Case: 20-2106 Document: 54 Page: 1 Filed: 02/10/2022
`
`United States Court of Appeals
`for the Federal Circuit
`______________________
`
`ADAPT PHARMA OPERATIONS LIMITED, ADAPT
`PHARMA, INC., ADAPT PHARMA LIMITED,
`OPIANT PHARMACEUTICALS, INC.,
`Plaintiffs-Appellants
`
`v.
`
`TEVA PHARMACEUTICALS USA, INC., TEVA
`PHARMACEUTICALS INDUSTRIES, LTD.,
`Defendants-Appellees
`______________________
`
`2020-2106
`______________________
`
`Appeal from the United States District Court for the
`District of New Jersey in Nos. 2:16-cv-07721-BRM-JAD,
`2:17-cv-00864-JLL-JAD, 2:17-cv-02877-JLL-JAD, 2:17-cv-
`05100-JLL-JAD, 2:18-cv-09880-JLL-JAD, Judge Brian R.
`Martinotti.
`
`______________________
`
`Decided: February 10, 2022
`______________________
`
`CATHERINE EMILY STETSON, Hogan Lovells US LLP,
`Washington, DC, argued for all plaintiffs-appellants.
`Plaintiffs-appellants Adapt Pharma Operations Limited,
`Adapt Pharma, Inc., Adapt Pharma Limited also repre-
`sented by JESSAMYN SHELI BERNIKER, DAVID M. KRINSKY,
`JESSICA PALMER RYEN, Williams & Connolly LLP, Wash-
`ington, DC.
`
`

`

`Case: 20-2106 Document: 54 Page: 2 Filed: 02/10/2022
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`2
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`ADAPT PHARMA OPERATIONS v. TEVA PHARMS. USA, INC.
`
`
` JESSICA TYRUS MACKAY, Green, Griffith & Borg-Breen
`LLP, Chicago, IL, for plaintiff-appellant Opiant Pharma-
`ceuticals, Inc.
`
` JOHN CHRISTOPHER ROZENDAAL, Sterne Kessler Gold-
`stein & Fox, PLLC, Washington, DC, argued for defend-
`ants-appellees.
` Also represented by PAUL ASHLEY
`AINSWORTH, MICHAEL E. JOFFRE, ADAM LAROCK, WILLIAM
`MILLIKEN, CHANDRIKA VIRA; LIZA M. WALSH, Walsh Pizzi
`O'Reilly Falanga LLP, Newark, NJ.
` ______________________
`
`Before NEWMAN, PROST, and STOLL, Circuit Judges.
`Opinion for the court filed by Circuit Judge STOLL.
`Dissenting opinion filed by Circuit Judge NEWMAN.
`STOLL, Circuit Judge.
`Adapt Pharma Operations Limited, Adapt Pharma,
`Inc., Adapt Pharma Limited, and Opiant Pharmaceuticals,
`Inc. (collectively, “Adapt”) appeal the United States Dis-
`trict Court for the District of New Jersey’s final judgment
`of invalidity. After a two-week bench trial, the district
`court determined that the asserted claims of U.S. Patent
`Nos. 9,468,747; 9,561,177; 9,629,965; and 9,775,838 (collec-
`tively, the “patents-in-suit”) would have been obvious in
`view of the prior art. For the reasons below, we conclude
`that the district court did not err in its obviousness deter-
`mination and therefore affirm.
`BACKGROUND
`I
`The patents-in-suit claim methods of treating opioid
`overdose by intranasal administration of a naloxone formu-
`lation, as well as devices for intranasal administration.
`Naloxone—the active ingredient in Adapt’s NARCAN®
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`ADAPT PHARMA OPERATIONS v. TEVA PHARMS. USA, INC.
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`3
`
`Nasal Spray—is an opioid receptor antagonist that blocks
`opioids from reaching the opioid receptors, thus helping re-
`verse the effects of opioid overdose. ’747 patent col. 2
`ll. 13–15.1
`The use of naloxone to treat opioid overdose was not a
`new concept at the time of the invention. Before the prior-
`ity date of the patents-in-suit, numerous naloxone products
`had been used to treat opioid overdose. For example, the
`specification explains that naloxone “approved for use by
`injection” was an option for treating opioid overdose. Id. It
`was also known in the prior art to administer naloxone in-
`tranasally. For example, before the priority date, naloxone
`was administered intranasally by “combin[ing] an FDA-
`approved naloxone injection product with a marketed[]
`medical device called the Mucosal Atomization Device.” Id.
