throbber
United States Court of Appeals
`for the Federal Circuit
`______________________
`
`NALPROPION PHARMACEUTICALS, INC.,
`Plaintiff-Appellee
`
`v.
`
`ACTAVIS LABORATORIES FL, INC.,
`Defendant-Appellant
`______________________
`
`2018-1221
`______________________
`
`Appeal from the United States District Court for the
`District of Delaware in No. 1:15-cv-00451-RGA, Judge
`Richard G. Andrews.
`______________________
`
`Decided: August 15, 2019
`______________________
`
`DOMINICK A. CONDE, Venable LLP, New York, NY, ar-
`gued
`for plaintiff-appellee.
` Also represented by
`CHRISTOPHER P. BORELLO, JOSHUA DANIEL CALABRO,
`ZACHARY GARRETT, BRENDAN M. O'MALLEY.
`
` JONATHAN D. BALL, Greenberg Traurig LLP, New York,
`NY, argued for defendant-appellant. Also represented by
`SCOTT JOSEPH BORNSTEIN, JUSTIN ALBANO MACLEAN,
`RICHARD CHARLES PETTUS.
` ______________________
`
`
`

`

`2
`
`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`Before PROST, Chief Judge, LOURIE and WALLACH, Circuit
`Judges.
`Opinion for the court filed by Circuit Judge LOURIE.
`Opinion dissenting in part filed by Chief Judge PROST.
`LOURIE, Circuit Judge.
`Actavis Laboratories FL, Inc. (“Actavis”) appeals from
`the judgment of the U.S. District Court for the District of
`Delaware that (1) its proposed naltrexone hydrochloride
`and bupropion hydrochloride extended-release tablets,
`which are the subject of Abbreviated New Drug Application
`No. 208043 (the “ANDA product”), would infringe claim 1
`of U.S. Patent 7,375,111 (“the ’111 patent”), claims 26 and
`31 of U.S. Patent 7,462,626 (“the ’626 patent”), and claim
`11 of U.S. Patent 8,916,195 (“the ’195 patent”); (2) the as-
`serted claims are not invalid; (3) the effective date of any
`FDA approval of ANDA No. 208043 shall be no earlier than
`the latest expiration of the ’111, ’626, and ’195 patents; and
`(4) Actavis is permanently enjoined from manufacturing,
`using, or selling its ANDA product before the expiration of
`the patents in suit. Orexigen Therapeutics, Inc. v. Actavis
`Labs. FL, Inc., 282 F. Supp. 3d 793 (D. Del. 2017) (“Deci-
`sion”); Final Judgment, Orexigen Therapeutics, Inc. v. Ac-
`tavis Labs. FL, Inc., No. 1:15-cv-451 (D. Del. Oct. 26, 2017),
`ECF No. 186. Because we conclude that the district court
`did not err in finding claim 11 of the ’195 patent not invalid
`for lack of written description, but did err in finding that
`claim 1 of the ’111 patent and claims 26 and 31 of the ’626
`patent would not have been obvious in view of the prior art,
`we affirm-in-part and reverse-in-part.
`
`

