gov
`571-272-7822
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` Paper 40
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` Entered: February 21, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`COALITION FOR AFFORDABLE DRUGS VII LLC,
`Petitioner,
`
`v.
`
`POZEN INC.,
`Patent Owner.
`
`
`Case IPR2015-01718
`Patent 8,945,621 B2
`
`
`
`Before JACQUELINE WRIGHT BONILLA, Vice Chief Administrative
`Patent Judge, TONI R. SCHEINER, and LORA M. GREEN, Administrative
`Patent Judges.
`
`SCHEINER, Administrative Patent Judge.
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318 AND 37 C.F.R. § 42.73
`
`
`
`
`
`
`571-272-7822
`
`
`
`
`
`
`
`
` Paper 40
`
`
`
` Entered: February 21, 2017
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`COALITION FOR AFFORDABLE DRUGS VII LLC,
`Petitioner,
`
`v.
`
`POZEN INC.,
`Patent Owner.
`
`
`Case IPR2015-01718
`Patent 8,945,621 B2
`
`
`
`Before JACQUELINE WRIGHT BONILLA, Vice Chief Administrative
`Patent Judge, TONI R. SCHEINER, and LORA M. GREEN, Administrative
`Patent Judges.
`
`SCHEINER, Administrative Patent Judge.
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318 AND 37 C.F.R. § 42.73
`
`
`
`
`
`
`
`IPR2015-01718
`Patent 8,945,621 B2
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`I. INTRODUCTION
`Coalition for Affordable Drugs VII, LLC (“Coalition” or “Petitioner”)
`filed a Petition (Paper 1, “Pet.”) on August 12, 2015, requesting an inter
`partes review of claims 1–16 of U.S. Patent No. 8,945,621 B2 (Ex. 1001,
`“the ’621 patent”). Pozen Inc. (“Pozen” or “Patent Owner”) filed a
`Preliminary Response (Paper 15, “Prelim. Resp.”) on November 23, 2015.
`On February 22, 2016, we instituted trial as to all of the challenged claims
`(Paper 17, “Decision” or “Dec.”) on the following grounds.1
`
`References
`
`Basis
`
`Claims Challenged
`
`Plachetka,2 Graham,3 and
`Goldstein4
`Plachetka
`
`
`§ 103(a)
`
`1–16
`
`§ 103(a)
`
`1–16
`
`
`1 Petitioner supported its challenges with the Declaration of Leon Shargel,
`Ph.D., R.Ph., executed August 12, 2015 (“Shargel Declaration”) (Ex. 1003).
`2 U.S. Patent No. 6,926,907 B2, issued August 9, 2005 (Ex. 1004,
`“Plachetka”).
`3 David Y. Graham et al., Ulcer Prevention in Long-term Users of
`Nonsteroidal Anti-inflammatory Drugs, 162 ARCH. INTERN MED. 169–175
`(2002) (Ex. 1005, “Graham”).
`4 Jay L. Goldstein et al., Ulcer Recurrence in High-Risk Patients Receiving
`Nonsteroidal Anti-Inflammatory Drugs Plus Low-Dose Aspirin: Results of a
`Post Hoc Subanalysis, 26 CLINICAL THERAPEUTICS 1637–1643 (2004) (Ex.
`1006, “Goldstein”).
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`Pozen filed a Patent Owner Response (Paper 25, “PO Resp.”),5 and
`Coalition filed a Reply (Paper 31, “Reply”). Pozen did not move to amend
`any claim of the ’621 patent.
`We heard oral argument on November 16, 2016. A transcript of the
`argument has been entered into the record as Paper 39.
`We have jurisdiction under 35 U.S.C. § 6. Petitioner bears the burden
`of proving unpatentability of the challenged claims, and that burden never
`shifts to Patent Owner. Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375, 1378 (Fed. Cir. 2015). To prevail, Petitioner must establish
`facts supporting its challenge by a preponderance of the evidence. See
`35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d). This Final Written Decision is
`issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
`For the reasons that follow, we determine that Coalition has not
`proved by a preponderance of the evidence that claims 1–16 are
`unpatentable.
