*1 AFFIRMED; ruling as to Hoffmann-La Roche Inc. and Count I is Inc., Genentech, Plaintiffs- II is REVERSED. Count Appellants, SO ORDERED. v. Mylan Inc., Mylan Pharmaceuticals Inc., (formerly Genpharm ULC known Genpharm Inc.), Genpharm, and L.P., Defendants-Appellees. 2013-1128, 2013-1161, Nos. 2013- 1162, 2013-1163, 2013-1164. HOFFMANN-LA ROCHE INC. and Appeals, United States Court
Genentech, Inc., Federal Circuit. Plaintiffs-
Appellants, April 2014. Rehearing* Rehearing
v. En Banc July Denied Apotex Corp., APOTEX INC. Defendants-Appellees.
Hoffmann-La Roche Inc. and
Genentech, Inc., Plaintiffs-
Appellants,
v. Reddy’s Laboratories,
Dr. Ltd. and Dr.
Reddy’s Laboratories, Inc.,
Defendants-Appellees.
Hoffmann-La Roche Inc. and
Genentech, Inc., Plaintiffs-
Appellants,
v. Laboratories, Inc., Actavis, Inc.,
Watson Pharma, Inc.,
Watson Cobalt Pharma Inc.,
ceuticals and Cobalt Laborato
ries, Inc., Defendants-Appellees.
Hoffmann-La Roche Inc. and
Genentech, Inc., Plaintiffs-
Appellants,
v.
Orchid Chemicals & Pharmaceuticals
Ltd., Healthcare, Orchid Orchid Phar Inc., Orgenus
maceuticals Phar Inc., Defendants-Appellees.
ma * Judge Bryson participated petition Circuit rehearing. decision on the
Laboratories, Ltd., al.; J. et William Uter- mohlen, Oliff, A. and John W. James PLC, O’Meara, Berridge, Oliff & of Alex- VA, andria, & Phar- for Orchid Chemicals Ltd., al. Of counsel were maceuticals et Cecchi, Carella, Bain, Byrne, E. James Cecchi, Olstein, Gilfillan, Stewart & of Laboratories, Roseland, NJ, for Watson Calmann, Saiber, Inc., al. Arnold B. et Newark, NJ, Inc., LLC, Mylan for et of Radin, Larner, P.C., al., of Bruce D. Budd Hills, NJ, Reddy’s Laborato- for Dr. Short ries, Ltd., Quinn, Fox et al. and Charles N. Rothschild, LLP, Exton, PA, of for Orchid Ltd., al. & Pharmaceuticals et Chemicals NEWMAN, LOURIE, and Before BRYSON, Judges. Circuit by for the court filed Circuit Opinion Dissenting opinion filed Judge BRYSON. by Judge NEWMAN. Circuit BRYSON, Judge. Circuit Roche, Inc., Hoffmann-La Plaintiff (“Roche”) from the decision of the appeals LLP, Waddell, Loeb of E. Loeb & Mark District for the Dis- States Court United York, NY, argued plaintiffs-appel- for New the defendant Jersey granting trict of New him on the brief were Warren lants. With summary judg- drug companies generic MacRae, Colbath, K and Kath- K. Paula invalidity as to claims 1-8 U.S. ment of leen Gersh. (“the patent”) '634 Patent No. Mazzochi, Rakoczy Molino Deanne M. 7,410,- No. and claims 1-10 of U.S. Patent IL, Siwik, LLP, Chicago, ar- Mazzochi (“the affirm. patent”). '957 We With defendants-appellees. for all gued Rakoczy, her on the brief were William I Hunt, Eric R. for Raghavan, Tara M. are appeal in this Laboratories, Inc., patents issue et al. On the
Watson osteopo- Feldman, treating P. directed to methods E. James brief were Steven monthly adminis- Walsh, through the once White, Philip Segrest, D. rosis Louise T. ibandronate, Rollo, of a class of tration of one Cherry, Sherry L. Daniel R. LLP, IL, bisphosphonates. compounds known Chicago, Blackwell for Husch acid, Ibandronate, of ibandronic Inc., al; Rich- salt Edgar Haug, et H. Apotex Kurz, as Roche’s once Parke, commercially From- available E. and Richard F. ard Boniva®, approved by LLP, which was of New Haug, mer Lawrence & Admin- Inc., al.; Drug Food and York, NY, D. the United States Mylan et Stuart (“FDA”) Larner, in 2005 for the treat- Choi, Budd istration and Michael Sender monthly Bo- Hills, NJ, osteoporosis. Once P.C., Reddy’s Dr. ment Short milligram (“mg”) provides postmenopausal osteopo- niva® or inhibition of pharmaceu- ibandronate. rosis administration of a tically acid, acceptable salt of ibandronic a disease characterized Osteoporosis is comprising: resorption. Resorption, bone abnormal by which bone is biological process (a) commencing the administration of down, causes decreased bone broken *3 pharmaceutically acceptable strength and an increased risk of frac- by orally salt of ibandronic acid Bisphosphonates “potent tures. are inhib- administering postmenopau- to the resorption.” patent, itors of bone '957 col. woman, single day, sal on a a first They 11.39-40. inhibit abnormal bone tablet, in the form of