`

`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`3
`
`BACKGROUND
`Appellee Nalpropion Pharmaceuticals, Inc. (“Nal-
`propion”)1 holds New Drug Application No. 200063 for and
`markets Contrave® for weight management in overweight
`or obese adults. Relevant here are the three Orange Book-
`listed patents for Contrave® that Nalpropion asserted
`against Actavis: the ’626, ’195, and ’111 patents.
`The ’626 patent is drawn to a method for treating over-
`weight or obesity comprising (1) diagnosing an individual
`as suffering from overweight or obesity by body mass index,
`(2) administering bupropion in an amount effective to in-
`duce weight loss, and (3) administering naltrexone in an
`
`1 Takeda Pharmaceutical Company Limited
`(“Takeda Ltd.”), Takeda Pharmaceuticals International
`GmbH, Takeda Pharmaceuticals USA, Inc. (“Takeda
`USA”), and Takeda Pharmaceuticals, America, Inc. (collec-
`tively, “Takeda”) and Orexigen Therapeutics, Inc. (“Orex-
`igen”) filed this suit in the District of Delaware. At the time
`of filing, Orexigen owned all three patents in suit, Takeda
`Ltd. was the exclusive licensee of the patents, and Takeda
`USA held approved New Drug Application No. 200063 for
`extended-release tablets containing 8 mg of naltrexone hy-
`drochloride and 90 mg of bupropion hydrochloride. During
`the litigation, Orexigen acquired all of Takeda’s rights to
`Contrave®, including ownership of the NDA. Stipulation
`and Order at 1, Orexigen Therapeutics, Inc. v. Actavis Labs.
`FL, Inc., No. 1:15-cv-451 (D. Del. Oct. 5, 2017), ECF No. 92.
`After this appeal was taken, however, Orexigen com-
`menced bankruptcy proceedings under Chapter 11 of Title
`11 of the United States Code in the U.S. Bankruptcy Court
`for the District of Delaware and transferred ownership of
`the patents-in-suit to Nalpropion. Unopposed Motion for
`Substitution of Nalpropion Pharms. Inc. for Orexigen Ther-
`apeutics, Inc. at 1, Nalpropion Pharm. Inc. v. Actavis Labs.
`FL, Inc., No. 18-1221 (Fed. Cir. Aug. 28, 2018), ECF No. 30.
`
`

`

`4
`
`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`amount effective to enhance the weight loss activity of bu-
`propion. ’626 patent col. 38 l. 60–col. 39 l. 4. Nalpropion
`asserted claims 26 and 31. Claim 26 depends from claim
`25, which recites:
`A method of treating overweight or obesity, com-
`prising administering a weight loss effective
`amount of a first and second compound to an indi-
`vidual who has been diagnosed as suffering from
`overweight or obesity in order to treat said over-
`weight or obesity, wherein said first compound is
`bupropion, or a pharmaceutically acceptable salt
`thereof, and said second compound is naltrexone,
`or a pharmaceutically acceptable salt thereof, and
`wherein the weight loss activity of said first and
`second compounds is enhanced compared to the ad-
`ministration of the same amount of either com-
`pound alone.
`Id. col. 40 ll. 16–26. Claim 26 adds the additional limita-
`tion that naltrexone and bupropion “are administered to-
`gether.” Id. col. 40. ll. 27–30. Claim 30 depends from claim
`25 and requires that at least one of the drugs be in a “sus-
`tained-release formulation,” id. col. 40 ll. 41–44, while
`claim 31, which depends from claim 30, requires that the
`drugs be “administered in a single oral dosage form,” id.
`col. 40 ll. 45–49.
`The ’195 patent is also directed to methods of treating
`overweight or obesity, but the claims are drawn to specific
`dosages of sustained-release naltrexone and bupropion
`that achieve a specific dissolution profile. At issue here is
`claim 11:
`A method of treating overweight or obesity having
`reduced adverse effects comprising orally adminis-
`tering daily about 32 mg of naltrexone and about
`360 mg of bupropion, or pharmaceutically accepta-
`ble salts thereof, to a person in need thereof,
`wherein
`the bupropion or pharmaceutically
`
`

`

`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`5
`
`acceptable salt thereof is administered as a sus-
`tained release formulation, wherein the naltrexone
`or pharmaceutically acceptable salt thereof is ad-
`ministered as a sustained release formulation, and
`wherein said sustained release formulation of nal-
`trexone has an in vitro naltrexone dissolution pro-
`file in a dissolution test of USP Apparatus 2 Paddle
`Method at 100 rpm in a dissolution medium of wa-
`ter at 37° C. of:
`a) between 39% and 70% of naltrexone re-
`leased in one hour;
`b) between 62% and 90% of naltrexone re-
`leased in two hours; and
`c) at least 99% in 8 hours;
`wherein about 16 mg of said sustained re-
`lease formulation of naltrexone or a phar-
`maceutically acceptable salt thereof is
`administered twice daily, and about 180
`mg of said sustained release formulation of
`bupropion or a pharmaceutically accepta-
`ble salt thereof is administered twice daily.
`’195 patent col. 31 l. 5–col. 32 l. 3.
`Finally, the ’111 patent is directed to a composition of
`sustained-release bupropion and naltrexone for affecting
`weight loss. Asserted here is claim 1:
`A composition for affecting weight loss comprising:
`(a) a sustained release formulation of bu-
`propion or a pharmaceutically acceptable
`salt thereof in an amount effective to in-
`duce weight loss in an individual; and
`(b) a sustained release formulation of nal-
`trexone or a pharmaceutically acceptable
`salt thereof in an amount effective to
`
`