`
`A. Related Proceedings
`Petitioner represents it is unaware of any judicial or administrative
`
`matters involving the ’621 patent. However, Petitioner represents that the
`’621 patent is listed in the Food and Drug Administration’s Orange Book for
`Vimovo®, and Petitioner has filed other Petitions for inter partes review
`
`
`5 Pozen supports its position with the Declarations of Robert W. Makuch,
`Ph.D., dated June 22, 2016 (Ex. 2021, “Makuch Declaration”) and David A.
`Johnson, M.D., dated June 23, 2016 (Ex. 2022, “Johnson Declaration”).
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`involving patents also listed in the Orange Book for Vimovo®, including
`Petitions filed in Case Nos. IPR2015-01241, IPR2015-01344, and IPR2015-
`01680. Pet. 2–3; see also Paper 7 (listing four district court matters
`involving Horizon Pharma USA, Inc., a real party-in-interest of Pozen) 2, 8–
`9.
`
`B. The ’621 Patent (Ex. 1001)
`The ’621 patent—titled “METHOD FOR TREATING A PATIENT AT RISK
`FOR DEVELOPING AN NSAID-ASSOCIATED ULCER”—issued on February 3,
`2015, listing inventors Brian Ault, Clara Hwang, Everardus Orlemans, John
`R. Plachetka, and Mark Sostek.
`According to the ’621 patent, the cumulative incidence of
`gastroduodenal ulcers (GDUs) with conventional non-steroidal anti-
`inflammatory drug (NSAID) use has been reported to be as high as 25–30%
`at 3 months and 45% at 6 months versus 3–7% for placebo, and at any given
`time, the incidence of upper gastrointestinal (UGI) ulcers in NSAID users
`has been estimated to be as high as 30%. Id. at 1:25–30. Further according
`to the ’621 patent, “[t]he risk factors associated with an NSAID user
`developing UGI ulcers include: age ≥ 50 years, history of UGI ulcer or
`bleeding, or concomitant aspirin use.” Ex. 1001, 1:30–32.
`The ’621 patent discloses a pharmaceutical formulation comprising
`immediate release esomeprazole (an acid inhibitor, specifically a proton
`pump inhibitor (PPI)), and enteric-coated naproxen (an NSAID). Id. at
`1:48–50. According to the ’621 patent:
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`[T]he pharmaceutical formulation comprising immediate
`release (IR) esomeprazole magnesium and enteric-coated (EC)
`naproxen has been found to reduce the incidence of ulcers in
`patients at risk for developing NSAID-associated ulcers when
`compared to EC-naproxen. Such a formulation has also been
`found to reduce the incidence of ulcers in patients taking low
`dose aspirin (LDA) who are at risk for developing NSAID-
`associated ulcers when compared to EC-naproxen. Furthermore,
`patients taking this new formulation of IR esomeprazole and EC-
`naproxen were able to continue treatment longer than patients
`taking EC-naproxen.
`Id. at 1:48–58. “The term ‘low dose aspirin’ [LDA] refers to dosages of
`aspirin that are ≤ 325 mg.” Id. at 5:9–10.
`C. Illustrative Claim
`Petitioner challenges claims 1–16 of the ’621 patent, of which claims
`1, 8, 15, and 16 are independent. Claim 1, reproduced below, is illustrative.
`1. A method of reducing the incidence of NSAID-associated
`gastric ulcers in patients taking low dose aspirin who are at risk
`of developing such ulcers, wherein the method comprises
`administering to said patient in need thereof a pharmaceutical
`composition in unit dose form comprising:
`(a) 20 mg of esomeprazole, or pharmaceutically
`acceptable salt thereof, in a form and route sufficient to
`raise the gastric pH of said patient to at least 3.5 upon the
`administration of one or more of said unit dosage forms,
`and
`(b) 500 mg of naproxen, or pharmaceutically acceptable
`salt thereof;
`wherein said unit dose form provides for coordinated
`release of the esomeprazole and the naproxen,
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`wherein at least a portion of said esomeprazole, or
`pharmaceutically acceptable salt thereof, is released
`independent of the pH of the surrounding medium,
`wherein the unit dosage form releases less than 10% of
`the naproxen or a pharmaceutically acceptable salt thereof after
`2 hours when tested using the USP Paddle Method in 1000 ml
`of 0.1N HCl at 75 rpm at 37º C.+/-0.5º C.,
`wherein said pharmaceutical composition in unit dose
`form reduces the incidence of NSAID-associated ulcers in said
`patient and wherein administration of the unit dose form is
`more effective at reducing the incidence of the NSAID-
`associated ulcers in patients taking LDA than in patients not
`taking LDA who are administered the unit dose form.
