Azurity Pharmaceuticals, Inc. v. Alkem Laboratories Ltd.

• Court: District Court, D. Delaware
• Decided: February 10, 2023
• Docket: 1:19-cv-02100
• Status: Unknown

Opinion

INTHEUNITEDSTATESDISTRICTCOURT FORTHEDISTRICTOFDELAWARE AZURITYPHARMACEUTICALS,INC., Plaintiff, CivilAction v. No. 19-cv-2100

ALKEMLABORATORIESLTD., Defendant. MEMORANDUMOPINION Goldberg,J.1 February10,2023

This lawsuit was brought under the Hatch Waxman Act for patent infringement pursuant to 35 U.S.C. § 271(e)(2)(a). Plaintiff Azurity Pharmaceuticals, Inc. (“Azurity”) claims that an Abbreviated New Drug Application (ANDA) submitted by Defendant Alkem Laboratories Ltd. (“Alkem”) infringes U.S. Patent Nos. 10,786,482 (the ’482 patent) and 10,918,621 (the ’621 patent), both titled “Enalapril formulations.” Azurity asserts claims 16, 18, 22, 23, and 28 of the ’482 patent and claims 4, 7, 17, and 18 of the ’621 patent. Alkem denies infringement and alleges thatthepatentsinsuitareinvalidduetoobviousnessandinsufficientwrittendescription.

After presiding over a three-day bench trial, I find that Azurity has established by a pre- ponderance of the evidence that Alkem’s ANDA infringes all asserted claims. However, I also conclude that Alkem has presented clear and convincing evidence that those claims are invalid for obviousness and lack of written description. This opinion sets forth my reasons in reaching these verdicts.

1 Pursuantto28U.S.C.§292(b),IhavebeendesignatedtoserveasavisitingjudgefortheDistrict ofDelawaretohandlethismatterandotherDistrictofDelawarecases. I. BACKGROUND Thepatentsinsuitclaimliquidscontainingthebloodpressuremedicineenalapril. Azurity did not invent enalapril, which had existed for decades preceding Azurity’s invention. Azurity

claimstohaveinventedawaytomixenalaprilwithwaterandpreventthemixturefromdegrading over a period of 12 to 24 months. Alkem’s ANDA is also a mixture of enalapril in water that does notdegradeover24months. Alkem concedes that its ANDA infringes most asserted claim limitations, disputing only two. First, Alkem contends that its ANDA does not infringe because it contains an ingredient that is not recited in any asserted claim: a “pH adjuster” added to ensure that the pH of the mixture is

withinatargetrange. AccordingtoAlkem,becausenoneoftheassertedclaimsrecitepHadjusters, the presence of these ingredients precludes infringement of those claims that are partially closed to unlisted ingredients. Azurity responds that pH adjusters are optional in Alkem’s ANDA and therefore do not affect the infringement analysis. Alternatively, Azurity argues that when a pH adjuster is added, it disappears by reacting with other ingredients in the mixture such that it is no longerpresentinthefinalliquid,thusdefeatingAlkem’snoninfringementargument. Alkem also contends that Azurity failed to prove that the concentration of the buffer in

Alkem’sANDAiswithintheclaimedrange,againrelyingonthepHadjustersinconjunctionwith testimony from Azurity’s expert Dr. Little, who opined that the pH adjusters react with citric acid to form components of the buffer. Alkem reasons that if Dr. Little’s testimony is credited, the reactionhedescribedmustproducesomeunknownquantityofbuffer,meaningthereisafailureof proofthattheamountofbufferleftafterthereactioniswithintheclaimedrange. Ontheissueofvalidity,Alkemallegesthattheassertedpatentclaimswouldhavebeenob-

viousinlightofthepriorartandthattheclaimsareinadequatelydescribedbythepatents’written specification. More specifically, Alkem alleges that it would have been obvious to a person of or- dinary skill in the art (a POSA) to make an enalapril liquid as set out in the claims: (1) using each claimedingredient;(2)intheclaimedamounts;(3)withnootheringredientsthat“materiallyaffect

the basic and novel properties of the invention”; and (4) meeting the two limitations regarding the liquidbeing“stable”andhavingatleast95%enalaprilwithnomorethan5%impuritiesattheend ofthestorageperiod. (See,e.g.,’621patent,Claim4.) WhileAzuritydidnotconcedethatanyaspectofitsinventionwasobvious,attrialAzurity did not dispute that the individual claimed ingredients—enalapril, water, citrate buffers, paraben preservatives, sweeteners, and flavors—were known prior to its invention. Instead, the focus of

the parties’ dispute is whether it would have been obvious how to combine those ingredients into a liquid that would be stable for as long as the claims require—12 to 24 months. As set forth in greater detail below, the parties offered prior studies on the tendency of enalapril to degrade in waterandpresentedconflictingviewsastowhataPOSAwouldgleanfromthosestudiesaboutthe possibilityofkeepingenalaprilstablefor12to24months. Regarding written description, the issue is whether the patents’ specification adequately describes stable enalapril liquids that contain paraben preservatives. Alkem asserts that although

the specification states that parabens can be used as a preservative, it does not say which liquids containingparabenswillbestablefor12to24months. II. INFRINGEMENT A. FactsRelevanttoInfringement 1. ExpertTestimony Thepartiesstipulatedthatallexpertswerequalified,and,indeed,thebackgroundandexpe-

rience of each expert was impressive. Briefly summarized, Azurity’s witness Dr. Stephen Little is an expert in pharmaceutical formulation who has undergraduate and doctoral degrees in chemical engineering and has founded multiple companies engaged in pharmaceutical formulation. (N.T. 93-97.) Azurity’s witness Dr. John Mahan is an expert in the treatment of young children with hypertension who holds various teaching, research, and leadership roles in pediatric nephrology. (N.T. 387-90.) Alkem’s witness Dr. Barrett Rabinow is also an expert in pharmaceutical formula- tionwhohasundergraduateanddoctoraldegreesinchemistryandspentover39yearsasachemist

working on pharmaceutical formulations. (N.T. 177-85.) Finally, Alkem’s witness Dr. Panayi- otis Constantinides, also an expert in pharmaceutical formulation, has degrees in chemistry and biochemistry and has developed pharmaceutical formulations over a period of 35 years. (N.T. 244-50.)2

2. AssertedClaims Azurity asserts claims 16, 18, 22, 23, and 28 of the ’482 patent and claims 4, 7, 17, and 18 ofthe’621patent. Claim4ofthe’621patentisillustrative,andreads: Astableoralliquidformulation,consistingessentiallyof: (i) about0.6toabout1.2mg/mLenalaprilorapharmaceuticallyacceptable saltorsolvatethereof; (ii) a buffer to maintain the pH about 4.5 or below, wherein the buffer con- centrationisabout5mMtoabout20mM; 2 Theseexpertsalsoofferedtestimonyrelevanttovalidity. (iii) a preservative, wherein the preservative is a paraben or a mixture of parabens;and (iv) water; wherein the formulation optionally comprises a sweetener, a flavoring agent, or both; whereintheformulationisstableatabout5±3°C.foratleast12months;[] wherein the stable oral liquid formulation has about 95% w/w or greater of the initial enalapril amount and about 5% w/w or less total impurity or related sub- stancesattheendofthegivenstorageperiod[;and] wherein the buffer comprises a citrate, a phosphate, a citrate/phosphate, an ac- etate,aglycinate,anaminoacid,oratartratebuffer. (’621patent,Claim4(independentclaimsinserted).)3 3. Alkem’sAccusedProduct Alkem’s accused product is an abbreviated new drug application (ANDA) for an enalapril liquid. It is undisputed that Alkem’s ANDA contains many of the same ingredients in the same amounts as the asserted claims require, including the same active ingredient, preservative, water, and sweetener. (Amended Undisputed Facts ¶¶ 38-48; N.T. 115-16 (Little).) It is also undisputed thatAlkem’sANDAmeetsthepHandstabilitylimitationsofallassertedclaims,andthatitmeets thelimitationofclaim18ofthe’482patentthattheformulationnotcontainmannitol. (N.T.118-23 (Little).) But for two reasons, Alkem does not concede infringement. First, Alkem points to the fact that its ANDA states that pH adjusters—sodium hydroxide and hydrochloric acid—should be addedinanamount“q.s.”Theterm“q.s.”means“quantumsatis”or“thequantitythat’snecessary.” (N.T. 138 (Little).) Thus, sodium hydroxide and hydrochloric acid will be added as necessary to Alkem’s ANDA to achieve the target pH range. (N.T. 141, 172 (Little).) Alkem’s ANDA does 3 The parties stipulated that “no terms of the patents-in-suit require construction” and thus no hearingonclaimconstructionwasheld. (ECFNo.84.) not explicitly say whether the target pH range can be achieved without adding pH adjusters. (N.T. 173-74 (Little).) The ANDA describes “exhibit batches” of the formulation, all of which required the addition of sodium hydroxide to meet the target pH range. (N.T. 139-40, 151-52, 158-59, 164

(Little).) The patents in suit do not claim pH adjusters, and, for that reason, Alkem argues that its ANDA does not infringe certain asserted claims. In response, Azurity’s expert Dr. Little testified that sodium hydroxide (the pH adjuster) “dissociates” or splits apart in water. (N.T. 140 (Little).) In addition, when sodium hydroxide is added to the citrate buffer present in Alkem’s ANDA, it reacts with citric acid. (N.T. 140-43 (Little).) For either of these two reasons, Azurity maintains

that the pH adjusters are no longer present after Alkem’s ANDA solution is mixed, meaning that theiradditiondoesnotprecludeinfringement. Alkem’s second reason for asserting that its ANDA does not infringe is that Azurity has not proven that its ANDA has a buffer in the same concentration that the claims require. Alkem’s ANDA specifies that a buffer should be added that consists of 1.820 mg/mL (milligrams per milliliter) of citric acid and 0.150 mg/mL of sodium citrate. (N.T. 116 (Little).) Dr. Little testified that when these numbers are converted from mg/mL to molar concentration and added together,

the total is between 5 mM (“millimolar”) and 20 mM, which matches the asserted claims. (N.T. 117(Little).) Butforreasonsexplainedinmoredetailbelow,Alkemdisputesthatthiscomputation showsthatthebufferconcentrationlimitationismet. Alkempointstothereactionbetweensodium hydroxide and citric acid Dr. Little testified to, and argues that the products of this reaction must affect the buffer concentration in some unknown way. Alkem did not offer testimony to support thisargument. B. Discussion It is an act of patent infringement to “submit ... an application under ... the Federal Food, Drug, and Cosmetic Act ... for a drug claimed in a patent or the use of which is claimed in

a patent[.]” 35 U.S.C. § 271(e)(2)(A). “The patentee bears the burden of proving infringement by a preponderance of the evidence.” SRI Int’l v. Matsushita Elec. Corp., 775 F.2d 1107, 1123 (Fed.Cir.1985). “Determininginfringement requirestwo steps. First, theclaim mustbe properlyconstrued to determine its scope and meaning. Second, the claim as properly construed must be compared to the accused device or process.” Absolute Software, Inc. v. Stealth Signal, Inc., 659 F.3d 1121,

1129 (Fed. Cir. 2011). “For literal infringement, the patentee must prove that the accused prod- uct meets all the limitations of the asserted claims; if even one limitation is not met, there is no literal infringement.” E.I. du Pont De Nemours & Co. v. Unifrax I LLC, 921 F.3d 1060, 1073 (Fed.Cir.2019). After considering the evidence presented at trial, I find that Azurity has proven by a pre- ponderance of the evidence that Alkem’s ANDA infringes all asserted claims. I address the two disputedclaimlimitationsbelow.