`

`6
`
`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`enhance the weight loss effect of the bu-
`propion or salt thereof;
`wherein said composition is in a single oral
`dosage form fixed combination.
`’111 patent col. 41 ll. 26–35.
`Actavis filed an ANDA seeking to enter the market
`with a generic version of Contrave® prior to the expiration
`of the patents in suit, and Nalpropion responded by bring-
`ing an action for patent infringement, alleging that Ac-
`tavis’s ANDA product would infringe the ’111, ’626, and
`’195 patents. Actavis in turn brought invalidity counter-
`claims, challenging claim 11 of the ’195 patent as invalid
`for lack of adequate written description and challenging
`claim 1 of the ’111 patent and claims 26 and 31 of the ’626
`patents as invalid as obvious. The district court held a
`bench trial on all of these issues and held each claim not
`invalid and infringed. Decision, 282 F. Supp. 3d at 797.
`First, the district court considered Actavis’s written de-
`scription argument. Actavis argued that claim 11 of the
`’195 patent lacked adequate written description support
`because its claimed dissolution profile was achieved using
`the USP Apparatus 2 Paddle Method (“USP 2”), but the
`specification discloses data obtained using the different
`USP Apparatus 1 Basket Method (“USP 1”). The court was
`not persuaded that the use of a different method from what
`is prescribed in the claim presented a written description
`problem, holding that “whether the dissolution data re-
`ported in the specification was obtained using the basket
`method or the paddle method is not relevant to whether the
`inventors had possession of the invention.” Id. at 802. In-
`stead, the court credited Nalpropion’s expert who opined
`that a person of ordinary skill would recognize that the in-
`ventors possessed an embodiment of the invention as de-
`scribed in Table 10, regardless whether USP 2 or a
`“‘substantially equivalent’ method” was used. Id. at 801
`(citation omitted).
`
`

`

`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`7
`
`Next, the district court addressed the question of obvi-
`ousness of claim 1 of the ’111 patent and claims 26 and 31
`of the ’626 patent. Actavis argued that it would have been
`obvious for a person of skill to combine bupropion and nal-
`trexone for treating overweight and obesity because both
`drugs were known to cause weight loss, but the court disa-
`greed, finding Actavis’s argument to be “a classic case of
`hindsight bias.” Id. at 809.
`Actavis appealed from the district court judgment, and
`we have jurisdiction under 28 U.S.C. § 1295(a)(1).
`DISCUSSION
`On appeal from a bench trial, we review a district
`court’s conclusions of law de novo and its findings of fact
`for clear error. Braintree Labs., Inc. v. Novel Labs., Inc.,
`749 F.3d 1349, 1358 (Fed. Cir. 2014). “A factual finding is
`clearly erroneous when, despite some supporting evidence,
`we are left with a definite and firm conviction that the dis-
`trict court was in error.” Alcon Research Ltd. v. Barr Labs.,
`Inc., 745 F.3d 1180, 1186 (Fed. Cir. 2014) (citing Alza Corp.
`v. Mylan Labs., Inc., 464 F.3d 1286, 1289 (Fed. Cir. 2006)).
`“The burden of overcoming the district court’s factual find-
`ings is, as it should be, a heavy one.” Polaroid Corp. v.
`Eastman Kodak Co., 789 F.2d 1556, 1559 (Fed. Cir. 1986).
`“Where there are two permissible views of the evidence, the
`factfinder’s choice between them cannot be clearly errone-
`ous.” Anderson v. City of Bessemer City, 470 U.S. 564, 574
`(1985) (citing United States v. Yellow Cab Co., 338 U.S.
`338, 342 (1949)).
`Whether a claim satisfies the written description re-
`quirement is a question of fact, Ariad Pharm., Inc. v. Eli
`Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc),
`that we review for clear error, Alcon, 745 F.3d at 1190.
`“Whether an invention would have been obvious at the
`time it was made is a question of law, which we review de
`novo, based on underlying facts, which we review for clear
`error.” Tokai Corp. v. Easton Enters., Inc., 632 F.3d 1358,
`
`