`at col. 6 ll. 46–51. This device, which the parties and the
`district court refer to as the MAD Kit, allows a liquid for-
`mulation to be sprayed into the nostrils. The specification
`also describes a number of prior art studies that adminis-
`tered 2 mg of naloxone intranasally to overdose victims, id.
`at col. 3 l. 1–col. 4 l. 26, col. 5 ll. 29–54 (citations omitted),
`and another that administered 8 mg and 16 mg of naloxone
`intranasally, id. at col. 5 l. 55–col. 6 l. 3 (citing PCT Pub.
`No. WO 2012/156317).
`Administering naloxone by injection or using the MAD
`Kit was not without disadvantages. For example, the spec-
`ification explains that only trained medical personnel can
`administer naloxone by injection (either intramuscularly,
`which is an injection in the muscle, or intravenously, which
`is an injection in the vein), id. at col. 6 ll. 14–35, preventing
`many first responders from administering naloxone to
`overdose victims. And while the MAD Kit provided first
`
`1 Each of the patents-in-suit are in the same family
`and have overlapping specifications, so we generally cite
`only the ’747 patent’s specification.
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`ADAPT PHARMA OPERATIONS v. TEVA PHARMS. USA, INC.
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`responders with a mechanism to quickly administer nalox-
`one intranasally, it too had disadvantages in that it re-
`quired assembly prior to use and delivered too much fluid
`into the nose.
`On April 12, 2012, amidst the growing opioid addiction
`crisis, the U.S. Food & Drug Administration (FDA) held a
`public meeting to “promote and encourage the industry to
`develop an intranasal naloxone product that could be FDA-
`approved.” J.A. 3859–60 (Trial Tr. 336:16–337:3). At this
`meeting, the FDA explained that any intranasal naloxone
`formulation should provide exposure at least comparable
`to already-approved injectable naloxone products. That is,
`the intranasal formulation should deliver the same amount
`of drug to the bloodstream as the injectable formulations.
`Shortly thereafter, on May 24, 2012, Lightlake Therapeu-
`tics, Inc.—Opiant’s predecessor—met with the FDA to dis-
`cuss a potential investigational new drug application.
`Although Lightlake expressed its view that there was “lit-
`tle if any commercial incentive” to develop an intranasal
`product, J.A. 3824 (Trial Tr. 301:3–17), it nevertheless
`sought input from the FDA on its plans to develop a 2 mg
`intranasal naloxone formulation, relying on an approved
`2 mg intramuscular naloxone formulation as a reference
`formulation. In response, the FDA explained that numer-
`ous studies indicated that a 2 mg intranasal dose would
`have poor bioavailability compared to a 2 mg intramuscu-
`lar dose and therefore recommended that Lightlake in-
`crease the dose of its proposed product to achieve
`bioavailability similar to the intramuscular product.
`Lightlake did just that, ultimately submitting New Drug
`Application (NDA) No. 208411 for a 4 mg intranasal nalox-
`one product, approved under the name NARCAN®.2
`
`
`2 Adapt is the current holder of the NDA for
`NARCAN® Nasal Spray.
`
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`ADAPT PHARMA OPERATIONS v. TEVA PHARMS. USA, INC.