1. PresenceofpHAdjusters The asserted claims of the ’621 patent recite an ingredient list preceded by the phrase “consisting essentially of.” By using this phrase, a patentee “signals that the invention necessarily includes the listed ingredients but is open to unlisted ingredients that do not materially affect the

basic and novel properties of the invention.” HZNP Medicines LLC v. Actavis Labs. UT, Inc., 940 F.3d 680, 893 (Fed. Cir. 2019) (alterations omitted). Alkem argues that this limitation is not met because its ANDA contains pH adjusters—sodium hydroxide and hydrochloric acid—that materiallyaffectitspH,which,inturn,impactsstability. Azurityoffersseveralresponses. ThefirstisthattheANDAinfringesundertheassumption

that the pH adjusters will not be added to every batch. In Azurity’s view, the designation “q.s.” for the pH adjusters was a representation to the FDA that Alkem could make a compliant batch withoutaddingthepHadjusters. (SeeN.T.142-43,151(Little).) To prove infringement under 35 U.S.C. § 271(e)(2)(A), Azurity must establish that if the ANDA is approved, Alkem “will likely market an infringing product.” Glaxo, Inc. v. Novopharm, Ltd., 110 F.3d 1562, 1570 (Fed. Cir. 1997). Where the ANDA itself “does not clearly describe a

product that meets the limitations of the asserted claims,” a court must look to factual evidence bearing on “[w]hat is likely to be sold, or, preferably, what will be sold.” Ferring B.V. v. Watson Labs.,Inc.,764F.3d1382,1387-88(Fed.Cir.2014)(quotationmarksandalterationsomitted). Azurity’s assertion that the pH adjusters will not be added to every batch misreads the ANDA. The designation “q.s.” means that Alkem will add as much sodium hydroxide or hy- drochloricacidasneededtoachievethetargetpH.(N.T.138,207.) Whetherthatamountcouldbe zero is a factual question the ANDA does not answer. (See N.T. 173-74 (Little).) As an analogy,

if a recipe were to call for “1 cup of flour and enough water to make the dough hold together,” it wouldbeincorrecttoreadthatasstatingthatthedoughcouldbemadewithoutwaterortosaythat infringementcouldbeprovenontheassumptionthatwaterwouldnotbeadded. Azurity argues that this case is analogous to Sunovion Pharmaceuticals, Inc. v. Teva Phar- maceuticals, Inc., 731 F.3d 1271 (Fed. Cir. 2013). There, Teva’s ANDA permitted it to sell a range of products, some of which would infringe Sunovion’s patent. Id. at 1278. The Federal

Circuit held that Teva could not avoid infringement based on “internal manufacturing guidelines” anda“declaration”thatitwouldlimittheproductsactuallysoldtoonesoutsidethepatent’sscope. Id. Here, unlike in Sunovion, Alkem’s ANDA does not leave Alkem free to add or not add pH adjustersatitsdiscretion. Rather,theANDArequirespHadjusterstobeaddedwhenevertheother

ingredients do not yield a pH within the specified range. (See PTX-60 at ALK_ENPL_00000402 (“Check the pH of the solution ... and adjust the pH about 3.30 (ranges 3.00 to 3.60) ... .”); id. at 414 (“If required adjust the pH ... .”).) Thus, Alkem’s ANDA does not authorize Alkem to sell a range of products, some infringing and some not. And, although the ANDA is silent as to how oftenliquidsmadeusingtherequiredprocedurewillneedpHadjustment,“silencedoesnotanswer thequestionofinfringement.”SeeFerringB.V.,764F.3dat1409.4

BecausetheANDAdoesnotanswerthequestionofwhetherthepHadjusterswillbeadded toeverybatch,Azurity“mustrelyonevidence”toshowwhatproductwouldbesoldiftheANDA were approved. See Ferring B.V., 764 F.3d at 1388. Azurity offers only speculation that some batches might vary in pH such that no pH adjustment would be necessary. Contrary to Azurity’s argument, I do not read Alkem’s expert Dr. Rabinow’s statement that sodium hydroxide is “not necessarily” added to every batch as a concession that pH adjustment is sometimes unnecessary. (N.T. 207-09.) Rather, I view this testimony only as an acknowledgment that the ANDA is am-

biguous as to how often the pH adjusters will be added. For these reasons, Azurity has failed to provethatAlkemwouldlikelymarketsomebatchesofitsproductwithoutpHadjusters.

4 At oral argument, Azurity noted that Alkem’s ANDA includes a proposed product label stating thatthedrug“may”containsodiumhydroxideandhydrochloricacid. Butthisstatementisconsis- tentwiththeANDA’srequirementtoaddpHadjustorswheneverthepHisoutsideofthespecified range. And, even if the word “may” in the label carried a negative inference that some units of the product would lack pH adjusters, Azurity cites no authority that Alkem would be allowed to deviate from the product’s specification in the ANDA based on more permissive language in a proposedlabel. Azurity next argues that pH adjusters do not matter for infringement because they do not “materially affect the basic and novel properties” of Azurity’s claimed invention. Azurity notes that after the pH of Alkem’s ANDA is adjusted, the final pH will always be within the ranges

specified in the asserted claims. Azurity thus reasons that pH adjusters must not materially affect the pH because they do not change whether claim limitations related to the pH are satisfied. But Azurity presented no evidence that Alkem’s ANDA would be stable if its pH were not adjusted. AndexperttestimonypersuasivelydemonstratedthataddingpHadjusterstoaliquiddoesaffectits pH, that pH affects stability, and that stability is a basic and novel property of Azurity’s invention. (N.T. 149 (Little); N.T. 200-01 (Rabinow).) Therefore, I agree with Alkem that the pH adjusters, totheextenttheyarepresent,“materiallyaffectthebasicandnovelpropertiesoftheinvention.”5

Importantly, however, I do accept Azurity’s final alternative argument that adding pH ad- justers to the mixture does not avoid the “consisting essentially of” limitation. This is because the pH adjusters are consumed and are no longer present once the solution is mixed. On this point, I credit Dr. Little’s testimony that the pH adjuster sodium hydroxide is consumed when it reacts with citric acid. (N.T. 140-43 (Little).) Alkem’s expert Dr. Rabinow essentially conceded that this reaction occurs and that it results in the pH adjusters being eliminated. (N.T. 211-13 (Rabinow).)

The products of this reaction are water and sodium citrate, both of which are ingredients listed in the asserted claims (either verbatim or contained within the term “citrate buffer”). (See N.T. 140-43.) While neither party requested construction of whether the claimed ingredients must be

5 I also note that Azurity’s argument that the effect of an unlisted ingredient is not “material” so long as all other claim limitations are met would make the “consisting essentially of” limitation superfluous. present before or after mixing, claims to a mixture ordinarily go to “a composition that contains the specified ingredients at any time from the moment the ingredients are mixed together.” Mars, Inc. v. H.J. Heinz Co., L.P., 377 F.3d 1369, 1374 (Fed. Cir. 2004) (emphasis deleted). Therefore,

the fact that sodium hydroxide is an unlisted ingredient does not preclude infringement provided that the mixture ultimately contains only listed ingredients, and I accept Dr. Little’s explanation that it does. For that reason, Azurity has proven by a preponderance of the evidence that the “consistingessentiallyof”limitationismet. 2. BufferConcentration

All asserted claims require that a buffer be present in a certain concentration, such as “wherein the buffer concentration is about 5 mM to about 20 mM.” (’621 patent, Claim 4 (in- dependent claim inserted).) Alkem argues that Azurity has not proven that the ANDA contains a buffer in the same concentration. Specifically, Alkem characterizes Dr. Little’s testimony that the pH adjuster sodium hydroxide reacts with citric acid to form sodium citrate as suggesting that adding pH adjusters alters the buffer concentration, a detail that Azurity’s infringement testimony

does not account for. As before, I will analyze the issue under the assumption that pH adjusters will be added to every batch because Azurity has not proven that Alkem would likely market a batchwithoutthem. IcreditDr.Little’stestimonythatthebufferconcentrationinAlkem’sANDAcanbedeter- minedbycalculatingtheamountsofcitricacidandsodiumcitrateandaddingthosetwoquantities together. (See N.T. 117 (“[Y]ou do this calculation and add them together” to obtain “the total

of the buffer concentration ... .”).) I also find convincing Dr. Little’s explanation that when this calculationisperformedforAlkem’sANDA,theresultiswithinthelimitationrecitedintheclaim. Basedonthesefacts,Iconcludethattheassertedbufferconcentrationlimitationsaremet. Alkem asks me to not accept Dr. Little’s calculation because he also testified that added sodium hydroxide reacts with citric acid to form water and sodium citrate, which Alkem hypoth-

esizes must “grow” the buffer. But no expert testified that this reaction grows the buffer; rather, Alkemasksmetoinferitasamatteroflogic. Acourtmustnot“dr[aw]onitsownknowledge”of technical matters without the aid of expert testimony. See Flash-Control, LLC v. Intel, No. 2020- 2141,2021WL2944592,at*4(Fed.Cir.July14,2021). AndevenifAlkemiscorrectthatadding sodiumhydroxidecouldchangethebufferconcentration,Alkemprovidednoreasontobelievethe effect is so substantial that Dr. Little should have accounted for it. For these reasons, Alkem’s

unsupportedhypothesisthataddingsodiumhydroxide“grows”thebufferdoesnotpersuademeto discreditDr.Little’sotherwiseconvincingcalculationthatthebufferlimitationismet.6 BecauseAzurityhasprovenbyapreponderanceoftheevidencethatAlkem’sANDAmeets allassertedclaimlimitations,IconcludethatAlkem’sANDAinfringesallassertedclaims.

III. OBVIOUSNESS A. FactsRelevanttoObviousness 1. BackgroundonLiquidDosageFormsforDrugs Azurity’sclaimedinventionisaliquiddosageformofenalapril,whichisimportantbecause not all patients can swallow pills. (See N.T. 104 (Little).) The parties’ experts testified to three

6 Inlightofthisdisposition,itisunnecessarytoaddressAzurity’scontentionthatAlkemforfeited itsargumentthattheadditionofpHadjustersaffectsthebufferconcentration. However,Inotethat the issue in dispute is whether Dr. Little’s testimony should be disbelieved because it is internally inconsistent. GiventhatitwasAzurity’sburdentopresentevidenceofinfringementand“credibil- ity is always at issue,” United States v. Green, 617 F.3d 233, 251 (3d Cir. 2010), it is unlikely that AlkemcouldforfeititsrighttopointoutinconsistenciesinDr.Little’stestimony. waysthatliquiddosageformscanbeproduced. Thefirstisbycompounding,inwhichapharmacist crushes a tablet and mixes it with a liquid. (N.T. 69 (Beckloff); N.T. 104 (Little).) Compounding has drawbacks in that it creates risks of contamination and causes variation from pharmacy to

pharmacy. (N.T.105(Little).) Asecondwayisreconstitution,inwhichthedrugissoldasapowder and a pharmacist mixes the powder with a liquid. (N.T. 69 (Beckloff); N.T. 106-07 (Little).) The third way is for the drug itself to be manufactured as a “ready-to-use” (or “RTU”) liquid. (N.T. 107 (Little).) Ready-to-use liquids avoid the contamination issues associated with compounding. (N.T.107(Little).)