`

`8
`
`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`1366 (Fed. Cir. 2011) (citing Media Techs. Licensing, LLC
`v. Upper Deck Co., 596 F.3d 1334, 1337 (Fed. Cir. 2010)).
`The district court rejected Actavis’s invalidity argu-
`ments that (1) claim 11 of the ’195 patent is invalid for lack
`of adequate written description and (2) claim 1 of the ’111
`patent and claims 26 and 31 of the ’626 patent are invalid
`as obvious. We address the court’s holdings in turn.
`I. Written Description
`Claim 11 of the ’195 patent recites a method of treating
`overweight or obesity comprising orally administering
`about 16 mg of naltrexone and about 180 mg of bupropion,
`both in sustained-release formulations administered twice
`daily. This method claim also requires that the claimed
`naltrexone formulation have an in vitro dissolution profile
`in a dissolution test of USP Apparatus 2 Paddle
`Method at 100 rpm in a dissolution medium of wa-
`ter at 37ºC. of:
`a) between 39% and 70% of naltrexone released in
`one hour;
`b) between 62% and 90% of naltrexone released in
`two hours; and
`c) at least 99% in 8 hours . . . .
`’195 patent col. 31 l. 14–col. 32 l. 3.
`Example 1 of the specification discloses formulations of
`sustained-release naltrexone with varying amounts of ei-
`ther hydroxypropylmethyl cellulose (HPMC) or polyeth-
`ylene oxide as excipients. The HPMC formulations range
`from 5% HPMC to 66% HPMC, and dissolution of these for-
`mulations was tested in Example 2 using 10-mesh baskets
`at 100 rpm. The 15% HPMC tablet released 39% of its nal-
`trexone at one hour and 62% at two hours. Id. col. 17–18
`(Table 5).
`
`

`

`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`9
`
`The first example in the specification to discuss a nal-
`trexone-bupropion combination is Example 3, which de-
`scribes tri-layer tablets with sustained-release naltrexone
`and bupropion layers on opposite sides of an inert layer.
`That formulation includes 10% HPMC. Dissolution of nal-
`trexone was measured and reported in Table 10, but the
`specification is silent as to whether the data were obtained
`using USP 1 or USP 2. Id. at col. 20 ll. 1–11.
`In finding adequate written description support for the
`claimed dissolution profile, the district court found that the
`values in Table 10—67% release in one hour and 85% re-
`lease in two—fell squarely within the claimed range in
`claim 11. Decision, 282 F. Supp. 3d at 802. The court found
`the lower bounds were supported by the dissolution data
`for the 15% HPMC formulation in Table 5. Id.
`Actavis had argued that neither table provided ade-
`quate written description support because the data listed
`were obtained using USP 1, but the court held that the dis-
`solution technique used was not relevant because a person
`of skill would understand in the context of the patent that
`the inventors possessed the claimed invention. The court
`relied on Nalpropion’s expert’s testimony that a person of
`skill would understand that the inventors possessed the in-
`vention—whether USP 2 or a substantially equivalent
`method was used to measure it.
`On appeal, Actavis repeats its argument that Tables 5
`and 10 fail to provide adequate written description support
`for the claimed dissolution profile because the data in those
`tables were obtained using USP 1. According to Actavis,
`both inventor and expert testimony demonstrated that the
`two dissolution methods would produce different results.
`Actavis further argues that the data in Table 5 cannot sup-
`port the claimed range because a person of ordinary skill
`in the art would not appreciate that the 15% HPMC data
`were relevant to the claims.
`
`