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`5
`
`On March 16, 2015, Adapt filed U.S. Patent Applica-
`tion No. 14/659,472, from which each of the patents-in-suit
`claim priority. All of the patents-in-suit are listed in the
`FDA’s publication “Approved Drug Products with Thera-
`peutic Equivalence Evaluations,” commonly known as the
`Orange Book, as covering NARCAN®. At trial, the district
`court treated dependent claim 9 of the ’747 patent as rep-
`resentative, which includes claims 1 and 2 in its depend-
`ency. Because the issues on appeal relate to the
`formulation limitations of the asserted claims, which are
`recited in claims 1 and 2, we reproduce only those claims
`below:
`1. A method of treatment of opioid overdose or a
`symptom thereof, comprising nasally administer-
`ing to a patient in need thereof a dose of naloxone
`hydrochloride using a single-use, pre-primed de-
`vice adapted for nasal delivery of a pharmaceutical
`composition to a patient by one actuation of said
`device into one nostril of said patient, having a sin-
`gle reservoir comprising a pharmaceutical compo-
`sition which is an aqueous solution of about 100 μL
`comprising:
`about 4 mg naloxone hydrochloride or a hy-
`drate thereof;
`between about 0.2 mg and about 1.2 mg of
`an isotonicity agent;
`between about 0.005 mg and about 0.015
`mg of a compound which is at least one of a
`preservative, a cationic surfactant, and a
`permeation enhancer;
`between about 0.1 mg and about 0.5 mg of
`a stabilizing agent; and
`an amount of an acid sufficient to achieve a
`pH of 3.5-5.5.
`
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`Case: 20-2106 Document: 54 Page: 6 Filed: 02/10/2022
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`ADAPT PHARMA OPERATIONS v. TEVA PHARMS. USA, INC.
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`2. The method as recited in claim 1 wherein:
`the isotonicity agent is NaCl;
`the preservative is benzalkonium chloride;
`the stabilizing agent is disodium edetate; and
`the acid is hydrochloric acid.
`’747 patent col. 53 ll. 8–29.
`
`II
`Teva Pharmaceuticals USA, Inc. and Teva Pharmaceu-
`ticals Industries, Ltd. (collectively, “Teva”) asserted two
`different combinations of prior art at trial: (1) Davies3 in
`view of Kerr 20094/the Kerr Formulation and Bahal5 (the
`“Davies combination”); and (2) Strang6 in view of Kul-
`karni7 and Djupesland8 (the “Strang combination”). We
`discuss each combination and reference in turn.
`
`
`3 PCT Pub. No. WO 2000/62757.
`4 Debra Kerr et al., Randomized controlled trial com-
`paring the effectiveness and safety of intranasal and intra-
`muscular naloxone for the treatment of suspected heroin
`overdose, 104 Addiction 2067–74 (2009).
`5 U.S. Patent No. 5,866,154.
`6 PCT Pub. No. WO 2012/15317.
`7 Vitthal Kulkarni & Charles Shaw, Formulation
`and characterization of nasal sprays: An examination of na-
`sal spray formulation parameters and excipients and their
`in vitro
`tests, Inhalation 10–15
`influence on key
`(June 2012).
`8 Per Gisle Djupesland, Nasal drug delivery devices:
`characteristics and performance in a clinical perspective—
`a review, 3 Drug Delivery & Translational Rsch. 42–62
`(2013).
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`ADAPT PHARMA OPERATIONS v. TEVA PHARMS. USA, INC.
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`
`A
`The first combination involves Davies, Kerr 2009/the
`Kerr Formulation, and Bahal. Davies relates to spray ap-
`plicators for administering naloxone and formulations of
`naloxone for nasal administration. Davies, Abstract. Spe-
`cifically, Davies “provide[s] systems of administering an
`opioid antagonist,” such as naloxone, “which can be carried
`out by an unskilled person, rapidly and with a good chance
`of successfully reviving a patient suffering from opioid
`over-dosage.” Id. at 1. Davies provides a detailed descrip-
`tion and drawings of a spray applicator that can be used
`for intranasal administration. See id. at 4–5 & Figs. 1–2.
`Davies teaches that naloxone, the “preferred opioid antag-
`onist,” is preferably administered “as a sprayable liquid
`composition.” Id. at 2. Davies also teaches that naloxone
`is “freely soluble in water . . . when in the form of a salt,
`such as a hydrochloride,” and so it therefore may be dis-
`solved in dilute saline solutions such as a solution contain-
`ing about 0.9% w/v sodium chloride. Id. Davies explains
`that the formulation should be slightly acidic (e.g., pH 6.5),
`to maintain the naloxone in its salt form. Id. at 2, 4. Ad-
`ditionally, Davies teaches that a suitable dose of naloxone
`for nasal administration ranges from 0.2 to 5 mg, with the
`volume for administration ranging from 20 to 100 μL. Id.