`Ex. 1001, 26:61–27:20 (emphasis added).
`
`II. ANALYSIS
`A. Claim Construction
`We determine that no claim term requires express construction for
`purposes of this Final Written Decision.
`B. Claims 1–16—Asserted Obviousness over Plachetka,
`Graham, and Goldstein
`Petitioner contends that the method of claims 1–16—administering a
`unit dosage form comprising the acid inhibitor, esomeprazole, and the
`NSAID, naproxen, to a subject also taking low dose aspirin (“LDA”)—
`would have been obvious over the combined teachings of Plachetka,
`Graham, and Goldstein. Pet. 10–17. Moreover, Petitioner contends that one
`of ordinary skill in the art would have expected that the claimed method
`would be “more effective at reducing the incidence of NSAID-associated
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`ulcers in patients taking LDA than in patients not taking LDA,” given the
`teachings of Graham and Goldstein. Id. at 17–19.
`
`Patent Owner contends that the cited references do not suggest that
`LDA should be taken concurrently with an acid inhibitor and an NSAID, and
`moreover, nothing in the references would have led one of ordinary skill in
`the art to expect that administering a unit dose form of immediate-release
`esomeprazole and delayed release naproxen would be more effective at
`reducing NSAID-associated ulcers in patients taking LDA than in patients
`not taking LDA, an unexpected result “specifically recited in the final
`‘wherein’ clause of the challenged claims.” PO Resp. 3, 34–35, 43–44.
`
`We begin our analysis with a discussion of the prior art cited by
`Petitioner.
`
`1. Plachetka (Ex. 1004)
`Plachetka teaches that NSAIDs are effective agents for controlling
`pain, but their administration can lead to the development of gastroduodenal
`lesions, e.g., ulcers and erosions, in susceptible individuals. Ex. 1004, 1:22–
`26. According to Plachetka:
`Attempts to develop NSAIDs that are inherently less toxic
`to the gastrointestinal tract have met with only limited success.
`For example . . . cyclooxygenase-2 (COX-2) inhibitors show a
`reduced tendency to produce gastrointestinal ulcers and erosions,
`but a significant risk is still present, especially if the patient is
`exposed to other ulcerogens . . . In this regard, it appears that
`even low doses of aspirin will negate most of the benefit relating
`to lower gastrointestinal lesions.
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`Id. at 2:31–40.
`Plachetka discloses a “method for reducing the risk of gastrointestinal
`side effects in people taking NSAIDs for pain relief and for other conditions,
`particularly during chronic treatment.” Id. at 3:3–6. Plachetka’s method
`involves administering a pharmaceutical composition in unit-dose form “that
`combines: a) an agent that actively raises intragastric pH to levels associated
`with less risk of NSAID-induced ulcers; and b) an NSAID . . . specifically
`formulated to be released in a coordinated way that minimizes the adverse
`effects of the NSAID on the gastroduodenal mucosa.” Id. at 3:8–13.
`According to Plachetka, “[t]his method has the added benefit of being able
`to protect patients from other gastrointestinal ulcerogens whose effect may
`otherwise be enhanced by the disruption of gastroprotective prostaglandins
`due to NSAID therapy.” Id. at 3:12–17.
`Specifically, Plachetka discloses administering “a pharmaceutical
`composition in unit dosage form suitable for oral administration . . .
`contain[ing] an acid inhibitor present in an amount effective to raise the
`gastric pH of a patient to at least 3.5” (id. at 3:18–22), and an enteric-coated
`NSAID “in an amount effective to reduce or eliminate pain or inflammation”
`(id. at 3:39–41).
`Plachetka’s preferred acid inhibiters are H2-blockers, such as
`famotidine, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, and
`loxtidine. Id. at 3:32–34. Plachetka also states that “[o]ther agents that may
`be effectively used include proton pump inhibitors such as omeprazole,
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`esomeprazole, pantoprazole, lansoprazole or rabeprazole.” Id. at 3:36–38.