`

`10
`
`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`Nalpropion responds that there was no evidence that
`the data in either table were obtained using USP 1. Even
`if USP 1 had been used, however, Nalpropion submits that
`a person of skill would understand the inventors to have
`had possession of their invention “irrespective of whether
`they used USP 1 or USP 2 because those methods are ‘sub-
`stantially equivalent.’” Appellee’s Br. 22 (citing J.A. Deci-
`sion, 282 F. Supp. 3d at 801–02). We conclude that the
`district court did not clearly err in finding that the inven-
`tors had possession of the invention consisting of treating
`overweight and obesity with the stated amounts of bu-
`propion.
`It is important to take note of the peculiarity of claim
`11, which begins clearly enough by reciting a method of
`treating overweight or obesity by carrying out the specific,
`positive steps of administering a formulation of specific
`amounts of sustained-release naltrexone and bupropion in
`twice a day. The claim then records the dissolution data
`resulting from that formulation.
`But that dissolution profile for naltrexone as measured
`by USP 2 relates only to the measurement of resultant in
`vitro parameters, not to the operative steps to treat over-
`weight or obesity. And the district court concluded, on the
`facts, that USP 1 and USP 2 would be “substantially equiv-
`alent,” Decision, 282 F. Supp. 3d at 801 (citation omitted).
`Thus, it found that, irrespective of the method of measure-
`ment used, the specification shows that the inventors pos-
`sessed the invention of treating overweight or obesity with
`naltrexone and bupropion in particular amounts and ade-
`quately described it. We conclude that this finding does not
`present clear error.
`As we explained in Ariad, the written description of an
`invention “must ‘clearly allow persons of ordinary skill in
`the art to recognize that [the inventor] invented what is
`claimed.’” 598 F.3d at 1351 (alteration in original) (quoting
`Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir.
`
`

`

`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`11
`
`1991) (Rich, J.) (citing In re Gosteli, 872 F.2d 1008, 1012
`(Fed. Cir. 1989))). “In other words, the test for sufficiency
`is whether the disclosure of the application relied upon rea-
`sonably conveys to those skilled in the art that the inventor
`had possession of the claimed subject matter as of the filing
`date.” Id. (emphasis added). It is not necessary that the
`exact terms of a claim be used in haec verba in the specifi-
`cation, and equivalent language may be sufficient.
`To support their respective positions, both parties point
`to evidence regarding whether a person of skill would un-
`derstand USP 1 and USP 2 to be “substantially equiva-
`lent.” But the court credited Nalpropion’s expert, Dr.
`Treacy, as more credible over what it interpreted as un-
`trustworthy, self-serving statements by Actavis’s expert,
`Dr. Mayersohn. See Decision, 282 F. Supp. 3d at 801–02
`(“It seems to me that Dr. Mayersohn’s theoretical opinion
`that the methods would yield different results is at odds
`with his reliance on a prior art reference using the basket
`method to argue that claim 11, which specifies the paddle
`method, was obvious.”). The district court performed pre-
`cisely its fact-finding function, weighing credibility of tes-
`timony. See Fed. R. Civ. P. 52(a)(6) (“Findings of fact,
`whether based on oral or other evidence, must not be set
`aside unless clearly erroneous, and the reviewing court
`must give due regard to the trial court’s opportunity to
`judge the witnesses’ credibility.”). We do not disturb this
`finding.
`Having found USP 1 and USP 2 substantially equiva-
`lent, the district court found Table 5 and Table 10 ade-
`quately supported the dissolution data ranges in claim 11.
`Particularly, the court was not convinced that relying on
`data from two tables presented a written description issue,
`noting that it found “nothing odd or invalidating about the
`inventors looking to different tables of dissolution data and
`other places in the specification to determine the ranges for
`the claimed dissolution profile,” and finding that “multiple
`tests are necessarily required to establish a range.”
`
`