a gradual and destruction enable the resto- comprises wherein the an tablet density ration of lost bone mineral amount of pharmaceutically (“BMD”). acceptable salt of ibandronic acid Bisphosphonates generally are known to equivalent that is to about 150 bioavailability have a low when adminis- acid; of ibandronic i.e., orally, tered a small fraction of a (b) continuing the administration given dose is absorbed into the blood. Ad- orally administering, monthly once ditionally, oral administration of bisphos- day, on a single compris- a tablet phonates esophageal can result adverse pharmaceuti- an amount of the gastrointestinal side effects. As a re- cally acceptable salt of ibandronic improve sult of the side effects and to equivalent acid that is to about bioavailability drug, patients taking of the of ibandronic acid. bisphosphonates must dosing adhere to a regimen requires a bisphosphonate
tablet to be taken in a fasting state at least II eating 30 minutes before drinking. or In generic defendants this case are past, regimen the inconvenience of that drug manufacturers who submitted Abbre- problems patient created compliance. (“ANDAs”) Drug Applications viated New Researchers in the field believed that less- to the FDA for approval engage in the frequent dosing patients would result generic manufacture and sale of versions continuing the treatment the long for of Boniva® expiration to the term, required which is for bisphosphonate patents. Roche’s Roche sued the defen- treatments to be successful. dants in the United States District Court patent Roche owns the '634 and the '957 for the Jersey alleging District New patent, parent which is the of the '634 271(e)(2) infringement § under 35 U.S.C. patent. Claims 1-8 of the patent '634 filings. based on the defendants’ ANDA patent claims 1-10 of the '957 are at issue in this case and describe method of preliminary injunc Roche moved for a treating osteoporosis consisting orally motion, tion. The district court denied the administering about 150 of ibandronic holding that prove Roche had failed to monthly single day. acid once on a Claim likely in defeating succeed the de 1 of the '634 representative of the challenge. fendants’ obviousness This court appeal: claims on affirmed the district court’s denial of the 1. A treating method for or inhibiting preliminary injunction. See Hoffmann-La Inc., Apotex Roche Inc. v. postmenopausal osteoporosis post- in a Fed.Appx. (Fed.Cir.2012). menopausal woman need of treatment on which Roche relied in- that the evidence preliminary of the appeal While that a of skill in the person failed to show pending, the district decision junction expec- art would not have had a reasonable motion granted the defendants’ court patented claims tation that the method would suc- invalidity summary judgment reducing fractures. The court ex- to obviousness ceed patent due 1-8 of the '634 103(a). that a plained “empirical § to the fre- confirmation As under 35 U.S.C. increasing that method for bone mineral densi- dosing, the court found quency of ty strength enough increase bone helps of ibandronate once easily would not art. As to the that bones break less was established appear surprising.” the court to be all that amount combination of several found that the reconsideration, In its motion suggested level of art references improp- had argued that district court month, or at least indi- mg per about 150 erly failed to consider evidence *4 monthly mg of 150 cated that a dose an dose of ibandronate showed try. to obvious unexpected bioavailability level of as com- of lower doses. On the merits pared with Roche’s ev- The district court considered argument, that the district court found of non- objective of considerations idence 150mg dosage that the that the “evidence that “Roche’s but concluded obviousness by body simply was absorbed better does not objective considerations evidence finding the core has no relevance to scintilla, it is of a mere rise to the level 150mg dose the difference between to defeat the motion sum- not sufficient art was and that there prior and the small” In to Roche’s mary judgment.” response of success reasonable monthly mg once argument that the 150 with superior that were gave results daily the court found that timely grants of appealed Roche sup- “pointed Roche had to no evidence summary judgment of obviousness. artisan claim that the skilled port [its] Ill that the 150 surprised