2. DrugDevelopmentProcess ThepartiesagreedthataPOSAwouldhaveexperiencedevelopingdrugformulations. (N.T. 110-11, 191.) The process by which drug formulations are developed is relevant to understanding whetherAzurity’sclaimedinventionwouldhavebeenobviousbeforetheprioritydate. When developing a drug formulation, a formulator (someone who develops drug formula- tions)wouldstartwitha“targetproductprofile,”whichdescribesthedesiredcharacteristicsofthe

drug. (N.T. 258-59 (Constantinides); Mosher7 26.) The target product profile includes the dosage form(suchasanoralliquid)andtherequiredstability. (N.T.259.) Before the invention at issue, it was known in the art that stability is a critical part of thedevelopmentofanoralliquid. (N.T.259(Constantinides).) Forexample,aready-to-useliquid needstobestableforatleast12monthstoaccountfordistributiontime. (Mosher63-64.) Theterm “stability” encompasses many different kinds of stability: chemical stability, physical stability,

stabilityoftaste,stabilityofsmell,andothers. (N.T.328.) Thiscaseinvolveschemicalstability. 7 Citationsto“Mosher”refertoDr.Mosher’svideodepositiontranscript. “The chemical stability of many drugs in solution may be improved by maintaining the pH of the solution in a particular range.” (DTX-1118, de Villiers8 at 225; see also Casas9 at 272 (“[S]omeactiveingredients...requireacertainpHrangetoachievemaximumstabilityinaqueous

solution, and in such cases, the pH must be adjusted to the requirements of stability of the prepa- ration.”).) Thus,aformulatordevelopingadrugwoulddeterminehowthedrug’sstabilitydepends onthepHoftheformulation. (N.T.260(Constantinides).) Formulators sometimes measure the stability of a drug for a short time and use that data to predict stability over a longer period, a process called “accelerated” stability testing. (N.T. 553 (Little).) Accelerated stability testing can be an “exploratory tool.” (N.T. 553 (Little).) But

accelerated stability testing is not always predictive of long-term stability because the way a drug degradesintheshort-termcanbedifferentthanthewayitdegradesinthelong-term. (N.T.551-52.) The FDA has published a guidance document, dated November 2003, that “is intended to define what stability data package for a new drug substance or drug product is sufficient for a registration application ... .” (FDA Guidance10 § 1.1.) For drugs intended to be stored in a refrigerator,theFDAGuidancepermitsaregistrationapplicationtouse12monthsofstabilitydata atrefrigeratedtemperatureor6monthsofstabilitydataatanelevatedtemperature. (Id.§2.1.7.2.)

The FDA Guidance defines a “significant change” during testing as, among other things, “[a] 5 percentchangeinassayfrom[thedrug’s]initialvalue.”(Id.§2.2.7.1.)

8 deVilliers,“BuffersandpHAdjustingAgents”(3ded.,J.EThomsoned.2009)(“deVilliers”). 9 PTX-78,Casasetal.,“Physicochemicalstabilityofcaptoprilandenalaprilextemporaneousfor- mulationsforpediatricpatients,”Pharm. Dev. &Tech.,20(3):271-78(Nov.26,2013)(“Casas”). 10DTX-1109, “Guidance for Industry: Q1A(R2) Stability Testing of New Drug Substances and Products,”UnitedStatesFoodandDrugAdministration(“FDAGuidance”). 3. Buffers Buffers are used to maintain pH, and their use was basic knowledge for a POSA as of the prioritydate. (N.T.192(Rabinow);N.T.257(Constantinides).)

Alkem’s expert Dr. Constantinides, Azurity’s employee Dr. Mosher, and the published source de Villiers provided consistent information about how a POSA would choose a buffer for a drug, taking into account information such as the desired pH, among other factors (such as the buffer’s “pKa”). (See Mosher 33-35.) de Villiers suggests buffer types appropriate for specific pH ranges, with a citrate buffer being appropriate for a pH of 2.5 to 6.5. (de Villiers at 225-29.) A formulatorwillalsousuallyhaveexperiencewithmanybuffersystemsandmayrelyonexperience

tochooseone. (Mosher58-59.) Oncethetypeofbufferisselected,theconcentrationofthebufferneedstobechosen. The buffer concentration can be determined using well-known chemical principles such as those de- scribed in the literature. (N.T. 291-94 (Constantinides, citing de Villiers).) The literature includes exampleconcentrationsofcitricacidandsodiumcitratethatcanbeusedtomakeabuffersuitable overapHrangefrom2.5to6.5(deVilliersat228-30.)

4. Enalapril Enalaprilisadrugusedtotreathypertension(highbloodpressure). (N.T.100(Little).) Be- foreenalaprilcanaffectbloodpressure,itmustbeconvertedtoanotherchemicalcalled“enalapri- lat.” (N.T. 100-01 (Little).) But because enalaprilat is not absorbed by the body, the drug that is administered to the patient must be enalapril, which then converts to enalaprilat in the body. (N.T.

103(Little).) Thereactionthatconvertsenalapriltoenalaprilatiscalled“hydrolysis,”and,whenenalapril ismixedwithwater,itcanundergohydrolysisevenwhenitisnotinthehumanbody. (N.T.100-02 (Little).) It was thus known before the present invention that enalapril can degrade in water, a fact relevant to enalapril’s chemical stability. (N.T. 102-03, 454-55 (Little); N.T. 328; Allen11 at

1917-18.) It was also known in the art that the stability of enalapril in water depends strongly on the pH of the solution. (N.T. 202 (Rabinow); Allen at 1917-18; Al-Omari12 at 898.) Thus, a formulator seeking to make an oral liquid formulation of enalapril could increase its stability by usinganappropriatepH.(Allenat1918.) Two prior art sources state that enalapril is most stable when the pH of the solution is

near 3. (Allen at 1917; Sosnowska13 at 322.) These prior-art teachings are important because a centralpointindisputeiswhetheraPOSAwouldhaveknownhowtomakeenalaprilstablebefore Azurity’sinvention.14 The parties’ experts disagreed how easy it would have been before Azurity’s invention to make enalapril stable in water. Alkem’s expert Dr. Constantinides testified that it would have

11DTX-1074, Allen et al., “Stability of alprazolam, chloroquine phosphate, cisapride, enalapril maleate, and hydralazine hydrochloride in extemporaneously compounded oral liquids,” Am. J. Health-Syst. Pharm.,55:1915-1920(Sept.1998)(“Allen”). 12DTX-1144, Al-Omari et al., “Effect of the drug-matrix on the stability of enalapril maleate in tabletformulations,”J.Pharm. Biomed. Anal.,25(5-6),pp.893-902(July2001)(“Al-Omari”). 13DTX-1077, Sosnowska et al., “Stability of extemporaneous enalapril maleate suspensions for pediatric use prepared from commercially available tables,” Acta Poloniae Pharmaceutica-Drug Research,66(3):321-26(2009). 14Azurity argued at trial that one or both of these publications may inaccurately cite enalapril’s stable pH to another source, The Merck Index, An Encyclopedia of Chemicals, Drugs, and Bio- logicals (12th ed.) (the “Merck Index”). In context, it appears that Allen’s citation to the Merck Index corresponds to other information in the same sentence (enalapril’s “pKa values”) and does notinaccuratelycitetheMerckIndexforenalapril’sstablepH.Sosnowska,ontheotherhand,does inaccuratelycitetheMerckIndexforenalapril’sstablepH. been “easy” for a POSA to make enalapril in water 95% stable for 24 months at refrigerated temperature through “routine experimentation” based on what was known in the prior art. (N.T. 315-16.) Azurity’s expert Dr. Little opined that a formulator would not consider stability for 18

months an achievable goal. (N.T. 486, 532.) In Dr. Little’s view, “all of the various things in the formulation” are needed to achieve long-term stability, and, therefore, if a POSA attempted to “optimize”anenalaprilliquidforstability,anyalterationtotheformulationcouldhaveundesirable effects. (N.T. 500, 526-27.) According to Dr. Little, Azurity managed to make enalapril stable in water by finding a “specific combination of things” that avoids “all of the different reactions that couldpotentiallyhappenwith”enalaprilinwater. (N.T.533.)

5. EnalaprilLiquidFormulationsPredatingAzurity’sInvention The priority date of the asserted patents is March 18, 2016. (Revised (8/14/2022) Uncon- testedFacts¶¶15,28.) Priorartpublicationsconsistofthosethatwerepublishedandpubliclyac- cessiblebeforethatdate. SeeVidStreamLLCv.Twitter,Inc.,981F.3d1060,1066(Fed.Cir.2020). LiquiddosageformsofenalaprilhadbeendevelopedpriortoAzurity’sinvention,although

nopriorliquidformofenalaprilmetalllimitationsofanyassertedclaim. (SeeN.T.352(Constan- tinides).) Inparticular,nopriorartpublicationhaddescribedanenalaprilliquidthatwasstablefor 12 months. (See N.T. 352 (Constantinides).) The liquid dosage forms of enalapril that had been developedbeforeAzurity’sinventionaresummarizedbelow. Nahata (June 1998) Nahata describes a study “to determine the stability of enalapril maleate” in various liquids at refrigerated and room temperature.15 (Nahata16 at 1156.) Nahata notesthatthisworkwasundertakenbecausetherewas“limiteddataonthestabilityofenalaprilin

extemporaneously prepared oral liquids” and, in particular, “no known stability data for enalapril inreadilyavailablevehicles....”(Id.at1155-56.) Nahata studiedenalapril in: (1) water, (2) acitrate buffer solution, and(3) a mixtureof the commerciallyavailableliquidsOra-PlusandOra-Sweet. ThepHsoftheseliquidsare,respectively, 7.1, 5.1, and 4.7. (Nahata at 1156.) pH is important to the obviousness analysis because enalapril was reported to be more stable at some pHs than others. As noted above, enalapril was known

to be most stable at a pH near 3, and Nahata’s Ora-Plus and Ora-Sweet mixture is closest to this value. Nahata reports data on the stability of the three studied enalapril liquids. Nahata evaluates stability by measuring how much enalapril remains in the liquid over time. The data for the Ora- Plus and Ora-Sweet mixture at refrigerated temperature start at 100.0 plus-or-minus 3.6% at the beginningofthestudyandendat95.8plus-or-minus5.9%after90days,withavisibledownward trendinbetween. (Nahataat1156.)

Allen (Sept. 1998) Allen reports on a study of liquid forms of various drugs, including enalapril. Like Nahata, Allen studied enalapril in three different liquids: (1) a mixture of Ora- Sweet and Ora-Plus, (2) a mixture of Ora-Sweet SF and Ora-Plus, and (3) cherry syrup. The pHs of these liquids are 4.7-4.8, 4.7-4.8 again, and 3.9. As noted, Allen states that enalapril is most

15Refrigeratedtemperatureis5plus-or-minus3°C.(N.T.548(Little).) 16DTX-1078, Nahata et al., “Stability of enalapril maleate in three extemporaneously prepared oralliquids,”Am.J.Health-Sys. Pharm.,55:1155-57(June1,1998)(“Nahata”). stable at a pH near 3, and the pH of the cherry syrup liquid is closest to this value. (Allen17 at 1918.) Allentestedthestabilityofthosethreeenalaprilliquidsandreportstheresultingdata. The

study runs for a period of 60 days. Some of the tests are done at refrigerated temperature. The reportedstabilitynumbersforthecherrysyrupliquidatrefrigeratedtemperaturestartat97.2plus- or-minus1.0%andendat97.0plus-or-minus1.1%. (Allenat1918.) Allen also discusses prior work on the stability of enalapril and notes that a prior study found that enalapril liquids with pHs of “2 and 5 were stable for 262 and 114 days, respectively,” at room temperature. (Allen at 1917-18.) Another study mentioned by Allen found that enalapril

in a citrate buffer with a pH of 5 was stable for 90 days at refrigerated temperature but not as stable at room temperature. (Id. at 1918.) Regarding those prior studies, Allen observes that “[t]hose liquids were buffered to a pH that was 2 units less acidic than the pH at which the drug has maximum stability.” (Id. at 1918.) In contrast to those studies, Allen’s enalapril liquids use pHs “somewhat closer to the pH for maximum stability”—i.e., 3. (Id. at 1918-19.) Thus, Allen provides evidence that as early as 1998, it was known in the art that a formulator seeking to make anenalaprilliquidshoulduseapHnear3toachievethegreateststability.