`In addition, according to Plachetka:
`Typical amounts for H2 blockers are: cimetidine, 100 to 800
`mg/unit dose; ranitidine, 50–300 mg/unit dose; famotidine, 5–
`100 mg/unit dose; ebrotidine 400–800 mg/unit dose; pabutidine
`40 mg/unit dose; lafutidine 5–20 mg/unit dose; and nizatidine,
`50–600 mg/unit dose. Proton pump inhibitors will typically be
`present at about 5 mg to 600 mg per unit dose. For example . . .
`omeprazole should be present in tablets or capsules in an amount
`from 5 to 50 mg, with about 20 mg per unit dosage form being
`preferred. Other typical amounts are: esomeprazole, 5–100 mg,
`with about 40 mg per unit dosage form being preferred;
`lansoprazole, 15–150 mg, with about 30 mg per unit dosage form
`being preferred; pantoprazole, 10–200 mg, with about 40 mg per
`unit dosage form being preferred; and rabeprazole, 5–100 mg,
`with about 20 mg per unit dosage form being preferred.
`Id. at 7:2–18.
`The NSAID in Plachetka’s unit-dosage form “may be a COX-2
`inhibitor such as celecoxib, rofecoxib, meloxicam, piroxicam, valdecoxib,
`parecoxib, etoricoxib . . . [or] may be aspirin, acetaminophen, ibuprofen,
`flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin,
`ketorolac, lornoxicam, nabumetone, or diclofenac.” Id. at 3:41–47. “The
`most preferred NSAID is naproxen in an amount of between 50 mg and
`1500 mg, and more preferably, in an amount of between 200 mg and 600
`mg.” Id. at 3:48–50.
`Plachetka discloses several specific unit dosage forms in which an
`acid inhibitor is released from the unit dosage form immediately upon
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`administration to a patient, while an enteric layer prevents release of the
`NSAID until the local pH is above about 4. For example, Plachetka
`discloses a unit dosage form with an enteric-coated naproxen core
`surrounded by an immediate-release layer of the H2-blocker, famotidine, and
`another dosage form with an enteric-coated naproxen core surrounded by an
`immediate-release layer of the proton pump inhibitor, omeprazole. Id. at
`8:14–67, 14:40–15:17.
`
`2. Graham (Ex. 1005)
`
`Graham discloses the results of a prospective, double-blind,
`active- and placebo-controlled study of the effectiveness of the acid
`inhibitors misoprostol (a synthetic prostaglandin) and lansoprazole (a
`proton pump inhibitor) in preventing gastric ulcers in long-term NSAID
`users. Ex. 1005, 169. The criteria for study participants included
`“treatment with stable, full-therapeutic doses of an NSAID (with the
`exception of nabumetone or aspirin [≥ 1300 mg/d; low-dose aspirin
`for cardiovascular protection was permitted]) for at least the previous
`month.” Id. at 170. “Patients could have taken more than 1 NSAID.”
`Id. at 171. “Forty percent of the patients used ibuprofen, 35% used
`naproxen, 32% used diclofenac, 22% used aspirin or aspirin
`combinations, 17% used piroxicam, and 34% used other NSAIDs”
`and “[t]he distribution across treatment groups was similar.” Id.
`
`According to Graham, “[p]roton pump inhibitors such as
`lansoprazole are superior to placebo for the prevention of NSAID-
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`induced gastric ulcers but not superior to misoprostol, 800 µg/d.” Id.
`at 169. However, Graham concluded that proton pump inhibitors and
`misoprostol are clinically equivalent, when the poor compliance and
`potential adverse side effects associated with full-dose misoprostol
`are considered. Id.
`
`
`
`3. Goldstein (Ex. 1006)
`According to Goldstein:
`Low-dose aspirin taken in combination with NSAIDs
`has been associated with an
`increased
`risk
`for
`complications of upper GI ulcer compared with NSAIDs
`alone; thus, concomitant aspirin use is a risk factor for
`NSAID-associated upper GI toxicity. The association of
`combined NSAIDs and low-dose aspirin with increased
`upper GI risk was supported by the results of a cohort study
`. . . in which patients taking low-dose aspirin (<150 mg/d)
`had a 2.6% incidence of GI bleeding, compared with a
`5.6% incidence in those taking low-dose aspirin plus an
`NSAID.