would have been once-monthly superior dose was to the 2.5 The issue in this case is whether con- The court refused to dose.” time of have obvious would been contentions, argument, at oral sider raised a once oral invention to select superior dose had a that the treat of ibandronate to dosing regimen bioavailability, level of because unexpected at 150 osteoporosis and to set in its argument had not raised that Roche opposition brief. Monthly Dosing A. Rule of Civil Proce- Pursuant to Federal 56(f) raised, dosing sched- relatively infrequent 1. A then on its own dure the court potential as a motion, long ule has been viewed summary judgment the issue compli- problem patient solution to the invalidity patent. claims 1-10 of the '957 submissions, stemming from the inconvenience ance considering parties’ After regimens. Fosa- bisphosphonate invalid for the oral the court held those claims max®, product bisphosphonate art applied to the claims of same reasons that Co., was administered by Merck & argued that it was sold patent. the '634 Roche art references weekly, ibandro- and several unexpected that an intermittent of iban- taught once would be effective reduc- regimen nate bisphosphonates. dronate or other But the court concluded ing fractures. First, journal longer than one or two would not be an article trade weeks contention, Update: Bisphospho- support effective. To Lunar News entitled News”) (“Lunar “[re- primarily alleged stated that relies on the fail- nates seeking study solutions for better ure of its intravenous ibandronate searchers are (“Recker”) compliance,” including approaches demonstrate antifracture ef- high potency ficacy quarterly dosing. Secondarily, with bisphosphonates “use yet irritability, as ... ibandro- on a low such Roche relies article (Roche). (“Schnitzer”) agents given speculat- nate Oral could be Thomas Schnitzer (once/month, intermittently example) study the failure of the Recker Second, quite potent.” long a 2001 was due to the dose-free and still be interval. Carey article Krause Chemical Mar- however, study, The Recker showed (“Krause”) Reporter ket disclosed that 26% reduction vertebral fractures with likely approval Roche would seek FDA intravenous ibandronate administered once onee-monthly” an “oral formulation of three months. The was a Finally, United “failure” in the sense that the 26% (“Chen”) No. States Patent dis- statistically insignificant giv- reduction was eoated-dosage bisphos- closed forms of large patients en the number of that would phonic orally acids and methods for admin- required statistically have been to reach a istering those forms. Ibandronic significant conclusion about the relative many acid was identified one of known rates of fractures in the control and sub- *5 bisphosphonic acids. Chen disclosed a ject groups. respect With to the reduction preferred embodiment in which “a dosage fractures, hip of example, Recker con- form of the invention is administered to a that “a meaningful cluded conclusion with patient preferably ... a once month.” Lu- efficacy regard owing to could not be made News, Krause, nar and Chen therefore to the hip low absolute number of frac- specifically taught monthly administra- tures.” generate Recker’s failure to statis- tion of ibandronate. tically significant points results fault
Similarly, art study; contained refer- it does not teach that infre- monthly ences to the oral quent dosing administration of ibandronate is in ineffective bisphosphonates general. in treating osteoporosis. United Application States Patent No.2003/0118634 interpret- art references that (“Schofield”) taught dosing of “bone-active ed Recker’s results demonstrate phosponate[s]” equivalent and referred to why it was unknown Recker was unsuc- doses that “can given every day, be other demonstrating statistically cessful in sig- week, weekly, twice a biweekly or month- efficacy. nificant antifracture Schnitzer ly.” United States Patent No. speculated long that the