Al-Omari (2001) Al-Omari’s study provides no information about long-term stable liq- uids but was offered by Alkem to demonstrate the importance of pH in making enalapril stable. Al-Omari’s primary aim was to study the stability of enalapril in tablets, but Al-Omari’s publica-

17DTX-1074, Allen et al., “Stability of alprazolam, chloroquine phosphate, cisapride, enalapril maleate, and hydralazine hydrochloride in extemporaneously compounded oral liquids,” Am. J. Health-Syst. Pharm.,55:1915-1920(Sept.1998)(“Allen”). tion contains information about enalapril liquids as well. (Al-Omari18 at 893.) Al-Omari studied enalapril liquids with pHs of 10.5, 7.0, 5.5, 3.4, and 2.2. Stability data for each of these liquids are presented in a graph showing how fast each liquid degraded over time. This data was col-

lectedat80°Cforunder140hours(thatis,substantiallywarmerthanrefrigeratedtemperatureand substantiallyshorterthanoneyear). (Al-Omariat898.) Al-Omari’s graph shows that the enalapril liquid with a pH of 3.4 degraded the slowest among the liquids tested. The liquid with a pH of 2.2 was the next slowest. (Al-Omari at 898; N.T. 196-97 (Rabinow).) Al-Omari concludes from these data that “the rate of enalapril loss is dependentuponthesolutionpHanditisobviousthatthedegradationatpH10.5ismoresignificant

thanthatatlowerpHvalues.”(Al-Omariat898.) Al-Omarialsonotesthatapriorstudyhadfound thattherateatwhichenalaprildegrades“depend[ed]upon[the]pHofthesolution[.]”(Id.at894.) Alkem thus offers Al-Omari to support its expert Dr. Rabinow’s opinion that pH was known to be the“dominant”driverofthestabilityofenalapril. (N.T.195-97,202(Rabinow).)19 Sosnowska (2009) The purpose of Sosnowska’s study was to examine enalapril liquids

“prepared from commercially available tablets” by compounding. (Sosnowska at 321 (abstract).) According to Sosnowska, “[i]t is important that the drug should be stable in the vehicle for the proposeddurationofstorageandadministrationoftheproduct.”(Id.at321.)

18DTX-1144, Al-Omari et al., “Effect of the drug-matrix on the stability of enalapril maleate in tabletformulations,”J.Pharm. Biomed. Anal.,25(5-6),pp.893-902(July2001)(“Al-Omari”). 19Attrial,AzuritypointedoutthatAl-Omari’sgraphispoorlylabeledandobscurestheexactrate at which each studied liquid degraded. (Al-Omari at 898.) Although Alkem’s expert Dr. Rabinow relied on Al-Omari for its teaching about the relationship between pH and stability, Dr. Rabi- now conceded that Al-Omari’s poorly labeled graph was a “mistake.” (N.T. 214 (Rabinow).) But Dr. Rabinow pointed out that, even though the exact rate at which each liquid degraded is unclear, he could tell that some of the liquids degraded at least “tenfold ..., perhaps more.” (See N.T. 214-15(Rabinow).) SosnowskastudiedenalaprilliquidsthatallhadapHof3—thevalueSosnowskaandAllen give for the pH at which enalapril is most stable. Sosnowska’s liquids used citric acid as a buffer to maintain this pH. (Sosnowska at 322.) Stability data for Sosnowska’s enalapril liquids are

reported. Sosnowska tested these liquids for 30 days, some at refrigerated temperature. (Id. at 322.) The average stability after 30 days was at least 98% under all studied conditions. (Id. at 322.) Casas(Nov.2013) Casas’sobjectivewastodevelopenalaprilliquidsthatcouldbemade by compounding and administered to children. (Casas20 at 271.) To achieve that objective, Casas

prepared solutions of enalapril in water and measured the stability of these solutions at various temperatures. The solutions had pHs in the range of 2.55 to 2.78. (Id. at 275.) According to Casas, these liquids are ones that “a Pharmacist could easily prepare with available and low cost materials....”(Id.at272.) Casasalsostatesthatparabenpreservativesshouldnotbeusedinthese formulations because parabens can cause allergic reactions, especially in infants, newborns, and toddlers. (Id.at272.)

Casas presents data on the stability of the studied liquids in a graph. At refrigerated tem- perature,thegraphshowsnovisiblechangeintheamountofenalaprilremainingoverthe50days of study. (Casas at 278.) But Casas also states, without corresponding data or points on the graph, that “[a]fter 3 months of study, at the three temperatures studied drug content of [the formulation] decreasedby40%.”(Id.at277.)

20PTX-78,Casasetal.,“Physicochemicalstabilityofcaptoprilandenalaprilextemporaneousfor- mulationsforpediatricpatients,”Pharm. Dev. &Tech.,20(3):271-78(Nov.26,2013)(“Casas”). The Epaned Kit and the ’747 Patent (Oct. 2013) The next prior liquid formulation of enalapril is Azurity’s own “Epaned Kit” product. Prior to inventing a ready-to-use enalapril liquid, Azurity marketed the Epaned Kit, which consisted of an enalapril powder and a liquid (the

“diluent”)thatcouldbecombinedtomakeanenalaprilliquid. (N.T.64-65(Beckloff).) Azurity’s patent related to the Epaned Kit is U.S. Patent No. 8,568,747 (the ’747 patent), which was published on October 29, 2013, and claims enalapril powders that are reconstituted into oral liquids. (See DTX-1094, ’747 patent, claim 1.) The ’747 patent states that some of the describedliquidsare“stable”for36weeksat“refrigeratedandambientconditions.”Thepatentde- fines“stable”as“havingatleastabout90%enalapriland5%orlesstotalimpuritiesorsubstances

at the end of a given storage period.” (Id., col. 13:5-33.) The ’747 patent reports stability data for some example reconstituted liquids measured over 12 weeks, including some tests at refrigerated temperatures. The data at refrigerated temperature consistently show at least 95% of the enalapril remainingoverthe12weeksofstudy. (Id.,col.23.) Relevant to some of the specific ingredients recited in the asserted claims, the ’747 patent includes example liquids in which the concentration of enalapril is 1.0 mg/mL and describes the use of paraben preservatives with an enalapril liquid that is described as “stable.” (’747 patent,

cols. 5:28-32, 7:51-59, 22:59.) It also describes the use of sweeteners in these enalapril liquids, includingsucraloseandxylitol. (Id.,cols.7:60-8:37.) KitInsert(2014) Azurity’sprescribingliteraturefortheEpanedKitincludedadocument the parties referred to as the “Epaned Kit Insert,” which is dated September 2014. (DTX-1073.) The Kit Insert contains information about the composition of the powder and liquid used to make

the Kit. It states that the Epaned Kit uses Ora-Sweet SF as the liquid, which contains citric acid andsodiumcitratethataredescribedasa“buffer[].”(KitInsert§11.) ItalsostatesthatOra-Sweet SF contains methylparaben and propyl paraben and gives the amounts of these ingredients. (Id.) Dr. Constantinides testified that the amount of preservative stated in the Kit Insert is very close to

theconcentrationofpreservativerecitedintheassertedclaims. (N.T.301-02(Constantinides).) TheKitInsertfurtherstatesthattheKitpowdercontainsmannitol,afactAzurityofferedin an effort to show that an enalapril liquid made without mannitol (as some asserted claims require) would not have been obvious. Mannitol is a “bulking agent” used in powders. (N.T. 265, 306 (Constantinides).) According to Alkem’s expert Dr. Constantinides, a POSA attempting to make a long-term stable solution of enalapril in water would not try adding mannitol because it is not

needed. (N.T. 265.) Azurity’s expert Dr. Little disagreed and stated that mannitol has uses in liquid formulations, including as a sweetener and as a “tonicity agent.” (N.T. 492-93.) Dr. Little alsotestifiedthatmannitolcanbeusedasa“stabilizingagent.”(N.T.492.) 6. IssueswithPrescribingEnalapriltoChildrenBeforethePresentInvention Azurity presented evidence that before the Epaned Kit became available, physicians pre-

scribingenalapriltochildrenwouldusecompounding,apracticewithnumerousdrawbacks. Azu- rity also attempted to show that there were drawbacks to using its own Epaned Kit product, al- thoughforthereasonsexplainedbelow,thattestimonywaslargelyspeculative. As of 2014, enalapril was the only anti-hypertensive drug that was usable by a broad age range of patients. (N.T. 403-04 (Mahan).) Given the lack of alternatives, Azurity’s expert Dr. Ma- han prescribed enalapril to children before there was a liquid form available, coming up with

work-arounds when patients could not swallow pills. (N.T. 404-05.) As described above, some of thesework-arounds,suchascompounding,createdsafetyrisks. Azurity’s Epaned Kit was an improvement over compounding, leading Dr. Mahan to use the Kit over compounding. (N.T. 422-23.) The Kit became available in 2013 and was safe and effective. (N.T. 439 (Mahan).) Even with the Kit, Dr. Mahan was still concerned that pharmacies

might make mistakes because many steps were involved in reconstitution. Dr. Mahan sometimes suspected that pharmacies made errors with reconstitution. (N.T. 423-25.) Azurity’s head of re- search and development Mr. Beckloff also testified that he believed pharmacy technicians some- times made errors with the Kit, including using the wrong diluent, poking a pen through the seal, andcausingcontaminationwithfibersfromthepharmacist’ssweater. (N.T.65-66.) ButDr.Mahancouldnotidentifyaspecificinstanceinwhichapharmacyreconstitutedthe

Kitincorrectly. Hehadonlyheard“stories.”(N.T.440-43.) Mr.Becklofftestifiedthatanerrorthat resultedinaliquidofthewrongconcentrationwouldhave“safetyimplications,”butdidnottestify thatanysucherroroccurred. (N.T.66.) B. Discussion—Obviousness

“A patent for a claimed invention may not be obtained ... if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.” 35 U.S.C. § 103. The accused infringer bears the burden of proving invalidity by clear and convincing evidence. Microsoft Corp. v. i4i Ltd. Partnership, 564 U.S. 91, 95 (2011). The obviousness inquiry is “flexible” and “functional.” KSR Int’l Co. v. Teleflex Inc. 550 U.S. 398, 415 (2007). “[A] court can take account of the

inferences and creative steps that a [POSA] would employ.” Id. at 418. But analysis based on hindsight is forbidden. Insite Vision Inc. v. Sandoz, Inc., 783 F.3d 853, 859 (Fed. Cir. 2015). An invention isnot obviousmerely because itis “sufficiently simple to appearobvious to judgesafter the discovery is finally made.” Outside the Box Innovations, LLC v. Travel Caddy, Inc., 695 F.3d 1285,1298(Fed.Cir.2012).

“[A] patent composed of several elements is not proved obvious merely by demonstrat- ing that each of its elements was, independently, known in the prior art.” KSR, 550 U.S. at 418. Rather, it must be shown “by clear and convincing evidence that a skilled artisan would have had reason to combine the teaching of the prior art references to achieve the claimed invention, and that the skilled artisan would have had a reasonable expectation of success from doing so.” In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1068-69

(Fed.Cir.2012). “Inconsideringmotivation...,theproblemexaminedisnotthespecificproblem solvedbytheinvention,”because“[d]efiningtheproblemintermsofitssolutionrevealsimproper hindsight in the selection of the prior art relevant to obviousness.” Insite Vision Inc. v. Sandoz, Inc., 783 F.3d 853, 859 (Fed. Cir. 2015). Rather, motivation must be viewed from the perspective ofthepriorart. Id. “The ultimate judgment of obviousness is a legal determination.” KSR, 550 U.S. at 427. The court must make subsidiary factual findings as to: “(1) the scope and content of the prior art;

(2)thedifferencesbetweentheclaimsandthepriorart;(3)thelevelofordinaryskillintheart;and (4) objective considerations of nonobviousness.” In re Cyclobenzaprine Hydrochloride, 676 F.3d at1068;seealsoGrahamv.JohnDeereCo.,383U.S.1,17(1966);KSR,550U.S.at415. Thepartiesagree thatallingredientsin theassertedclaims,including enalapril itself,were individually known prior to Azurity’s invention, and that it was known that enalapril could be mixed with water to make a liquid dosage form. Azurity also did not seriously challenge Alkem’s

evidence that it was known that enalapril liquids could include buffers, preservatives, sweeteners, and flavors—including the same choices for these ingredients as used in the asserted claims. No- tably,atthetimeoftheinventionatissue,AzurityitselfmarketedtheEpanedKit,whichcontained enalaprilintheclaimedconcentration,acitratebuffer,sweeteners,andparabenpreservatives. (Kit

Label§11.) Itwas,however,alsoundisputedthatthepriorartdidnotdiscloseanyliquidformulationof enalaprilknowntobestableforayearormoreatrefrigeratedtemperature. Thepartiesdisagreeas to whether a POSA would have expected, before Azurity’s invention, that enalapril in water could be as stable as the asserted claims require. The parties also disagree as to whether it would have beenobvioustousetheparticularcombinationofingredientsrecitedintheclaims.