`

`12
`
`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`Decision, 282 F. Supp. 3d at 803. The court relied on the
`15% HPMC data in Table 5, crediting both expert’s testi-
`mony that 15% HPMC formulations were the first listed in
`the table in which a person of skill in the art would observe
`“a sustained release profile.” Id. at 802 (quoting J.A.
`11369:6–19, 11409:10–17). The court also credited Dr.
`Treacy’s testimony that the 99% dissolution at eight-hour
`data point was supported by Table 10’s disclosure, dis-
`counting Dr. Mayersohn’s view that the dissolution profile
`would plateau and never reach the claimed 99% at eight
`hours. Id. While Actavis may disagree with the court’s
`findings, these findings are supported by the record, and
`we do not disturb them. See Anderson, 470 U.S. at 573–74
`(“If the district court’s account of the evidence is plausible
`in light of the record viewed in its entirety, the court of ap-
`peals may not reverse it even though convinced that had it
`been sitting as the trier of fact, it would have weighed the
`evidence differently.”).
`The district court was convinced by its fact findings
`that Actavis had not proven by clear and convincing evi-
`dence that claim 11 of the ’195 patent is invalid for lack of
`adequate written description. While as a general matter
`written description may not be satisfied by so-called equiv-
`alent disclosure, in this case, buttressed by the district
`court’s fact-finding, and where the so-called equivalence re-
`lates only to resultant dissolution parameters rather than
`operative claim steps, we affirm the district court’s conclu-
`sion. Rigidity should yield to flexible, sensible interpreta-
`tion.
`
`II. Obviousness
`Actavis also challenges claim 1 of the ’111 patent and
`claims 26 and 31 of the ’626 patent as obvious in view of
`O’Malley and Jain. We begin by reviewing the relevant ref-
`erences.
`O’Malley is U.S. Patent 6,541,478, entitled “Smoking
`Cessation Treatments Using Naltrexone and Related
`
`

`

`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`13
`
`Compounds.” J.A. 7912. O’Malley teaches that weight
`gain is “[t]he significant problem” with smoking cessation
`and discloses use of opioid antagonists, including naltrex-
`one, alone or with other withdrawal attenuating agents to
`minimize weight gain during treatment. O’Malley col. 1 l.
`59– 62. Claim 1 of O’Malley is drawn to a method of treat-
`ing a person for nicotine dependency and minimizing
`weight gain during smoking cessation therapy comprising
`“administering . . . an effective amount of naltrexone and
`another compound selected from the group consisting of . . .
`bupropion. . . .” Id. col. 12 ll. 30–37.
`Jain2 is a research paper entitled “Bupropion SR vs.
`Placebo for Weight Loss in Obese Patients with Depressive
`Symptoms.” J.A. 7171. Jain notes that “[p]reliminary
`studies suggest that bupropion SR is also an effective ad-
`junct to diet for weight loss during acute and long-term
`therapy in nondepressed patients” and “is associated with
`weight loss in overweight or obese depressed patients.”
`J.A. 7171. The authors then describe their double-blind
`study where sustained-release bupropion was adminis-
`tered in conjunction with a 500-kcal deficit diet. Sus-
`tained-release bupropion was found to be more effective
`than placebo at reducing weight in obese patients with de-
`pressive symptoms.
`Additional references provide context for the obvious-
`ness arguments in this case: (1) Anderson for bupropion,
`(2) Atkinson and Bernstein for naltrexone, and (3) Dante
`for both naltrexone and its combination with bupropion.
`
`
`2 desh K. Jain et al., Bupropion SR vs. Placebo for
`Weight Loss in Obese Patients with Depressive Symptoms,
`10 OBESITY RES. 1049–56 (2002), J.A. 7171–78 (“Jain”).
`
`