`at 3. One exemplary naloxone formulation in Davies in-
`cludes benzalkonium chloride (BZK) as a preservative in
`an amount of 0.025% w/v. Id. Example 1.
`Kerr 2009 recognized the benefits of administering na-
`loxone intranasally, noting that intranasal administration
`is one way to reduce the risk of accidental and unintended
`needlesticks often associated with injections. Kerr 2009
`at 2067–68, 2072. Kerr conducted a study aimed at “deter-
`min[ing] the effectiveness and safety of concentrated
`(2 mg/m[L]) i.n. [intranasal] naloxone compared to i.m. [in-
`tramuscular] naloxone for treatment of suspected opiate
`overdose.” Id. at 2068. Although the formulation Kerr
`used in their study (the “Kerr Formulation”) was not
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`ADAPT PHARMA OPERATIONS v. TEVA PHARMS. USA, INC.
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`disclosed in the reference itself, the evidence and testimony
`at trial established that the formulation Kerr used was
`purchased from a third party, ORION Laboratories Pty.
`Ltd., and is therefore prior art to the patents-in-suit. This
`is not disputed on appeal. This formulation comprised
`0.2% naloxone hydrochloride (HCl) (i.e., 2 mg/mL naloxone
`HCl), sodium chloride, 0.01% BZK as a preservative, water,
`and hydrochloric acid to adjust the pH of the solution.
`J.A. 11467.
`Bahal relates to “[p]hysically and chemically stable
`pharmaceutical compositions useful for administering na-
`loxone by injection.” Bahal, Abstract. Bahal describes the
`“[i]nstability of naloxone,” specifically noting that autoclav-
`ing naloxone formulations—a process that can be used to
`sterilize drug products—results in significant naloxone
`degradation. Id. at col. 1 ll. 44–47. After conducting a
`number of studies, Bahal concluded that the “addition of a
`chelating agent, such as sodium edetate” (EDTA) “prevents
`naloxone degradation, even in the presence of oxygen and
`after autoclaving.” Id. at col. 1 ll. 53–56.
`B
`The second combination involves Strang, Kulkarni,
`and Djupesland. Strang discloses various intranasal na-
`loxone formulations for treating opioid overdose. Strang,
`Abstract. In particular, Strang discloses intranasal formu-
`lations having between 0.5 and 20 mg naloxone HCl, id.
`at p. 5 ll. 16–17, identifying 4 mg as a “preferred” starting
`dose, id. at p. 29 ll. 17–22. Based on measured AUCs9 for
`both intravenously and intranasally administered nalox-
`one, Strang “estimated that the range of dose-proportion-
`ality to 1 mg IV [intravenous] is in the range of 3 mg to
`
`
`9 AUC (area under the curve) is a measure of bioa-
`vailability, that is, the amount of the active ingredient that
`is absorbed into blood circulation. Id. at p. 22 ll. 8–11.
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`9
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`4 mg for IN [intranasal] naloxone.” Id. Example 2. In
`other words, Strang determined that the bioavailability for
`a 1 mg dose of naloxone administered intravenously is
`about equal to that of a 3 or 4 mg dose of naloxone admin-
`istered intranasally. Strang further teaches that its nalox-
`one formulations are preferably aqueous saline solutions—
`that is, solutions comprising about 1.0% sodium chloride in
`water—and have a pH “most preferably” less than 5.5. Id.
`at p. 9 ll. 22–30. Strang also explains that because nalox-
`one must be present in the bloodstream in an amount suf-
`ficient to counter the effect of the opioids, “an effective
`amount of naloxone has to be provided in one application
`step,” with additional application steps as needed depend-
`ing on the severity of the overdose. Id. at p. 24 ll. 5–10.
`Additionally, to avoid loss of the drug due to swallowing or
`leaking from the nostrils, Strang recommends administer-
`ing intranasal naloxone in small volumes, id. at p. 23
`ll. 10–13, with 100 μL being “[p]articularly preferred,” id.
`at p. 9 ll. 2–3.