For the reasons discussed below, I find that Alkem has proven by clear and convincing evidence that the asserted claims would have been obvious to a POSA as of March 18, 2016. Alkem’s evidence persuasively established that a POSA would have expected that enalapril could bestableforayearormoreinwateratrefrigeratedtemperature. IalsocreditAlkem’sinterpretation of the prior art that enalapril in water would be most stable if combined with a buffer to keep the pH at “about 3,” a range that includes claimed pHs near 3.3. The remaining ingredients—flavors, sweeteners, and preservatives—were known, and the requirements of a manufactured oral liquid

would provide a motivation to combine these known ingredients into a single product. The result isAzurity’sclaimedinvention. 1. ExpectationofSuccessinDevelopingaLong-TermStableEnalaprilLiquid The heart of the parties’ obviousness dispute is whether a POSA would have reasonably

expected that enalapril in water could be as stable as the claims require—that is, at least 95% stable at refrigerated temperature after 12, 18, or 24 months. To prove that Azurity’s invention wasobvious,Alkemmustestablishthat“a[POSA]wouldhavehadareasonableexpectationthat” attemptingtomakealong-termstableenalaprilliquid“wouldsucceed.”LeoPharmaceuticalProds. v. REA, 726 F.3d 1346, 1357 (Fed. Cir. 2013). For Alkem to meet this burden, “the expectation

of success need only be reasonable, not absolute.” Pfizer, Inc. v. Apotex, Inc, 480 F.3d 1348, 1364 (Fed. Cir. 2007). It is not enough for Alkem to show that it would have been “obvious to try” making a long-term stable enalapril liquid, but, at the same time, “absolute predictability of success is not required.” Id. at 1365. And the fact that any candidate stable enalapril liquid would require “verifi[cation] through testing” does not necessarily mean that a POSA would not reasonablyexpecttheattempttosucceed. Id.at1364.

No prior art reference states either that it was or was not possible to make an enalapril liquid that was 95% stable for 12 to 24 months at refrigerated temperature. The longest examples ofstabilitymentionedinthepriorartarein: (1)the’747patent,whichstatesthatsomeliquidsare 90%stablefor36weeks(252days)atanunspecifiedtemperature;and(2)apriorstudymentioned in Allen, which reportedly produced enalapril liquids stable for 262 days (at an unspecified per- centage)atroomtemperaturedespiteusinganon-optimalpH.(See’747patent,col.13:5-33;Allen at1917-18.) Ontheotherhand,nopriorartreferenceincludesdatashowingthatenalaprilinwater

at refrigerated temperature and a pH near 3 was less than 95% stable for the duration of whatever test was conducted. Thus, prior art publications did not conclusively reveal whether enalapril in wateratapHnear3couldbestablefor12to24months. Azurity interprets this state of the art as teaching that enalapril was generally unstable in water and that long-term stability was out of reach. Azurity’s expert Dr. Little testified that the “breadcrumbs”inthepriorartsuggestinghowtoachievelong-termstabilityweretoothintocreate

alikelihoodofsuccess. (N.T.487-89.) Dr.Littlealsoconsidereditsignificantthatpriorartstudies ofenalaprilusedvariouspHs,somequitedifferentthanAllen’sreportedmoststablepHof3. (N.T. 488.) Alkem responds that a POSA would have expected that enalapril could be stable in water.

Alkem’s counsel acknowledged that the prior art did not provide a “direct road map” for making enalapril stable, but Alkem’s expert Dr. Constantinides testified that it would be an “easy task” to makeanenalaprilliquidstablefor18or24monthsbasedonknowledgeinthepriorart. (N.T.320 (counsel); N.T. 316, 371 (Constantinides).) Specifically, Dr. Constantinides testified that a POSA would be motivated to optimize the stability of an enalapril liquid to 12, 18, preferably 24 months and would have known how to do so, making such level of stability expected. (N.T. 308, 321-22,

355(Constantinides).) The parties agree on the contents of the prior art but disagree as to how a POSA would interpret statements in those publications. First, the parties disagree how a POSA would interpret positive statements expressing that enalapril could be stable in water. For example, Allen shows high stability at a pH of 3.9 over 60 days at refrigerated temperature and concludes that these liq- uids “were stable” for the duration of the test; Sosnowska shows enalapril liquids with a pH of 3 that are at least 98% stable over 30 days at refrigerated temperature; Nahata shows an enalapril

liquid with a pH of 4.7 having 95.8% of the enalapril remaining after 91 days and concludes that “enalapril maleate is stable in widely available vehicles”; Casas shows a graph with no visible changeinenalaprilconcentrationatpHsof2.55to2.78over50daysrefrigeratedtemperature(al- though Casas mentions, without data, significant degradation after 90 days); and the specification of the ’747 patent states that liquid formulations exist that are 90% stable for 36 weeks (which is 252daysor69%ofayear).

Dr. Constantinides opined that these studies would have given a POSA confidence that long-term stability was possible. (See N.T. 382-84.) I find his opinion convincing. The stability of enalapril had been investigated numerous times and was always found to be sufficiently stable for the application at hand. And, with the exception of one sentence unaccompanied by data in

Casas, no study had shown any substantial degradation of enalapril in water at a pH near 3 and refrigeratedtemperature. ContrarytoAzurity’sinterpretation,thepriorartsimplydoesnotconvey animpressionthatenalaprilisgenerallyunstableinwater.21 Azurity advocates that an expectation of success has not been proven on several grounds. First,AzuritynotesthatDr.Littletestifiedthatextrapolatingfromprior-artdatatothehighlevelof stability required by the claims (95% at12, 18, or 24 months) was too speculative to give a POSA

hope that the high level of stability required by the claims could be achieved. But Dr. Little’s opinion placed too much emphasis on studies of enalapril under conditions that were known not to be ideal. Such studies show only that some prior researchers who were not trying to achieve long-term stability made formulations that were not long-term stable, not that long-term stability wasdifficulttoachieve. For example, prior-art publications that studied the feasibility of compounding used com- merciallyavailableliquidstoevaluatewhetheranenalaprilmixturemadefromthoseliquidscould

21Alkem also asks me to consider the fact that formulators commonly use accelerated stability testing, in which degradation is measured at elevated temperatures. I agree with Alkem that this fact is relevant, but will give it less weight because no expert clarified how far the stability data in the prior art could be extrapolated. Alkem attempted to elicit this testimony from Dr. Constan- tinides, but it was objected to on the ground that it went outside the scope of his report, and the question was withdrawn. (N.T. 271-76.) I also place little weight on Alkem’s reference to the sta- bility of enalapril powders described in the ’747 patent because I credit Dr. Little’s testimony that enalaprilwasknowntoreactwithwaterandaPOSAwouldnotviewthestabilityofenalaprilpow- derasindicativeofitsstabilityinwater. Nevertheless,forthereasonsstatedabove,Iamultimately persuaded by Dr. Constantinides’s view that the prior art would have conferred an expectation of successthatenalaprilcouldbelong-termstableinwater. be left on the shelf, unrefrigerated, for short periods of time. (E.g., Casas at 272 (developing an enalapril liquid that “a Pharmacist could easily prepare with available and low cost materials”); Allenat1918(usingOra-Sweetandcherrysyrup);Sosnowskaat321(using“commerciallyavail-

able tablets”); Nahata at 1155-56 (using “readily available vehicles”); N.T. 558 (Little) (prior art studies were not trying to achieve long-term stability); N.T. 373-74 (Constantinides) (Nahata was using“commerciallyavailablevehicles”).) Allenitselfmakesthepointthatpriorstudiesthatused a pH of 5 rather than 3 may not be indicative of the stability that could be achieved at a pH closer to 3. (Allen at 1918.) I find that a POSA would not be dissuaded by these studies from believing thatlong-termstabilitywasachievable.

AzurityalsopointstoasentenceinCasasstatingthat“[a]fter3monthsofstudy,atthethree temperaturesstudieddrugcontentof[theformulation]decreasedby40%.”(Casasat277.) Azurity notes that although Casas was studying compounded liquids, it included liquids with pHs of 2.78 (which Dr. Constantinides testified was “about 3”) that were stored at refrigerated temperatures. I agree with Azurity that Casas could suggest to a POSA that it was possible to make an enalapril liquid that was not stable in water at refrigerated temperature for more than 90 days even if a pH near 3 were used. Dr. Constantinides also acknowledged that the stability data presented in Casas

is not predictive of 12 months of stability. (N.T. 347-48.) However, in the context of the other prior art, I conclude that Casas would not dissuade a POSA or teach away from expecting success in making a long-term stable enalapril liquid. Notably, the ’747 patent mentions that some liquids created by mixing enalapril in Ora-Sweet SF remain at least 90% stable after 252 days. (’747 patent, cols. 13:5-33.) Thus, a POSA could interpret Casas’s mention of 40% degradation after 90 days not as the inevitable result of putting enalapril in water but as only the result of “[that]

particular study.” (See N.T. 347 (Constantinides).) And, moreover, Casas was not attempting to achieve long-term stability, Casas’s graph contains no data beyond 60 days, and Casas discarded testformulationsafter30daysduetomicrobialcontamination. (Casasat275.) I also find that Dr. Little’s testimony overemphasized the way prior art references defined

“stable”ratherthanthelevelofstabilitythatwasactuallyachieved. Forexample,Dr.Littleopined thataPOSAwouldnotexpectthat95%stabilitywasachievablebecauseSosnowskadefined“sta- ble” as at least 90% enalapril remaining, even though the data in Sosnowska showed that the averageamountofenalaprilremainingattheendofthetestperiodwasatleast98%. (N.T.517-18; Sosnowska at 322.) Similarly, the fact that prior-art researchers collected data for less than a year reflects the requirements of compounding and does not convey the researchers’ view that the drug

would become unstable after the testing period. (E.g., Nahata at 1157 (concluding that enalapril “isstable”basedonshort-termstudies).) Throughouttrial,Azuritypointedtothe60-dayshelflifeofitsEpanedKitasevidencethat the two-year stability of the present invention was a dramatic improvement. (E.g., N.T. 64-65, 74 (Beckloff).) But the present invention claims stability at refrigerated temperature, not room tem- perature. No witness testified how long the Kit liquid would be stable if it were kept refrigerated. And Azurity’s ready-to-use Epaned product also has a shelf-life of 60 days when not refrigerated,

the same as the Kit. (N.T. 74 (Beckloff).) The comparison Azurity attempts to draw between the presentinventionandtheEpanedKitisthereforeuninformative. AzurityalsodirectsmetoFDAguidancestatingthata“registrationapplication”submitted to that Agency should contain stability data spanning at least 6, and preferably 12 months. (FDA Guidance §§ 1.1 (scope), 2.2.7.) I do not find the FDA’s guidance informative on the question beforeme. Therigoroftestingneededtoapproveaproductisnaturallygreaterthanthatneededto

confer an expectation of success, which “need only be reasonable, not absolute.” Pfizer v. Apotex, 480F.3dat1364. For these reasons, I find that Alkem has proven by clear and convincing evidence that the prior art would have led a POSA to expect success in making a long-term stable enalapril liquid.