drug-free interval (“Geddes”) bisphosphonate disclosed a ad- was to blame for the inconclusive results regimen ministration in which “said bis- dosing longer and that intervals than one phosphonate is day administered at least 1 or two weeks would be ineffective. theOn every of thirty(30)-day said peri- treatment hand, by an other article Dr. Dennis Black od.” (“Black”) speculation described argues taught doses used in Recker were too low. In away because, fact, monthly dosing once subsequently Roche itself acknowl- Roche, according to widely it was edged believed that the Recker was under- Thus, bisphos- of the date of invention that a speculation dosed. Schnitzer’s did phonate regimen with a teaching dose-free interval not amount to an affirmative reducing able of success dosing of ibandro- away from fracture risk. nate, face of Black’s com- especially of the Recker results. explanation peting it is true that BMD improvements While perfectly do not correlate with antifracture efficacy of oral Any doubt about the efficacy, it was well established the art may have been dosing ibandronate powerful surrogate that BMD is a speculation put by created Schnitzer’s measuring example, fracture risk. For published to rest an article expert explained: Roche’s own Ibandronate: A Com- Riis et al. entitled density directly Bone mineral is related In- Daily Dosing Versus parison Oral fracture risk. It is one of the most Dosing Postmenopausal Os- termittent surrogate in the field powerful markers (“Riis”). Riis demonstrated teoporosis powerful medicine. It is as an indica- ibandronate is as effec- that “intermittent osteoporosis pressure tor of as blood in terms the continuous treatment tive as every For standard predictor stroke. increasing BMD at significantly in bone mineral den- deviation reduction suppressing markers spine hip sity, fracture risk is doubled. that increas- turnover.” Riis showed bone patents pres- Roche’s do not themselves to those obtained equivalent es in BMD demonstrating ent data antifracture effica- regimen treatment mg per day with a 2.5 In cy for a once regimen with a of 20 were obtained fact, efficacy for Boniva® antifracture every day for the first ibandronate FDA through to the demonstrated period. days three-month “bridging study” that used BMD and bone concluded, results, “confirm[ed] Riis Those turnover results —not antifracture test- showing that it is the total preelinical data noninferi- therapeutic establish the —to period and not the predefined dose over mg monthly dose relative ority of the 150 determining is the regimens approved mg daily previously to the on bone mass and archi- factor for effect efficacy antifracture had for which treatment.” tecture after *6 been demonstrated. teaching that a dose-free interval of Riis’s efficacy proof of is not Conclusive impact did not the more than two months All that is necessary to show obviousness. directly efficacy BMD of ibandronate expectation a reasonable required is contrary speculation to Schnitzer’s Therapeutics, PharmaStem success. See not be dosing regimen such a would effec- ViaCell, Inc., 1342, 1363- Inc. v. 491 F.3d Therefore, if tive. even Schnitzer’s inter- (Fed.Cir.2007); Pfizer, Apotex, Inc. v. 64 study the were pretation of Recker viewed (Fed.Cir.2007). Inc., 480 F.3d 1364 monthly dosing, teaching away from prior art that used along with Riis— un- contrary findings substantially Riis’s efficacy primary as the improvement BMD interpretation. dermined treating osteoporosis marker —estab not overcome argues that Riis did lished at least reasonable interpretation because Riis was monthly dosing Schnitzer’s of ibandronate that once argues successfully osteoporosis an antifracture trial. Roche treat could only on BMD and fracture risk. focusing art reduce instead of on improvements, bone-turnover mg the 150 Dose Selecting B. efficacy, does not bear on the antifracture total-dose con- in because 1. Riis confirmed the analysis this case obviousness efficacy of ibandronate cept whereby “the art not establish a reason- such does given mg weekly corresponds rather The 35 dose to the on the total oral dose depends daily mg Riis there- same total dose as a 5 dose. The than on