`Kulkarni is a review article that examines nasal spray
`formulations and the impact various excipients have on
`drug performance. Kulkarni provides a table of “key” ex-
`cipients used in nasal spray formulations, identifying the
`function and the FDA’s concentration limits for each excip-
`ient. Kulkarni at 12, Tbl. 2. This list was compiled from
`the FDA’s Inactive Ingredient Guide (IIG) for nasal spray
`products, which contains “only a limited number of excipi-
`ents.” Id. at 12. Kulkarni’s table lists (1) BZK, a preserv-
`ative, in concentrations up to 0.119% w/w; (2) EDTA, a
`chelating agent, in concentrations up to 0.5% w/w; and
`(3) sodium chloride, a tonicity agent, in concentrations up
`to 1.9% w/w. Kulkarni also explains that the “optimal
`range for pH” of intranasal formulations is between 4.5
`and 6.5. Id. at 11.
`Djupesland is a review article that discusses delivery
`devices for intranasal administration of drug products.
`Djupesland explains that, for drugs like naloxone that are
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`ADAPT PHARMA OPERATIONS v. TEVA PHARMS. USA, INC.
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`“intended for single administration or sporadic use and
`where tight control of the dose and formulation is of partic-
`ular importance, single-dose or duo-dose spray devices are
`preferred.” Djupesland at 48. Djupesland refers specifi-
`cally to the Aptar UnitDose device—an FDA-approved
`medical device that delivers 100 μL of a drug intranasally,
`J.A. 3858 (Trial Tr. 335:17–21), 11664—as one such spray
`device for intranasal administration. Djupesland at 48
`(citing www.aptar.com).
`
`III
`Teva submitted to the FDA Abbreviated New Drug Ap-
`plication (ANDA) No. 209522 seeking approval to manufac-
`ture and sell a generic version of NARCAN®. Teva’s ANDA
`filing included a Paragraph IV certification asserting that
`the patents-in-suit are invalid, unenforceable, and/or not
`infringed. See 21 U.S.C. § 355(j)(2)(A)(vii)(IV). On Octo-
`ber 21, 2016, Adapt sued Teva for infringement under
`35 U.S.C. § 271(e)(2) based on Teva’s ANDA submission.
`Before trial, Teva stipulated to infringement, and the par-
`ties agreed to try validity of a subset of claims,
`namely: claims 7 and 9 of the ’747 patent; claim 4 of the
`’177 patent; claims 21, 24, and 25 of the ’965 patent; and
`claims 2, 24, 33, and 38 of the ’838 patent (the “asserted
`claims”).
`The district court held a two-week bench trial on valid-
`ity. After considering the evidence of record—including
`testimony from thirteen fact and expert witnesses—the
`district court issued a nearly 100-page, comprehensive
`opinion setting forth its findings of fact and conclusions of
`law under Federal Rule of Civil Procedure 52(a), as well as
`making specific credibility determinations as to each of the
`witnesses that testified. Adapt Pharma Operations Ltd.
`v. Teva Pharms. USA, Inc., Case No. 2:16-cv-7721 (BRM)
`(JAD), 2020 WL 3428078 (D.N.J. June 22, 2020) (Judgment
`Op.). The district court ultimately determined that Teva
`had proven by clear and convincing evidence that the
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`11
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`asserted claims would have been obvious in view of the
`prior art and entered a final judgment of invalidity. Id.
`at *47.
`Adapt appeals. We have jurisdiction under 28 U.S.C.
`§ 1295(a)(1).
`
`DISCUSSION
`Following a bench trial, we review the district court’s
`legal determinations de novo and its factual findings for
`clear error. See Merck Sharp & Dohme Corp. v. Hospira,
`Inc., 874 F.3d 724, 728 (Fed. Cir. 2017). “A factual finding
`is only clearly erroneous if . . . we are left with the definite
`and firm conviction that a mistake has been made.” Id.
`“Obviousness is a question of law based on underlying find-
`ings of fact.” OSI Pharms., LLC v. Apotex Inc., 939 F.3d
`1375, 1382 (Fed. Cir. 2019) (quoting In re Kubin, 561 F.3d
`1351, 1355 (Fed. Cir. 2009)). What the prior art teaches
`(including whether it teaches away from the claimed inven-
`tion), whether a skilled artisan would have been motivated
`to combine the prior art references, and the existence of
`and weight assigned to any objective indicia of nonobvious-
`ness are underlying factual questions we review for clear
`error. Merck, 874 F.3d at 728; see also AstraZeneca AB
`v. Mylan Pharms. Inc., 19 F.4th 1325, 1335 (Fed. Cir.