The prior art did not show that enalapril’s long-term stability in water was guaranteed, or that it would necessarily be stable for any particular length of time or meet any particular threshold. But thepriorartdidconferareasonableexpectationthatmixingenalaprilwithwaterandadjustingthe pHtoabout3couldresultinadrugthatwashighlystableforalongperiodoftime. 2. MotivationtoMakeanEnalaprilLiquidLong-TermStable

Alkem must also prove that a POSA would be motivated to make an enalapril liquid as stable as the claims require. Motivation “may be found in many different places and forms.” PAR Pharmaceutical,Inc.v.TWIPharmaceuticals,Inc.,773F.3d1186,1197(Fed.Cir.2014). It“does not have to be explicitly stated in the prior art, and can be supported by testimony of an expert witnessregardingknowledgeofapersonofskillintheartatthetimeofinvention.”Id. I conclude that a POSA would know that it was necessary to make an enalapril liquid with

long-termstabilityduetotherequirementsofdistributiontimeandtheFDA’srequirementsregard- ing shelf-life. (See, e.g., N.T. 63-64 (Beckloff); N.T. 316 (Constantinides); Sosnowska at 321 (“It is important that the drug should be stable in the vehicle for the proposed duration of storage and administration of the product.”).) Dr. Constantinides also credibly testified that a formulator mak- ing a ready-to-use liquid would want it to be as stable as the product already on the market—the Kit—which was 24 months. (N.T. 379.) The FDA’s guidance provides a motivation to measure

stability with a 95% threshold because it defines a “significant change” as, among other things, “[a] 5 percent change in assay from [the drug’s] initial value.” (FDA Guidance § 2.2.7.1.) Thus, a POSAwouldhavebeenmotivatedtomakeanenalaprilformulationasstableastheclaimsrequire. AzuritypositsthatoncetheEpanedKitbecameavailable,therewasnolongeramotivation to make enalapril stable enough to be used as a ready-to-use liquid. But Alkem does not need to

showthataready-to-useliquidwasabetterwaytomakealiquiddosageformofenalaprilthanthe Epaned Kit, just that it was a “suitable” way “from which the prior art did not teach away.” PAR Pharmaceutical,773F.3dat1197-98. IfindthatAlkemhasmetthatburden. 3. AchievingClaimedStability Alkem must also show that it would have been obvious to a POSA “how” to make

an enalapril liquid as stable as the claims require. See In re O’Farrell, 853 F.2d 894, 903 (Fed.Cir.1988)(inventionnotobviouswherepriorartdidnotteach“howtoachieveit”). I disagree with Alkem that the stability limitations would have been obvious through the doctrine of “inherency,” which renders a claim limitation obvious if it is “the natural result of the combination of elements explicitly disclosed by the prior art.” PAR Pharmaceutical, 773 F.3d at 1196. No evidence was offered at trial that the claimed stability was a “property[] inherently

possessed” by any formulation made prior to Azurity’s invention. Persion Pharmaceuticals LLC v. Alvogen Malta Operations Ltd., 945 F.3d 1184, 1190 (Fed. Cir. 2019). Alkem also failed to establishthatstabilityis“necessarilypresent”inthecombinationofclaimedingredients. SeeInre Kubin,561F.3d1351,1357(Fed.Cir.2009). ButIagreewithAlkemthattheclaimedstabilitywouldhavebeenobviousbecauseaPOSA wouldhaveknownhowtoachieveitthrough“routineapplicationofawell-knownproblem-solving

strategy.” Pfizer v. Apotex, 480 F.3d at 1368 (quotation marks omitted); see also Jerry Harvey 809 F. App’x 919, 922-23 (Fed. Cir. 2020) (finding obviousness where there was a motivation to achieve the claimed result, an expectation of success in doing so, and capability to achieve it through routine experimentation). A formulator would have been immediately guided to focus on adjusting a single variable, the pH. The prior-art literature strongly conveys that pH drives the

stabilityofenalaprilinwateranddoesnotsuggestthatanyothervariableshouldbeadjusted. (Azu- rity’s contention with respect to mannitol is discussed later.) In view of these teachings, I accept Dr. Constantinides’s opinion that this optimization would have been “easy” through “routine ex- perimentation.”(N.T.316,352;seealsoN.T.469(Little)(notingtheeasewithwhichaformulator could make formulations and test them for stability).) The variable was known, the target range (about3)wasknown,andthemethodofadjustingandtestingwasknown. Forexample,Al-Omari

provides a clear template for a POSA to prepare enalapril formulations at a range of pHs within thetargetrangeandtestthestabilityofeachformulation. In addition, a formulator would not have needed to wait years for the experimental formu- lations to degrade; the formulator would have stored the preparations at an elevated temperature and measured the rate of degradation, as in Al-Omari. Azurity criticizes the use of accelerated stability studies, but those criticisms are unavailing. Azurity’s first criticism is that accelerated stabilityresultscanbemisleadingbecausedifferentreactionscanoccurintheshortandlongterm,

such that a solution that appears stable short-term can “fall off a cliff” when tested for longer. But the vague suggestion that short-term stability tests can, in theory, be misleading does not in- form whether they would have been misleading for enalapril specifically. Dr. Little did not testify that enalapril degrades differently in the short and long term. Azurity’s second criticism is that short-term stability cannot guarantee long-term stability. For example, the FDA does not accept short-termstabilitytests foruseindemonstrating thataformulationisstable for12months. Buta

POSAwouldnothavetoconcludethatlong-termstabilitywasguaranteedtochooseaformulation forlong-termtesting. Although Azurity makes a principled argument that optimizing pharmaceutical formula- tionscansometimesbeadauntingtaskduetothenumberofvariablespotentiallyinvolved,thefacts

of this case show that optimizing the stability of enalapril in water is a narrower task that does not involvemanyvariables. “[O]bviousnesslaw...recognizesanimportantdistinctionbetweencom- biningknownoptionsintoafinitenumberofidentified,predictablesolutionsandmerelythrowing metaphorical darts at a board in hopes of arriving at a successful result[.]” Leo Pharmaceutical Prods., 726 F.3d at 1357 (citations and quotation marks omitted); see also Adapt Pharma Opera- tions Ltd. v. Teva Pharmaceuticals USA, Inc., 25 F.4th 1354, 1383 (Fed. Cir. 2022) (a “‘general

motivation’ to experiment” does not make an invention obvious). Thus, “the discovery of an op- timum value of a variable in a known process is usually obvious,” in contrast to situations “where there are ‘numerous parameters’ to try.” Pfizer v. Apotex, 480 F.3d at 1368. In addition, a narrow range within which to optimize (a pH of about 3) was known. See In re Cohen, 767 F. App’x 985, 988-89 (Fed. Cir. 2019) (finding optimization within a range known in the prior art to be obvious); In re Peterson 315 F.3d 1325, 1329-30 (Fed. Cir. 2003) (selecting within a range known in the prior art usually obvious). Optimizing a known variable within a known range is a more

straightforwardtaskthantheopen-endedproblemoffindingsomecombinationofingredientsthat achievesstability. Givenalloftheabove,IfindthatAlkemhasprovenbyclearandconvincingevidencethata POSAwouldhavebeenabletomakealiquidformulationthatwaslong-termstableatrefrigerated temperature through routine application of the known method of adjusting the formulation and testingforstability. 4. ChoosingtheClaimedpH Some of the asserted claims require that the formulation have a pH within a certain range. The narrowest of these limitations requires that the pH be “about 3.3.” (E.g., ’621 patent, Claim

7.) Alkemthereforemustprovethattheassertedclaimsremainobviouswhentheselimitationsare included. APOSAseekingtodevelopaliquidformulationofenalaprilwouldreviewpublishedliter- ature and conclude that the pH at which enalapril was most stable in water was about 3. (Mosher 30(discussingliteraturereviewingeneral);N.T.202(Rabinow);N.T.260(Constantinides);Allen at1917-18;Al-Omariat898;Casasat272.) Dr.Constantinides’sopinionthataPOSAwouldview

3.3 as “about 3” is credible in light of Allen’s statement setting the cut-off for stability at about 2 units away from optimal. (See Allen at 1917 (“At a pH >5, the rate of decomposition increases.”); id. at1918 (“Those liquidswere buffered toa pH thatwas 2 unitsless acidic thanthe pH atwhich thedrughasmaximumstability.”).) Azurity criticizes the reported optimal pH based on the fact that two references reporting it—AllenandSosnowska—includeacitationtotheMerckIndex,whichlacksthatinformation. In context,however,itappearsthatAllencitestheMerckIndexonlyforthe“pKa value”ofenalapril.

(See Allen at 1917; Sosnowska at 322; Merck Index at No. 3605.) I conclude that a POSA would notinferfromtheMerckIndexcitationsthatAllenwasincorrectaboutthemaximallystablepH. Azurity also counters that some published studies on enalapril liquids used pHs other than 3. (E.g.,Allenat1918;Nahataat1156.) However,thosesourcesdonotrepresenttheformulations theydescribetobeideal,andseveralstudiesexpresslystatethattheyusedreadilyavailableliquids rather than liquids optimized for stability. (E.g., Casas at 272 (developing an enalapril liquid that

“a Pharmacist could easily prepare with available and low cost materials”); Allen at 1918 (using Ora-Sweet and cherry syrup); Sosnowska at 321 (using “commercially available tablets”); Nahata at 1155-56(using “readilyavailable vehicles”); N.T.559 (Little)(“the priorart do notstate thatin thosepublicationsthegoalwastoachieve”long-termstability);N.T.373(Constantinides)(Nahata

was an “academic investigation”).) A POSA would not read these publications as suggesting that apHotherthanthosenear3shouldbeused. Alkem does not contend that a formulator in 2016 would have known before trying to choose 3.3 from among the pHs that are about 3, but takes the position that a formulator would have “optimized” the formulation to find the right pH—that is, tried different values until stability was achieved. For the reasons stated previously, a POSA would have expected success in opti-

mizing stability through pH adjustment and would have been able to achieve the claimed stability through “ordinary skill and common sense” rather than “innovation.” KSR, 550 U.S. at 402-03. In particular, a POSA would have focused on pH as the variable to adjust and would have known to adjust it within the range of pHs that are about 3, including 3.3. “[D]iscovery of an optimum valueofaresulteffectivevariableinaknownprocessisordinarilywithintheskilloftheart.”Inre Boesch,617F.2d272,276(Fed.Cir.1980). For these reasons, I find that Alkem has proven by clear and convincing evidence that

the pH limitations of the asserted claims would have been obvious in combination with the other limitations. 5. ChoosingtheClaimedIngredients Alkem must also show, by clear and convincing evidence, that the particular formulation