the schedule.” mg to 5 of ibandro- setting equivalent in total-dose fore teaches only regi- per day ibandronate nate is thus the dose that level for an intermittent men, only up appears sug- scale in both Ravn and one need known- Daifotis — regi- gesting expec- a short-interval that there was a reasonable effective dose from daily dosing ap- equiv- achieve tation of success with the total-dose e.g., —to men — dose, i.e., mg daily mg proximately the same BMD and bone-loss alents of the regimen. per month. efficacy long-interval with a guid- Accordingly, prior art to a provided pointed substantial dose, given monthly total within a treatment of 150 of ibandro- ance as to the least, very period, produce time that would effective nate. At the the 150 dose try: article Ravn et al. was obvious to There was a need to results. A 1996 (“Ravn”) reported problem patient compliance by the results of a solve the looking less-frequent dosing regimens. BMD improvements that measured And, Daifotis, daily light markers for ibandro- based on Ravn and in bone-turnover mg, mg, mg, concept, nate of 0.25 1.0 2.5 of Riis’s total-dose there doses were identified, mg, only predict The authors concluded that a “finite number of Teleflex, bone mass showed able solutions.” KSR Int'l Co. v. “average change 398, 421, regions in all positive outcome 550 U.S. 127 S.Ct. (2007). groups receiving ibandronate 2.5 and 5.0 L.Ed.2d 705 mg.” The 2.5 dose exhibited a re- that findings Roche contends “virtually sponse equal” to the 5 taught away FDA develop- further dose, though even it contained (and ment of mg daily the 5 its total- half the amount of ibandronate. The 2.5 equivalents) ap- because the FDA thereby dose was deemed the “most proved mg daily a 2.5 dose of ibandronate effective dose.” mg daily instead of a 5 But A person looking contrary skilled in the art to FDA never findings made dose, to a mg daily scale dose of oral ibandronate the 5 because it was never Instead, daily from a thus approve known-effective dose was asked to that dose. possibili- faced set of very approving mg daily limited the 2.5 the FDA merely ties: Of the five doses tested restated the results of Ravn and Ravn, only mg daily the 2.5 and 5 doses “showed concluded that “the 2.5 dose of positive regions.” outcome all Even has the most favorable bene- though 5 mg appropriate dose did not demonstrate fit—risk ratio and is the most *7 greater efficacy dose, than mg prevention the 2.5 it dose for the and treatment of still an equivalently postmenopausal osteoporosis.” was deemed effective scaling single dose so someone it to a Roche next contends that Schofield (5 x monthly mg mg/day dose 30 taught away using anything from other days/month) would have anticipated equiv- than a bisphos- the lowest effective dose of raising alent in and limiting success BMD which, Roche, phonate, according to turnover, on bone based Riis. mg established Ravn to be 2.5 for iban- Schofield, however, Additionally, United Patent No. States dronate. does not (“Daifotis”) weekly teach that the dose disclosed dos- lowest effective is the group es of ibandronate “from the consist- dose that should be when used treat- ing mg, mg, mg, mg.” ing osteoporosis bisphosphonate. of 35 or 50 with a First, Instead, merely argues taught defined the low- Roche that Ravn Schofield drug’s away development a a from further dose as measure of the 5 est effective mg daily thereby therapeutic effects. its total-dose potency relative its equivalents, taught because Ravn that the preferred then a em- Schofield described mg 2.5 daily dose was more effective treating bone than bodiment of a method mg daily the 5 dose and had fewer side in which the maintenance dose of disorders Ravn, however, effects. concluded that phosphonate” ranged a from “bone-active “the in responses groups receiving 2.5 day. clearly That mg per range 2.5 to 15 mg and 5 ibandronate virtually were just more than a lowest effec- encompasses equal,” not that the dose was more Moreover, purport- tive dose. Ravn never although patients effective. And on the 5 a ed to establish lowest effective dose. mg daily dropped study dose out of the at Instead, sought to establish a “most higher patients