`2021).
`Adapt challenges the district court’s determination
`that the asserted claims would have been obvious over ei-
`ther combination of prior art. Specifically, Adapt chal-
`lenges several of the district court’s factual findings
`underlying its obviousness determination as clearly erro-
`neous, namely: (1) its finding that a skilled artisan would
`have been motivated to combine the prior art references to
`arrive at the claimed invention; (2) its finding that the
`prior art, as a whole, does not teach away from the claimed
`invention; and (3) its findings related to Adapt’s proffered
`objective indicia of nonobviousness. We address each issue
`in turn.
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`ADAPT PHARMA OPERATIONS v. TEVA PHARMS. USA, INC.
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`I
`We begin with the district court’s motivation-to-com-
`bine analysis. Adapt’s principal argument on appeal is
`that the district court failed to articulate a reason why a
`skilled artisan would have been motivated to combine the
`prior art references to arrive at the claimed invention. We
`disagree. The district court found that a skilled artisan
`would have been motivated to: (1) formulate an intranasal
`naloxone product that would improve upon the MAD Kit;
`(2) select the claimed excipients—sodium chloride, BZK,
`EDTA, and hydrochloric acid for adjusting the pH—and the
`Aptar UnitDose device for intranasal delivery; (3) select a
`4 mg dose of naloxone; and, accordingly, (4) combine the
`prior art references themselves. These findings—sup-
`ported by ample evidence in the record—provide a detailed
`explanation as to why a skilled artisan would have been
`motivated to combine the prior art references to arrive at
`the claimed invention.
`A determination of obviousness “requires finding that
`a person of ordinary skill in the art would have been moti-
`vated to combine or modify the teachings in the prior art
`and would have had a reasonable expectation of success in
`doing so.” OSI Pharms., 939 F.3d at 1382 (quoting Regents
`of Univ. of Cal. v. Broad Inst., Inc., 903 F.3d 1286, 1291
`(Fed. Cir. 2018)). This requires “identify[ing] a reason that
`would have prompted a person of ordinary skill in the rel-
`evant field to combine the elements in the way the claimed
`new invention does.” KSR Int’l Co. v. Teleflex Inc., 550 U.S.
`398, 418 (2007). This “motivation to combine may be found
`explicitly or implicitly in market forces; design incentives;
`the ‘interrelated teachings of multiple patents’; ‘any need
`or problem known in the field of endeavor at the time of
`invention and addressed by the patent’; and the back-
`ground knowledge, creativity, and common sense of the
`person of ordinary skill.” Plantronics, Inc. v. Aliph, Inc.,
`724 F.3d 1343, 1354 (Fed. Cir. 2013) (quoting Perfect Web
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`13
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`Techs., Inc. v. InfoUSA, Inc., 587 F.3d 1324, 1328–29
`(Fed. Cir. 2009)); accord KSR, 550 U.S. at 418–21.
`First, the district court found that a skilled artisan
`would have been “motivat[ed] to improve on the MAD Kit
`because its shortcomings were well-known.” Judgment
`Op., 2020 WL 3428078, at *42. As the district court ex-
`plained, the FDA in 2012 discussed its “interest in improv-
`ing the MAD Kit,” id. at *8 (citing J.A. 3859 (Trial
`Tr. 336:11–15)), and encouraged the industry to “develop
`an intranasal naloxone product that could be FDA ap-
`proved,” id. (quoting J.A. 3859 (Trial Tr. 336:23–25)).
`Thus, several years before the priority date of the patents-
`in-suit, the FDA explicitly provided a motivation to formu-
`late an intranasal naloxone product by identifying a “need
`or problem known in the [industry] . . . at the time of the
`invention,” Plantronics, 724 F.3d at 1354—the known
`drawbacks of the MAD Kit and the need for an intranasal
`naloxone product. A skilled artisan, therefore, would have
`been motivated to develop an intranasal naloxone product.