`Ex. 1006, 1638 (internal citations omitted).
`Goldstein discloses a post hoc subanalysis of Graham’s study
`(see Ex. 1005, discussed immediately above), “conducted to examine
`whether the efficacy of gastro-protective therapy [with misoprostol or
`lansoprazole] against ulcer recurrence extends to patients taking
`concomitant nonspecific NSAIDs and low dose aspirin.” Id. at 1640
`n.24. Goldstein’s “subanalysis included data from [seventy] patients
`in [Graham’s] intent-to-treat cohort who took aspirin at an amount ≤
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`325 mg/d.” Id. at 1637. “The most frequently used nonaspirin
`NSAIDs were ibuprofen, naproxen, and diclofenac.” Id. at 1639.
`“Antacids were provided for symptom relief as needed.” Id. at 1638.
`Goldstein concluded that “[c]otherapy with misoprostol or
`lansoprazole lowered the risk of ulcer recurrence in these high risk
`individuals.” Id. at 1641.
`
`4. Analysis
`Petitioner cites portions of Plachetka, Graham, and Goldman as
`disclosing various limitations of independent claims 1, 8, 15, and 16. Pet.
`13–19, 22–25, and 28–33. For instance, with respect to the preambles of the
`independent claims, Petitioner cites Goldstein’s disclosure of a study
`wherein patients taking both LDA and another NSAID were further
`administered misoprostol or lansoprazole. Id. at 13 (citing Ex. 1006, 1638,
`1640). Petitioner cites Plachetka as disclosing a pharmaceutical composition
`in unit dosage form which provides for the coordinated release of 20 mg of
`esomeprazole and 500 mg of naproxen. Id. at 14–15 (citing Ex. 1004, 1:11–
`14, 3:19–36, 39–59, 3:63–4:2, 4:18–20, 6:6–11, 7:7–13, 20:20–32, 21:46–
`22:17).
`Petitioner contends that Plachetka’s “pharmaceutical compositions
`that provide for the coordinated release of an acid inhibitor and a non-
`steroidal anti-inflammatory drug (NSAID),” result in “less risk of NSAID-
`induced ulcers.” Id. at 15 (citing Ex. 1004, 1:11–14), 17 (citing Ex. 1004,
`3:3–13). Petitioner further contends that an ordinary artisan, being aware of
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`the reduced incidence of gastric ulcers in patients taking both LDA and
`another NSAID who also were administered the acid inhibitor lansoprazole,
`as disclosed by Graham and Goldstein, would have had a reason to
`administer Plachetka’s coordinated unit dosage form to patients in need of
`NSAID therapy and at risk of developing gastric ulcers, including those
`patients taking low dose aspirin in addition to another NSAID. Pet. 11
`(citing Ex. 1004, 2:35–40). Petitioner contends “the results disclosed by
`Graham and Goldstein would indicate that the compositions disclosed in
`Plachetka could be used for treating patients on an LDA regimen to achieve
`the predictable result of lower gastric ulcer incidence.” Id. at 12.
`Patent Owner contends that the method of the challenged claims
`would not have been obvious over the cited art because “Plachetka includes
`only a single mention of LDA, in the context of co-administration [of]
`COX-2 inhibitors” (PO Resp. 34 (citing Ex. 1004, 2:31–40; Ex. 2021 ¶ 43)),
`and “never once mentions that LDA could or should be administered with
`the unit dosage forms taught therein” (id. (citing Ex. 2022 ¶ 60)). Similarly,
`Patent Owner contends that Graham “does not teach or suggest that LDA
`should be taken concurrently with an acid inhibitor and an NSAID.” Id. at
`35.
`
`Nevertheless, the issue presented by Petitioner’s rationale is not
`whether the cited art would have suggested administering LDA to a patient
`already taking Plachetka’s unit dosage form. Rather, the salient issue is
`whether the art would have suggested that a patient already taking LDA in
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`addition to a non-aspirin NSAID—which Goldstein teaches was known to
`increase the incidence of gastric ulcers—would have benefited by taking the
`non-aspirin NSAID in the form of Plachetka’s coordinated unit dose form
`containing an acid inhibitor in addition to the NSAID.