Azurity claimed would have been obvious, including the particular combination of all claimed ingredients. This inquiry “requires assessment of the invention as a whole.” Princeton Biochem- icals, Inc. v. Beckman Coulter, Inc., 411 F.3d 1332, 1337 (Fed. Cir. 2005). “This ‘as a whole’ assessment of the invention requires a showing that an artisan of ordinary skill in the art at the time of invention, confronted by the same problems as the inventor and with no knowledge of the

claimedinvention,wouldhaveselectedthevariouselementsfromthepriorartandcombinedthem intheclaimedmanner.”Id.“[A]patentcomposedofseveralelementsisnotprovedobviousmerely by demonstrating that each of its elements was, independently, known in the prior art.” KSR, 550 U.S.at418. In evaluating whether a POSA would have been motivated to combine ingredients known inthepriorart,Ifindthattheprocessofdrugformulationisinstructive. ThetestimonyofDr.Con-

stantinides, which was consistent with that of Dr. Mosher, was that a formulator begins with the product’s desired characteristics—its “target product profile”—and proceeds by selecting ingredi- entstomeetthatgoal. Thus,theprocessofformulationprovidesamotivationtocombineelements needed to meet the target properties of the drug, such as combining a preservative (needed for a drug stored in a multi-use container) with a sweetener (needed for a drug administered orally to children). This process also provides a motivation to combine these ingredients with the stability andpHlimitations,asaliquidcontainingtheseingredientswouldneedtobestableforthereasons

statedaboveandwouldneedtohaveapHatwhichenalaprilisstable. With that background in mind, I note that it was generally known in the prior art that enalapril could be mixed with water, that those liquids should use pH at which enalapril is stable, that a buffer could be used to maintain the pH, and that enalapril liquids should include sweet- eners and preservatives necessary for liquids that are stored in a bottle and orally administered to children. (See N.T. 259, 288-89, 303 (Constantinides); Mosher 70.) In addition, the particular

choicesofbuffers,sweeteners,andpreservesclaimedwereindividuallyknownand—moreimpor- tantly—known to be usable with enalapril. (See, e.g., Kit Label § 11; ’747 patent, col. 8.) Several ofthemarefoundinAzurity’sownEpanedKit. Thus, a formulator seeking to make a ready-to-use enalapril liquid would know to mix

enalaprilwithwater,includeabuffertokeepitatapHnear3,andaddtheotheringredientsrequired by the target profile of an oral liquid stored in a bottle, including a sweetener like sucralose and a preservativesuchasamixtureofparabens. Thatis,essentially,theentiretyofAzurity’sinvention. While Azurity claims it found a “specific combination of things” that avoids “all of the different reactions that could potentially happen with” enalapril in water, the steps Azurity took to achieve thatgoalwerelargelytotrytheobviouscombinationofingredientsandrealizethattheyworked.

Azuritydisagreeswiththischaracterizationofitsinventionforseveralreasons. First,Azu- rity stresses that it would not have been obvious to take a given enalapril liquid described in the prior art and change its characteristics to match the claimed invention—for example, taking the Epaned Kit and removing mannitol. But the testimony at trial was that drug formulators do not work by taking existing formulations and adding or deleting ingredients. Rather, a formulator would work from a target product profile and add those ingredients required to meet it. (See N.T. 258-59 (Constantinides); Mosher 26.) Dr. Mosher specifically testified that a POSA seeking to

make an enalapril liquid would not start with the commercially available liquid Ora-Sweet and attempt to reverse engineer it because determining the effect of each of its numerous ingredients would be prohibitively complicated. (Mosher 69.) Thus, the fact that a prior art reference used, for example, a different preservative than the claimed one does not make the claimed preservative nonobvious if it would have been obvious to a POSA to use the claimed preservative to meet the targetproductprofile.

Azuritynextarguesthatitsspecificchoicesofclaimedingredientswerenotobvious,either individuallyorincombination. Iaddressthosespecificingredientsbelow. ChoiceandConcentrationofBuffer Thechoiceandconcentrationoftheclaimedbuffer

follow from the known stable pH of enalapril. Relying on de Villiers, a formulator would have selected a buffer made from sodium citrate and citric acid because de Villiers reports that such a buffer can be used at a pH near 3. And de Villiers shows that determining an appropriate buffer concentration for the target pH would have been routine. The need to make the drug stable would haveprovidedamotivationtocombinesuchabufferwiththeotherclaimlimitations.

Preservative and sweetener The need to use a preservative and sweetener follow from the drug’s target product profile as an oral liquid, which also provides the motivation to combine these ingredients with the other claim limitations. Azurity’s choice of preservative (parabens) and sweetener (sucralose) were known and known to work with enalapril. (’747 patent, cols. 5:28-32, 7:51-59, 7:60-8:37, 22:59; Kit Insert § 11; N.T. 301-02 (Constantinides).) To the extent other preservatives and sweeteners were also known to work with enalapril, a claimed design choice

need not “be the best option” to be obvious; it only needs to be “a suitable option from which the priorartdidnotteachaway.”PARPharmaceutical,773F.3dat1197-98. Azurity argues that Casas would dissuade a formulator from using preservatives—and, in particular, paraben preservatives—because it states that some patients (especially children) are allergic to them. But Casas made that statement in the context of compounded liquids with short shelf lives, and indeed some of Casas’s liquids showed “microbial contamination” after just 30

days. (Cases at 275.) By contrast, a drug in a multi-use container needs a preservative. (Mosher 70.) Casas therefore does not teach that preservatives should not be used in a liquid intended for long-term storage. I also note that Azurity does not claim that its invention dealt with the allergy risks of parabens any differently than the prior art; rather, Azurity used a known ingredient with allitsknownadvantagesanddisadvantages. IthereforeconcludethatAlkemhasproventhatAzurity’schoiceofpreservativeandsweet-

ener, and its decision to include a flavoring agent, would have been obvious in combination with theotherclaimlimitations. Absence of Mannitol and Silicon Dioxide Claim 18 of the ’482 patent requires that the invention not contain mannitol. In addition, all claims of the ’621 patent require that the invention not contain unlisted ingredients that “materially affect the basic and novel properties

of the invention,” which potentially excludes mannitol and silicon dioxide. Azurity argues that a POSA would not think it obvious to make a formulation without mannitol because the ’747 patent describes mannitol as a “stabilizing agent.” (See N.T. 492-93 (Little).) The ’747 patent also includes stability data for three liquids reconstituted from powders—one powder made with mannitol, one made with lactose, and the other made with sucrose—and states that the powder madewithmannitolwasmoststable. (’747patent,col.23.)

I find that Azurity’s argument is inconsistent with how a POSA would choose ingredients for a ready-to-use enalapril liquid. A formulator would not start with the formulation described in the ’747 patent and attempt to modify it to achieve long-term stability. (Mosher 69.) Rather, a formulator would start with a target product profile and add those ingredients required to meet it. I credit Dr. Constantinides’s testimony that a formulator working in this way would simply not introducemannitolbecauseitisrarelyusedinliquids. Because I find that a POSA would have no reason to include mannitol in a ready-to-use

enalapril liquid, its absence would have been obvious. To the extent the claims of the ’621 patent alsoexcludesilicondioxide,thesamereasoningapplies.

6. SecondaryConsiderations In determining whether patent claims are obvious, secondary considerations of nonob- viousness must be considered. Fromson v. Advance Offset Plate, Inc., 755 F.2d 1549, 1557 (Fed.Cir.1985). Azurityoffersthree: (1)unexpectedresults,(2)failureofothers,and(3)long-felt butunresolvedneed. Alkem makes a threshold argument that no secondary considerations apply because any such considerations would lack a nexus to the claimed invention. “In order to accord substantial

weight to secondary considerations in an obviousness analysis, the evidence of secondary consid- erations must have a ‘nexus’ to the claims, i.e., there must be a legally and factually sufficient connection between the evidence and the patented invention.” Fox Factory, Inc. v. SRAM, LLC, 944F.3d1366,1373(Fed.Cir.2017)(quotationmarksomitted). “Thepatenteebearstheburdenof showing that a nexus exists.” Id. Alkem argues there is no nexus in this case because Azurity hap- penstomarketacommercialenalaprilproduct—EpanedRTU—thatdoesnotpracticetheasserted

claims. I disagree with Alkem’s nexus argument. The nexus rule is that the evidence of secondary considerationsmustrelatetothe“thepatentedinvention,”notnecessarilytoanyparticularproduct. See Fox Factory, 944 F.3d at 1373. Azurity must show a nexus, but it is a nexus between the evidenceandtheclaims,notbetweentheclaimsandanunrelatedcommercialproduct. Withthatunderstanding,IconsiderAzurity’sevidenceofsecondaryconsiderations.

Unexpected Results “To be particularly probative, evidence of unexpected results must establish that there is a difference between the results obtained and those of the closest prior art, andthatthedifferencewouldnothavebeenexpectedbyoneofordinaryskillintheartatthetime oftheinvention.”Bristol-MeyersSquibbCo.v.TevaPharmaceuticalsUSA,Inc.,752F.3d967,977 (Fed. Cir. 2014). “While a ‘marked superiority’ in an expected property may be enough in some

circumstancestorenderacompoundpatentable,a‘meredifferenceindegree’isinsufficient.”Id. The parties’ experts disagreed as to whether it would have been unexpected as of March 2016 that an enalapril formulation using the claimed ingredients would have been stable, with Dr. Little testifying that the stability was unexpected and Dr. Constantinides testifying that it was not. (N.T. 321-22 (Constantinides); N.T. 534 (Little).) For the reasons discussed previously with respect to expectation of success, it was not unexpected that enalapril would be stable in water at

refrigerated temperature for 24 months. (See, e.g., N.T. 321-22 (Constantinides).) Although the exact stability was not known, published studies suggested it was likely enalapril could be stable long-term. Thissecondaryconsiderationdoesnotapply.22 Failure of Others Evidence that others “tried but failed” to make the claimed invention “isparticularlyprobativeofobviousness.”InreCyclobenzaprineHydrochloride,676F.3dat1082.

Azurity did not offer evidence that anyone tried and failed to make a liquid form of enalapril that was long-term stable. Some prior art references described enalapril liquids that were not long- termstable,but,forthereasonsdiscussedpreviously,noneoftheseauthorsweretryingtoachieve long-termstability. Thissecondaryconsiderationthereforedoesnotapply.

22Alkem asks me to disregard Azurity’s contention of unexpected results because the evidence Azurity used to support this contention before the Patent and Trademark Office (PTO) consisted of formulations that lacked parabens and therefore did not practice the asserted claims. Given my finding that Azurity’s invention was not unexpectedly stable, it is unnecessary to reach Alkem’s alternative argument. However, I note that while Azurity does have to prove that any unexpected results have a nexus to the asserted claims, Alkem has not pointed to any prohibition on using evidencegleanedfromalternativeformulationstosupportthatconclusion. Long-FeltbutUnresolvedNeed “Evidenceofalong-feltbutunresolvedneedcanweigh infavorofthenon-obviousnessofaninventionbecauseitisreasonabletoinfertheneedwouldnot have persisted had the solution been obvious.” Apple Inc. v. Samsung Electronics Co., 839 F.3d