`The prior art references themselves support this con-
`clusion by recognizing the drawbacks of administering na-
`loxone by injection and identifying intranasal naloxone as
`a solution. For example, crediting the testimony of Teva’s
`expert Dr. Hugh Smyth—whom the district court found to
`be “highly credible and convincing,” Judgment Op.,
`2020 WL 3428078, at *8—the district court found that Da-
`vies “discusses the difficulties associated with medically
`untrained individuals treating opioid overdoses with injec-
`tions and discusses how these difficulties could be allevi-
`ated with the use of intranasal naloxone.” Id. at *20 (citing
`J.A. 3922 (Trial Tr. 399:17–23)). The district court likewise
`credited Dr. Smyth’s testimony that Strang “identified var-
`ious risks associated with injectable naloxone” and that it
`“identified intranasal naloxone as a solution to these is-
`sues.” Id. at *19 (first citing J.A. 3890 (Trial Tr. 367:6–15);
`and then citing Strang at p. 2). Thus, we see no error in
`the district court’s finding that a skilled artisan would have
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`ADAPT PHARMA OPERATIONS v. TEVA PHARMS. USA, INC.
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`been motivated to improve upon the MAD Kit and develop
`an intranasal naloxone formulation for treating opioid
`overdose.
`Second, the district court found that a skilled artisan
`would have been motivated to use sodium chloride, hydro-
`chloric acid, BZK, and EDTA in an intranasal naloxone for-
`mulation.
` As Dr. Smyth explained, the injectable
`formulation that was administered using the MAD device
`was not optimized for intranasal administration. Id. at *28
`(citing J.A. 3852–53 (Trial Tr. 329:22–330:6)). The district
`court, therefore, found that a skilled artisan would “have
`been motivated to optimize th[e] formulation for nasal de-
`livery.” Id. Relying on testimony of both parties’ experts,
`the district court found that a skilled artisan would have
`been specifically motivated to use each of the claimed ex-
`cipients in a nasal formulation. These findings are well-
`supported by the record.
`For instance, the district court found that a skilled ar-
`tisan would have known that “intranasal formulations gen-
`erally have certain characteristics to make them
`acceptable and tolerable in the nose, things like the tonicity
`and pH.” Id. (quoting J.A. 3868 (Trial Tr. 345:16–18)); see
`also Plantronics, 724 F.3d at 1354 (explaining that the
`“background knowledge” of a skilled artisan can provide
`the requisite motivation to combine). The district court
`also found that a tonicity agent is often used with intrana-
`sal products to avoid nasal irritation and that a skilled ar-
`tisan would have used the claimed excipient sodium
`chloride in an intranasal naloxone formulation because it
`was a well-known tonicity agent. Judgment Op., 2020 WL
`3428078, at *28
`(first
`citing J.A. 3868
`(Trial
`Tr. 345:19–346:23); and then citing J.A. 4554 (Trial
`Tr. 1031:10–15)). Ample evidence before the district court
`supports this fact finding.
`Sodium chloride, for example, was listed in the FDA’s
`Inactive Ingredient Guide (IIG) as a tonicity agent for use
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`15
`
`in intranasal products. Davies and Strang also specifically
`identified sodium chloride for use in their intranasal nalox-
`one products, with both references disclosing specific con-
`centrations of sodium chloride falling within the claimed
`range. The Kerr formulation likewise included sodium
`chloride.
`The district court also did not clearly err in finding that
`the pH of an intranasal formulation is important to avoid
`nasal irritation, and that the pH—determined through rou-
`tine optimization—should be somewhere between 3.5
`and 7. Id. (citing J.A. 3870 (Trial Tr. 347:12–21)). Davies
`identified a pH of 6.5 and Strang identified a pH of most
`preferably less than 5.5 (the outer limit of the claimed
`range) for an intranasal naloxone formulation. And Kerr
`specifically used hydrochloric acid to adjust the pH of the
`formulation. Thus, the district court’s finding that a
`skilled artisan would have been motivated to use sodium
`chloride as a tonicity agent and hydrochloric acid to adjust
`the pH of the solution as a means to prevent nasal irrita-
`tion is not clearly erroneous.
`Additionally, recognizing that preservatives are com-
`monly used in intranasal formulations, the district court
`found that the claimed excipient BZK was “commonly used
`as a preservative and had been used in over 200 intranasal
`products.”