`Having considered Petitioner’s and Patent Owner’s arguments and
`observations with respect to this aspect of the challenged claims, as well as
`evidence of record establishing that administering an acid inhibitor to a
`patient taking both LDA and a non-aspirin NSAID was known to reduce the
`incidence of NSAID-associated gastric ulcers, we determine that Petitioner
`has demonstrated that an ordinary artisan would have had a reason to
`administer Plachetka’s coordinated unit dosage forms to patients in need of
`NSAID therapy and at risk of developing gastric ulcers—including those
`patients also taking low dose aspirin—in order to reduce the incidence of
`gastric ulcers.
`Moreover, we are persuaded that Petitioner has established that the
`ordinary artisan would have had a reason to administer a coordinated release
`unit dosage form comprising an enteric-coated naproxen core surrounded by
`an immediate release layer of esomeprazole. The record developed by
`Petitioner indicates that naproxen is a preferred NSAID in Plachetka’s
`combination NSAID/acid inhibitor unit dosage forms, and esomeprazole is
`one of a relatively small number of suitable acid inhibitors (which also
`includes lansoprazole) presented as essentially interchangeable for purposes
`of formulating the unit dosage forms. Moreover, Plachetka discloses ranges
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`for the acid inhibitors and NSAIDs that encompass the amounts required by
`the claims. Pet. 18; Ex. 1004, 3:36–38, 48–50, 7:2–18.
`As for the limitation “wherein the unit dosage form releases less than
`10% of the naproxen . . . after 2 hours when tested using the USP Paddle
`Method in 1000 ml of 0.1N HCl at 75 rpm at 37º C. +/-0.5º C” (the “Paddle
`Method clause”), the record indicates that this property would be a natural
`result when testing of a dosage form comprising 500 mg of enteric-coated
`naproxen and 20 mg of esomeprazole. See Pet. 16; Ex. 1001, 26:61–27:13.
`As for Petitioner’s contentions with respect to the limitations recited
`in dependent claims 2–7 and 9–14, we have reviewed the Petition and the
`cited art and are persuaded that Petitioner has demonstrated that these
`limitations are taught or suggested by the prior art relied on. For example,
`claim 2 depends from claim 1 and requires that “the risk is associated with
`chronic NSAID treatment,” and Petitioner points out that “Plachetka
`discloses ‘a risk of gastrointestinal side effects in people taking NSAIDs . . .
`particularly during chronic treatment.’” Pet. 20 (quoting Ex. 1004, 3:3–6).
`Similarly, claim 4 depends from claim 1 and specifies that the “patient is
`treated for a disease or disorder selected from osteoarthritis, rheumatoid
`arthritis, ankylosing spondylitis, and a combination thereof,” and Petitioner
`notes that Plachetka discloses “methods of treating a patient for . . .
`osteoarthritis or rheumatoid arthritis.” Id. (citing Ex. 1004, 4:18–23).
`Nevertheless, our determination that Petitioner has established that the
`ordinary artisan would have had a reason to administer Plachetka’s
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`coordinated unit dosage forms to patients in need of NSAID therapy and at
`risk of developing gastric ulcers—including those patients also taking low
`dose aspirin—do not end our obviousness analysis.
`The Final “Wherein” Clause; Unexpected Results
`Secondary considerations, when present, must “be considered en route
`to a determination of obviousness.” Transocean Offshore Deepwater
`Drilling, Inc. v. Maersk Drilling USA, Inc., 699 F.3d 1340, 1349 (Fed. Cir.
`2012) (citation omitted). Secondary considerations may include any or all of
`the following: long-felt but unsolved needs, failure of others, unexpected
`results, commercial success, copying, licensing, and praise. See Graham v.
`John Deere Co., 383 U.S. 1, 17 (1966); Leapfrog Enters., Inc. v. Fisher-
`Price, Inc., 485 F.3d 1157, 1162 (Fed. Cir. 2007). To be relevant, evidence
`of nonobviousness must be commensurate in scope with the claimed
`invention. In re Huai-Hung Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011).