`

`14
`
`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`Anderson3 discloses a 48-week double-blind, placebo-
`controlled trial where sustained-release bupropion was ad-
`ministered to obese adults. J.A. 7160. Adjusted for pla-
`cebo, subjects lost 2.2% and 5.5% of net bodyweight with
`300 mg/d and 400 mg/d of sustained-release bupropion, re-
`spectively. Id.
`Atkinson4 examined the effects of long-term naltrexone
`administration on body weight and obesity, administering
`naltrexone to 60 obese subjects over 8 weeks. J.A. 8948.
`Atkinson found a small but significant weight loss in
`women but no significant effect in men. Similarly, Bern-
`stein5 teaches a method for curbing carbohydrate cravings
`and overeating through long-term administration of low-
`dose naltrexone. Bernstein comments that the administra-
`tion of naltrexone as described “would benefit . . . obese per-
`sons.” J.A. 7181 ¶ 13.
`Dante, U.S. Patent 5,817,665, teaches use of an opioid
`antagonist like naltrexone with serotonin or norepineph-
`rine reuptake inhibitors to treat mental and emotional dis-
`orders. Of note are Examples 2 and 3. Example 2 describes
`a woman in her thirties who was started on naltrexone
`without making any other changes. Dante col. 6 ll. 16–17.
`She rapidly lost her craving for sweets and lost thirty
`pounds in three weeks. Id. col. 6. l. 18–19. Example 3 de-
`scribes similar results in an obese man. Id. col. 6. ll. 32–
`
`3 James Anderson et al., Bupropion SR Enhances
`Weight Loss: A 48-Week Double-Blind, Placebo-Controlled
`Trial, 10 OBESITY RES. 633–41 (2002), J.A. 7160–68 (“An-
`derson”).
`4 Richard Atkinson et al., Effects of Long-Term Ther-
`apy with Naltrexone on Body Weight in Obesity, 38 CLIN.
`PHARMACOL. THER. 419–22 (1985), J.A. 8948–51 (“Atkin-
`son”).
`5 U.S. Patent Application 2002/0198227, J.A. 7179–
`85 (“Bernstein”).
`
`

`

`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`15
`
`56. While these examples address only administration of
`naltrexone, the claims in Dante focus on its combination
`with bupropion. Claim 1 of Dante is drawn to “[a] method
`of treating depression comprising administering to a pa-
`tient a pharmacologically effective dose of an opioid antag-
`onist” and a “nontricyclic antidepressant[].” Id. col. 8 ll.
`19–30. Claim 7 requires that the “nontricyclic antidepres-
`sant” be “selected from a group” including bupropion. Id.
`col. 8. ll. 47–51.
`Despite these references, the district court rejected Ac-
`tavis’s obviousness argument. According to the district
`court, the weight loss effects of bupropion were known to
`be relatively modest at best, and prior art references re-
`ported potential risks, including a potential for seizures.
`Because a person of skill would not understand bupropion’s
`mechanism of action and because of its modest effective-
`ness, the court concluded that a person of skill would not
`have found bupropion to be an obvious starting point for
`further study. Decision, 282 F. Supp. 3d at 807.
`The district court was also convinced that a person of
`skill would not have understood naltrexone to be effective
`for weight loss. The court did not find Bernstein to disclose
`weight loss and read Atkinson’s disclosure of weight loss in
`women to be counterbalanced by increased body weight in
`men. Id. at 808.
`As for the combination of the two drugs, the district
`court concluded that Dante and O’Malley did not teach a
`person of ordinary skill that the combination was effective
`for weight loss. Id. at 809. According to the court, neither
`reference teaches anything about weight loss or that nal-
`trexone enhances bupropion’s weight loss effects. The
`court likewise discounted the disclosure in Jain because
`men experienced weight gain. Id.
`Finally, persuaded that the synergistic effect of the
`combination was an unexpected result and that others had
`failed to develop safe and effective weight loss drugs, the
`
`