`
`(first citing J.A. 3905–06
`(Trial
`Id.
`Tr. 382:11–383:3); then citing J.A. 4299–300
`(Trial
`Tr. 776:20–23, 777:5–8); and then citing J.A. 4557 (Trial
`Tr. 1034:17–21)). The evidence before the district court
`supports this fact finding. BZK, like sodium chloride, was
`listed in the IIG as a commonly used preservative. Kul-
`karni taught a skilled artisan that BZK had been used in
`concentrations up to 0.119% w/w, which encompasses the
`claimed range. And both Davies and Kerr specifically used
`the claimed excipient BZK as a preservative in their re-
`spective intranasal naloxone formulations, with the Kerr
`formulation using a concentration of BZK falling within the
`claimed range.
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`ADAPT PHARMA OPERATIONS v. TEVA PHARMS. USA, INC.
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`The district court also found that naloxone degradation
`was known in the prior art, and that the use of a stabilizer,
`such as the claimed excipient EDTA, prevents naloxone
`degradation.
`
`Id.
`(citing
`J.A.
`3872–73
`(Trial
`Tr. 349:8–350:12)). This was expressly taught in Bahal,
`which taught a “preferred” concentration of EDTA for sta-
`bilizing naloxone that encompasses the claimed range. Ba-
`hal col. 2 ll. 65–67. And Kulkarni, similarly, taught a
`skilled artisan that EDTA should be used in intranasal for-
`mulations in concentrations up to 0.5% w/w, which again
`falls within the claimed range. The district court found
`that, in view of Bahal’s teachings, “a POSA might be moti-
`vated to try combining EDTA and BZK” in a naloxone for-
`mulation,” Judgment Op., 2020 WL 3428078, at *21 (citing
`Trial Tr. 720:18–721:1, ECF No. 293), because “EDTA
`could be used with BZK in intranasal formulations to in-
`crease their preservative effects,” id. at *28 (first citing
`J.A. 4328–29
`(Trial Tr. 805:23–806:6);
`then
`citing
`J.A. 3901
`(Trial Tr. 378:9–19);
`and
`then
`citing
`J.A. 3953–54 (Trial Tr. 430:25–431:20)). Given the record
`evidence supporting its findings, we see no clear error in
`the district court’s findings that a skilled artisan “would
`have been motivated to select and use BZK as a preserva-
`tive” and “to select and use EDTA as a stabilizing agent”
`for use in an intranasal naloxone formulation, particularly
`given their synergistic interaction. Id.
`the Aptar
`that
`The district court—recognizing
`UnitDose Device was an already FDA-approved medical
`device specifically recommended in the prior art for use
`with drugs that are administered sporadically (like in-
`tranasal naloxone)—also found that a skilled artisan would
`have “been motivated to select the Aptar UnitDose device
`when developing an improved intranasal naloxone prod-
`uct” as a way of administering intranasal naloxone in lieu
`of using the MAD Kit. Id. at *24. Indeed, at the FDA’s
`2012 meeting, industry experts discussed the use of a one-
`step
`intranasal delivery device
`for administering
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`ADAPT PHARMA OPERATIONS v. TEVA PHARMS. USA, INC.
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`17
`
`intranasal naloxone. Id. at *8 (citing J.A. 3860 (Trial
`Tr. 337:15–20)). Davies and Strang likewise recognized
`that a one-step device would be beneficial. We therefore
`see no clear error in the district court’s finding.
`Third, the district court found that a skilled artisan
`would have been motivated to use the claimed 4 mg dose of
`intranasal naloxone. At the 2012 meeting, “[t]he FDA spe-
`cifically mentioned that it was curious about the bioavaila-
`bility of an intranasal naloxone product as compared to the
`existing intravenous or intramuscular products.” Id. at *2.
`The district court found that Strang estimated that “an in-
`tranasal dose of 3mg to 4mg would be bioequivalent to the
`FDA-approved 1mg injectable dose.” Id. at *29 (first citing
`J.A. 3916–17 (Trial Tr. 393:20–394:20); and then citing
`Strang at p. 48). Moreover, the district court noted that
`using a higher dose of intranasal naloxone would reduce
`the chances of having to administer a second dose, a con-
`sideration it found weighed in favor