`Each of independent claims 1, 8, 15, and 16 concludes with the
`clause: “wherein administration of the unit dose form is more effective at
`reducing the incidence of the NSAID-associated ulcers in patients taking
`LDA than in patients not taking LDA who are administered the unit dose
`form.” Ex. 1001, 27:16–20, 59–63, 28:36–39, 61–64.
`According to Patent Owner,
`at the time of the inventions claimed in the ’621 patent, not only
`was it widely known and accepted that NSAIDs, including LDA,
`cause gastrointestinal toxicity including gastrointestinal ulcer
`and hemorrhage . . . , it was also widely known and accepted that
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`taking LDA in addition to a non-aspirin NSAID further
`increased one’s risk for such gastrointestinal complications.
`PO Resp. 13 (citing Ex. 2022 ¶ 37; Ex. 2016, 827, 829).
`Patent Owner, supported by the testimony of Dr. Johnson, contends
`that the inventors of the ’621 patent unexpectedly found that a unit dose
`form comprising immediate-release esomeprazole and delayed-release
`naproxen is more effective at reducing NSAID-associated ulcers in patients
`taking LDA than in patients not taking LDA (PO Resp. 15–16 (citing Ex.
`2022 ¶ 46)), “despite the expectation that these patients would be at an
`increased risk for developing such ulcers based on concomitant use of LDA”
`(id. at 17).
`Dr. Johnson discusses Example 1 of the ’621 patent and attests that it
`“supports the surprising and unexpected results” represented by the final
`wherein clause of the challenged claims. Ex. 2022 ¶ 46. Dr. Johnson
`testifies:
`This example describes the results of two large, randomized
`clinical trials which were conducted to evaluate the incidence of
`gastric ulcers following the administration of either a dosage
`form consisting of 20 mg of immediate-release esomeprazole and
`500 mg of enteric-coated naproxen (PN400), or 500 mg of
`enteric-coated naproxen alone, in subjects at risk of developing
`NSAID-associated ulcers. ([Ex. 1001] at 12:37-46.) The study
`participants were stratified by LDA use and received either
`PN400 or naproxen twice daily. (Id. at 12:49-54, 12:63-67; 13:2-
`3.) The primary endpoint of the studies was the incidence of
`gastric ulceration. Secondary endpoints included incidence of
`endoscopic duodenal ulcer and other pre-specified NSAID-
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`associated upper gastrointestinal adverse events. (Id. at 13:5-7,
`13:9-12.) Consistent with other studies, approximately 20-25%
`of the subjects took LDA. However, a post-hoc analysis of
`gastric ulcer incidence in these patients was conducted and
`showed important findings. (Id. at 13:7-9.)
`In the both studies, the two treatment groups were well
`balanced with respect to baseline characteristics and did not have
`any relevant demographic differences. (Id. at 13:52-55; 14:7-
`11.) For example, in the first study (Study A), 24% of each set
`of patients also took LDA. (Id. at 13:57-59.) In the second study
`(Study B), of patients receiving PN400, 9% also took LDA, and
`of patients receiving naproxen-only, 11% also took LDA. (Id. at
`14:13-15.)
`The results demonstrated that, overall, the incidence of
`gastric ulcers was lower in PN400 patients than in naproxen-only
`patients. (Id. at 15:67-16:3, 17:23-25.) Specifically, for the 201
`subjects who were LDA users, the incidence of gastric ulcers was
`lower in PN400 patients than in naproxen-only patients, with 3%
`of PN400 patients having a gastric ulcer, while 28.4% of
`naproxen-only patients had gastric ulcer. (Id. at 17:26-34.) For
`the 653 patients who were not LDA users, the incidence of
`gastric ulcers was lower in PN400 patients than in naproxen-only
`patients, with only 6.4% of PN400 patients having a gastric ulcer,
`while 22.2% of naproxen-only patients having a gastric ulcer.
`(Id. at 17:34-37.)
`Ex. 2022 ¶¶ 46–48.
`
`Patent Owner summarizes: “[a]s expected, patients who took LDA in
`conjunction with naproxen had a higher incidence of gastric ulcers (28.4%)
`than those who took naproxen alone (22.2%)” (PO Resp. 17 (citing Ex.