`

`16
`
`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`district court held that secondary considerations supported
`a finding of nonobviousness. Id. at 810.
`On appeal, the parties primarily dispute whether a
`person of skill would have been motivated to combine bu-
`propion, as disclosed by Jain, and naltrexone, as disclosed
`in O’Malley, to arrive at the claimed composition of the ’111
`patent and the method of the ’626 patent with a reasonable
`expectation of success. Actavis argues that the district
`court incorrectly interpreted the prior art and discounted
`the fact that both compounds were known to affect weight
`loss and had been administered together for that purpose.
`Appellant’s Br. 56. In response, Nalpropion submits that
`naltrexone was not known to affect weight loss, bupropion
`had safety concerns and yielded only modest weight loss,
`and the combination had been used only to treat depression
`or to minimize weight gain in smoking cessation therapy.
`Nalpropion also argues that naltrexone was not known to
`enhance bupropion’s effectiveness for weight loss.
`Obviousness is a question of law, supported by under-
`lying fact questions. In re Baxter Int’l, Inc. 678 F.3d 1357,
`1361 (Fed. Cir. 2012). In evaluating obviousness, we con-
`sider the scope and content of the prior art, differences be-
`tween the prior art and the claims at issue, the level of
`ordinary skill in the pertinent art, and any secondary con-
`siderations. Graham v. John Deere Co. of Kan. City, 383
`U.S. 1, 17–18 (1966); see also Apple Inc. v. Samsung Elecs.
`Co., 839 F.3d 1034, 1048 (Fed. Cir. 2016) (en banc) (“Objec-
`tive indicia of nonobviousness must be considered in every
`case where present.”).
`We agree with Actavis and conclude that the claims at
`issue would have been obvious to a person of skill in the art
`in view of O’Malley and Jain. The prior art here discloses
`the claimed components of the composition claims and the
`steps of the method claims including the use claimed by the
`method.
`
`

`

`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`17
`
`The references teach that bupropion causes weight
`loss. For example, Jain specifically teaches that sustained-
`release bupropion was “an effective adjunct to diet for
`weight loss” in both non-depressed and depressed patients,
`J.A. 7171, and was well-tolerated, J.A. 7177. This state-
`ment is confirmed by Anderson, which discloses the results
`from a 48-week, double-blind, placebo-controlled trial. J.A.
`7160. Notably, Anderson’s data indicate that administra-
`tion of sustained-release bupropion yielded weight loss in
`non-depressed patients. J.A. 7161, 7165. Anderson’s re-
`ported weight loss was dependent on bupropion SR dosage.
`J.A. 7165. Even Dr. Weber, a named inventor of the ’626
`and ’111 patents, confirmed that bupropion had been con-
`sidered safe and had weight loss effects. J.A. 11028–29.
`Likewise, the record indicates that naltrexone can
`cause weight loss. Atkinson reports statistically signifi-
`cant weight loss in female obese patients and states that
`“naltrexone or similar drugs may have a role in the clinical
`treatment of obesity.” J.A. 8950. While Atkinson reports
`weight loss only in women, the claims are not limited to
`men, and Dante discloses weight loss in two examples—for
`both a man and a woman. In Example 2, an obese woman
`was started on 25 mg of naltrexone and rapidly “lost her
`craving for sweets and a weight loss effort which was
`stalled took off. She lost thirty pounds in three weeks.”
`Dante col. 6 ll. 16–19. Similarly, 25–50 mg of naltrexone
`was administered to an obese man in Example 3, and he
`reported losing about 10 pounds a week and no longer
`craved sweets. Id. col. 6 ll. 32–51. Bernstein also discloses
`that naltrexone reduces carbohydrate cravings and admin-
`istration of it would benefit “obese persons.” J.A. 7181 ¶
`13.
`Given that both drugs had shown weight loss effects,
`we conclude that a person of ordinary skill would have been
`motivated to combine them. In fact, such persons did so.
`O’Malley teaches a combination of effective amounts of sus-
`tained-release bupropion and naltrexone for minimizing
`
`

`

`18
`
`NALPROPION PHARMACEUTICALS v. ACTAVIS LABORATORIES
`FL, INC.
`
`weight gain. Likewise, Dante teaches use of an opioid an-
`tagonist, preferably naltrexone, and an antidepressant, in-
`cluding bupropion, for decreasing sugar cravings, noting
`that naltrexone administration alone led reduced sugar
`cravings and weight loss in two examples. A person of skill
`would have understood that a combination f

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