1034,1056(Fed.Cir.2016). Whethertherewasalong-feltbutunresolvedneedistypicallyassessedasofthefilingdate. Procter&GambleCo.v.TevaPharmaceuticalsUSA,Inc.,566F.3d989,998(Fed.Cir.2009). By the filing date here (March 2016), the Epaned Kit was available, and Azurity has not shown that therewasalong-feltbutunresolvedneedforanenalaprilliquidthatwasready-to-useasopposedto apowderkit. TheproblemsDr.MahanattemptedtoidentifywiththeEpanedKitwerespeculative,

ashecouldnotnameasingleinstanceofapharmacyreconstitutingtheKitincorrectly. (N.T.440- 43.) Similarly, Dr. Mahan’s comparison of shelf-life between the Epaned Kit and Epaned RTU is uninformative because it compared the Kit’s unrefrigerated shelf-life after compounding to the RTU’s refrigerated shelf-life from the date of manufacture. (See N.T. 434-36.) For these reasons, Iconcludetheredidnotexistalong-feltbutunresolvedneedforAzurity’sinventionasofitsfiling date. Azurity also argues that because enalapril was administered to children using compound-

ing for so many years, this is evidence that a long-term stable formulation was not obvious, even if compounding had ceased by the time the present invention came about. This evidence consists of Dr. Mahan’s testimony that compounding was routinely used to administer enalapril to chil- dren even though it entailed safety risks. Because the obviousness inquiry must be “expansive and flexible,” KSR, 550 U.S. at 415, I have considered this evidence, but I find it less probative of nonobviousness because it predates the Epaned Kit’s patent and label. Even if Dr. Mahan’s

testimony could show that a long-term stable enalapril liquid was nonobvious prior to the release of the Epaned Kit, his testimony would not rebut evidence that the Epaned Kit made the claimed invention obvious. In particular, Dr. Mahan’s testimony does not overcome Dr. Constantinides’s detailed explanation showing how the composition and stability information disclosed in the ’747

patent made it obvious how to to develop a ready-to-use enalapril liquid. (See N.T. 286-90 (Con- stantinides).)23 7. DeterminationofObviousness For the reasons set out above, and considering that secondary considerations of nonob- viousness are only minimally probative, I find that Alkem has proven by clear and convincing

evidencethattheassertedclaimswouldhavebeenobvioustoaPOSAasofthefilingdate.24

23The need Dr. Mahan identified is also not especially probative of nonobviousness because no testimony was offered tying the lack of a commercially available enalapril liquid to a lack of scientificknow-howformakingone—asopposedtoitbeingunprofitable,burdenedbyregulation, not in demand, or difficult to monetize. (Cf. N.T. 559-60; Casas at 272 (“There are many factors that determine the lack of cost-effectiveness of this market of commercial pediatric oral liquid forms.”).) Azurityhasthusnotshowna“nexus”betweenthelong-feltbutunresolvedneedandthe claimedinvention. FoxFactory,944F.3dat1373. 24Alkem further asks me to defer to the patent examiner’s initial decision to reject the asserted claims for obviousness before ultimately allowing those claims based on evidence that different formulations—ones not using the claimed preservatives—were unexpectedly stable. Azurity ob- jectsbecausethePTO’sreasonsforinitiallydenyingtheassertedclaimsarenotintherecord. “The basis(asopposedtothemereexistence)ofanexaminer’sinitialfindingofprimafacieobviousness of an issued patent is ... at most only one factual consideration that the trial court must consider in context of the totality of the evidence in determining whether the party asserting invalidity has met its statutory burden by clear and convincing evidence.” Pfizer v. Apotex, 480 F.3d at 1360. Alkem’s post-trial brief identifies the examiner’s initial rejection but provides little information about its basis. Because I find that the trial evidence constituted clear and convincing proof of obviousness, I need not consider what additional effect the examiner’s initial rejection might have onthatconclusion. IV. WRITTENDESCRIPTION A. FactsRelevanttoWrittenDescription The shared specification of the ’482 and ’621 patents describes enalapril liquid formula- tions based on their ingredients, pH, stability, and other characteristics. But, although every as-

sertedclaimrequiresthattheliquidcontainapreservativethatisaparabenormixtureofparabens, the patents’ shared specification does not contain a complete example of a liquid that uses only parabens as a preservative. (See N.T. 332-32 (Constantinides); N.T. 543 (Little).) Instead, liq- uids made using paraben preservatives can only be be constructed by combining ingredients from separateplacesinthespecification. First, the specification describes a formulation with all of the claimed ingredients except

forparabenpreservatives: In one aspect, the enalapril oral liquid formulation consists essentially of (i) about 1 mg/mL enalapril maleate; (ii) about 0.70 mg/mL of a sweetener that is sucralose; (iii) a buffer comprising about 1.82 mg/mL citric acid and about 0.15 mg/mL sodium citrate dihydrate; (iv) about 1 of a preservative that is sodium benzoate;(v)aflavoringagent;and(vi)water;whereinthepHoftheformulation is less than about 3.5 adjusted by sodium hydroxide or hydrochloric acid; and whereintheformulationisstableatabout5±3°C.foratleast12months. (Col. 3:39-48.) Second, the specification states that parabens can be used as the preservative, al- thoughitdoesnotsaywhichotheringredientstheseparabensshouldbecombinedwith. (Col. 6:37- 39.) Finally,withregardtothestabilitylimitations,thespecificationstatesthat“[t]heenalapriloral liquid formulations described herein are stable” under various definitions, some of which closely parallel the claim language and some of which are significantly less stringent (e.g., “for at least 1 month”). (Cols. 18:57-63,19:15-20.) Azurity’s expert Dr. Little acknowledged that the specification does not contain “a disclo- sure of a formulation that meets all of the asserted claim limitations” of any asserted claim. (N.T. 543 (Little).) Dr. Little also testified that to find a paraben-containing stable combination from ingredients in the specification, a POSA would “mak[e] ... embodiments which are described in thespecificationandtest[]themforstability.”(N.T.469.)

The specification also contains six sections of “examples” of enalapril liquids identified as A, B, C, D, E, and G. (’621 patent, cols. 32-40.) Examples A though E contain data on the stabilityofthoseliquids. (Seecols.32-39.) Eachexampleliquidcontainsatleastonepreservative that is not a paraben. (Id.; N.T. 332-32 (Constantinides).) Only Examples A and C describe liquids containing parabens, although these liquids also contain other preservatives, as well as other unclaimed ingredients such as mannitol and silicon dioxide. (’621 patent, cols. 32-34; N.T.

331-32 (Constantinides).) The specification contains stability data for these examples, none of which extends beyond 8 weeks of testing, and the specification does not state whether any of the exampleliquidswouldbestablefor12,18,or24months. B. Discussion

A patent must contain a written description that “clearly allow[s] persons of ordinary skill in the art to recognize that the inventor invented what is claimed.” Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (alterations and quotation marks omitted). “Theessenceofthewrittendescriptionrequirementisthatapatentapplicant,aspartofthebargain with the public, must describe his or her invention so that the public will know what it is and that he or she has truly made the claimed invention.” Nuvo Pharmaceuticals (Ireland) Designated Ac- tivity Co. v. Dr. Reddy’s Labs. Inc., 923 F.3d 1368, 1376 (Fed. Cir. 2019). “Requiring a written

description of the invention limits patent protection to those who actually perform the difficult work of ‘invention’—that is, conceive of the complete and final invention with all its claimed limitations—and disclose the fruits of that effort to the public.” Id. Therefore, “a description that merely renders the invention obvious does not satisfy the requirement[.]” Ariad Pharmaceuticals, 598 F.3d at 1351. And “[t]eaching how to make and use an invention does not necessarily satisfy

thewrittendescriptionrequirement.”NuvoPharmaceuticals,923F.3dat1382. “[T]hewrittendescriptionrequirementdoesnotdemandeitherexamplesoranactualreduc- tiontopractice;aconstructivereductiontopracticethatinadefinitewayidentifiestheclaimedin- ventioncansatisfythewrittendescriptionrequirement.”AriadPharmaceuticals,598F.3dat1352. “[W]ritten description is about whether the skilled reader of the patent disclosure can recognize thatwhatwasclaimedcorrespondstowhatwasdescribed;itisnotaboutwhetherthepatenteehas

proven to the skilled reader that the invention works, or how to make it work, which is an enable- ment issue.” Alcon Research Ltd. v. Barr Labs., Inc., 745 F.3d 1180, 1191 (Fed. Cir. 2014). Thus, a lack of empirical data showing that described formulations meet all claim limitations does not meanthattheclaimslackwrittendescription. Seeid. The claims at issue in this case use “functional language” to mark the boundaries of the claimed invention. See Ariad Pharmaceuticals, 598 F.3d at 1349. That is, Azurity does not claim ownership of all enalapril liquids made from water, buffers, sweeteners, and parabens—it only

claims the subset of those liquids that are stable. The need for written description “is especially acute” when functional language is used. Id. In such a case, “the specification must demonstrate thattheapplicanthasmadeagenericinventionthatachievestheclaimedresultanddosobyshow- ing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” Id. The specification can meet this standard by disclosing “either a representative number of species falling within the scope of the genus or structural features common to the members of

the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350. Alkem argues that the specification here does not meet this standard because a POSA reading the specification would not know which enalapril formulations containing parabens are as stableastheassertedclaimsrequire.

For the reasons that follow, I find that all asserted claims lack written description because the specification describes a large variety of ways to combine ingredients but does not say which combinations that use paraben preservatives are stable. That is, if a POSA were to combine ingre- dientsfromthespecification,theywouldnotknowwhethertheywouldhavetheclaimedinvention. Initially, Azurity is correct that aspects of the invention described separately in the specifi- cation can be combined to meet all limitations of the asserted claims. Those are: (1) ingredients

otherthanparabensthatappearincolumn3;(2)parabensthatappearincolumn6;and(3)stability characteristicsthataredescribedincolumn18. Thedifficultyisthatthespecificationdoesnotsay whetheranycombinationinvolvingparabensmeetsthestabilitylimitations. Thespecificationlists many buffers, sweeteners, preservatives, and pHs that can be combined, but is largely silent on howtheseingredientsrelatetostability. AsDr.Littleacknowledged,aPOSAseekingtodetermine which combinations involving parabens are stable would “mak[e] ... embodiments ... and test[] themforstability.”(N.T.469(Little).) Therefore,whileaformulationmeetingallclaimlimitations

could theoretically be constructed by picking and choosing different parts of the specification, “a POSA is deprived of any meaningful guidance into what [formulations] beyond the examples and formulas, if any, would provide the” claimed stability. Idenix Pharmaceuticals LLC v. Gilead Sci- ences Inc., 941 F.3d 1149, 1164 (Fed. Cir. 2019). Because “the claimed invention does not appear in the specification,” the patents’ written description is inadequate. Ariad Pharmaceuticals, 598 F.3dat1348.

Azurity also takes the position that it would have been simple for a POSA to determine experimentally which combinations involving parabens are stable. Azurity’s position is credible in light of my finding that a stable enalapril liquid with a paraben preservative was obvious even before Azurity’s invention. But “a description that merely renders the invention obvious does

not satisfy the written description requirement[.]” Ariad Pharmaceuticals, 598 F.3d at 1351. Be- cause “one could not know which, if any, individual [variants] would yield [the claimed stability] without actually making and testing the variants,” stable variants containing parabens are not ad- equately described. Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1350 (Fed. Cir. 2013). The specification does not need to prove which paraben-containing formulations are stable or provide evidence that they are stable, but it does need to guide a reader to identify

formulations meeting all claim limitations. Ariad Pharmaceuticals, 598 F.3d at 1348. The specifi- cation here does not provide the required guidance regarding which paraben-containing enalapril formulationsarestable. Azurity also references the stability testing data contained in the specification. But this data also fails to provide guidance as to which paraben-preserved formulations are stable. First, no example is preserved using only parabens: each contains at least one preservative that is not a paraben.25 (N.T. 331-34 (Constantinides).) Second, the specification draws no conclusion that

anytestedformulationsarestable. WhileIassume,givenAlkem’sburdenandthelackofcontrary evidence, that these short-term stability tests are valid, the specification does not identify any of

25Azurity points out that the asserted claims of the ’482 patent may be construed to encompass formulations that contain multiple preservatives. But Dr. Little’s concession that the specification does not disclose a formulation meeting all claim limitations implies that these examples differ from the claims. (See N.T. 543 (Little).) In any event, if the specification only describes how to make paraben formulations stable by mixing them with other preservatives, it does not describe formulationsthat(liketheaccusedproductinthiscase)useonlyparabenpreservatives. theseexamplesasastable,paraben-preservedliquid. For the foregoing reasons, I find that Alkem has proven by clear and convincing evidence thattheassertedclaimsareinvalidforlackofwrittendescription.26

V. CONCLUSION Forthereasonssetoutabove,IconcludethatAlkem’sANDAinfringesallassertedclaims. Ialsofindthatthoseclaimsareinvalidforobviousnessandlackofwrittendescription. Anappropriateorderfollows.

26I do not reach Alkem’s alternative argument that the asserted claims lack written description becausethespecificationdoesnotdescribeformulationsusingsingle-parabenpreservatives.