`1001, 17:26–37)), “[b]ut, surprisingly, patients taking PN400 in conjunction
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`with LDA had a decreased incidence of gastric ulcer (3%) as compared to
`patients taking PN400 without LDA (6.4%), despite the expectation that
`these patients would be at increased risk for developing such ulcers based on
`concomitant use of LDA” (id.). Patent Owner tabulates the percentage of
`patients exhibiting a gastric ulcer in Example 1 of the ’621 patent as follows:
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`PO Resp. 17 (citing Ex. 1001, 17:26–37).
`
`We further note Patent Owner’s assertion that the Examiner of the
`application that matured into the ’621 patent concluded that these results
`would have been unexpected over Plachetka’s disclosure (i.e., Plachetka
`alone) and that the unexpected results were commensurate in scope with the
`claims as ultimately allowed. PO Resp. 21 (citing Ex. 1002, 2 (Notice of
`Allowance) (“Applicants have demonstrated the unexpected result that
`patients taking low dose aspirin who were administered the instantly recited
`dosage form (PN400) showed a lower incidence of gastric ulcers than non-
`aspirin using patients administered PN400.”)).
`
`With respect to the present challenge over Plachetka in view of
`Graham and Goldstein, Patent Owner contends that “[n]one of these
`references . . . either alone or in combination, discloses that the combination
`of an acid inhibitor and an NSAID is more effective at reducing the
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`incidence of NSAID-associated ulcers in patients taking LDA than in
`patients not taking LDA.” PO Resp. 33–34.
`Petitioner, on the other hand, contends that the final wherein clause
`would not have been unexpected, because “Plachetka in view of Graham
`and Goldstein discloses this limitation.” Pet 17 (citing Ex. 1033 ¶ 82).
`Nevertheless, neither Petitioner nor Petitioner’s witness, Dr. Shargel,
`identifies sufficiently the basis for this assertion in the Petition. For
`example, according to Petitioner,
`Graham and Goldstein disclose that 6.25% of patients
`taking a combination of 15 mg of lansoprazole and an
`NSAID with LDA have gastric ulcers, while 23% of patients
`taking a combination of 15 mg of lansoprazole and an
`NSAID without LDA have gastric ulcers. . . . Similarly,
`Graham and Goldstein disclose that 0% of patients taking
`a combination of 30 mg of lansoprazole and an NSAID with
`LDA have gastric ulcers, while 17% of patients taking a
`combination of 30 mg of lansoprazole and an NSAID
`without LDA have gastric ulcers.
`Pet. 17–18 (citing Ex. 1003 ¶ 83). Paragraph 83 of Dr. Shargel’s
`Declaration is virtually identical to the Petition. Neither Petitioner nor
`Dr. Shargel identifies the basis for these purported results in the Petition, or
`in the cited portion of the Declaration, much less the basis for the conclusion
`that an ordinary artisan “would have understood that a combination of
`lansoprazole and naproxen was more effective at reducing the incidence of
`the NSAID-associated ulcers in patients taking LDA than in patients not
`taking LDA.” Pet. 18 (citing Ex. 1003 ¶ 83). As we stated in the Decision
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`of Institution, “[e]xpert testimony that does not disclose the underlying facts
`or data on which the opinion is based is entitled to little or no weight”—
`accordingly, we are not persuaded by these conclusory and unsupported
`statements by Petitioner or Dr. Shargel. Dec. 15 (quoting 37 C.F.R.
`§ 42.65(a)).
`
`In its Reply, Petitioner concedes that it “did not quote Dr. Shargel’s
`full analysis of the Graham and Goldstein results in the body of the Petition
`due to page-limit constraints” (Reply 13), but argues that “Dr. Shargel’s full
`analysis—the basis for the conclusion that Graham and Goldstein render the
`final ‘wherein’ clause obvious—is located in Appendix B to the Shargel
`Declaration” (id.).
`We determine that Petitioner has not established that the prior art at
`issue discloses or suggests that the combination of an acid inhibitor and an
`NSAID is more effective at reducing the incidence of NSAID-associated
`ulcers in patients taking LDA than in patients not taking LDA. Under our
`rules, a petition must contain a “full statement of the reasons for the relief
`requested, including a detailed explanation of the significance of the
`evidence” (37 C.F.R. § 42.22(a)(2)), and arguments made in a supporting
`document may not be incorporated by reference into a petition (37 C.F.R.
`§ 42.6(a)
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