rate than on lower dos- [daily] effective dose.” es, higher Ravn did not conclude that the argues that the district court mis- drop-out statistically significant. rate was interpreted misapplied the total-dose Instead, merely the authors noted that a Roche, According from Riis. concept higher frequency of diarrhea experi- in leap” district court “took a technical enced with the 5 A higher fre- finding concept that Riis’s total-dose im- quency of diarrhea necessarily does not plied only simple multiplication to scale away teach mg daily the 5 dose or daily from an efficacious dose to a however, equivalents, its as the prior art dose. The evidence before the district indicated that gastrointestinal modest side however, court, showed that the total-dose weighed light effects must be concept can be used as an effective rule of Indeed, drug. benefits of the Ravn itself by person thumb skilled in the art decid- present study, concluded that “[i]n to scale to an efficacious intermit- how profile side effect of ibandronate seemed study, tent of ibandronate. The Riis dose general, to be safe” and that “[i]n particular, established that the total safety any evaluation did not reveal differ- reliably concept predict dose can that the placebo ences between ibandronate and efficacy an ibandronate treatment de- groups.” treated pends on the total dose administered to a Moreover, if higher even incidence patient given period, on the over larger drop- diarrhea and the number any amount single point administered initially outs the Ravn were evidence, In light time. of that it was enough away to teach from further devel- expect reasonable to that a once daily total opment of the 5 its would have roughly dose of away equivalents, teaching such efficacy same dose of 5 would have been overcome Riis’s find- of 20 ing that an oral administration Safety of the 150 Dose C. day days, for 24 by a phase, followed nine-week rest result- Roche next contends that there dis- are as a 2.5 ed the same rate side effects puted issues of fact as to whether it would mg daily regimen. have been obvious to administer once *8 Ravn, mg light alleged point doses of 150 in of Aside from Roche does not safety gas- suggesting the to references that there concerns about adverse safety of and were concerns associated with the trointestinal effects ibandronate expert, Roche’s Dr. bisphosphonates. mg 150 dose. Nor was 1334 monthly dose taking mg the 150 taught patients
Harris, anything aware taking year patients after one mg dose of ibandro- and 3.9% monthly, 150 a once study mg daily dose. Another the be unsafe. nate would that the extent in 2005 showed published art estab- contrary, To bioavailability is nonlinear of ibandronate’s mg higher than 150 that doses even lishes Increasing the increasing dosages: Pat- United States safe. were considered mg from 100 to percent, dose 50 (“Mockel”) stated ent No. nearly percent mg, resulted in a formulations rapid-release ibandronate drug ab- in the amount of the increase in ... significant “no side effects showed sorbed the blood. even at using ibandronate clinical studies single-dose dosages” and disclosed high support the evidence would find While expert, mg. to 250 Defendants’ up units efficacy mg the 150 superior Yates, in that the disclosures Dr. testified levels, raising in BMD monthly dose of ordi- person have led a Mockel would dose, compared to a 2.5 in the art to understand that nary skill rebut improved efficacy does not to 250 would be up doses ibandronate showing that the art disclosed strong Likewise, Daifotis dis- well tolerated. monthly dosing and that there was a rea compositions human oral “[f]or closed In re mg. that dose at 150 See son set ... a unit comprising (Fed.Cir. Co., 1091, 1099 Merck & 800 F.2d mg to comprises from about 3.5 typically 1986). superior efficacy The evidence com- of the ibandronate about showing that nothing does to undercut the pound.” of suc there was reasonable dose, if mg monthly with the 150 even cess genuine no issue of fact
There is thus may the level of success have turned out to taught concerning whether the greater somewhat than would have the 150 dose based on be away from expected. safety concerns. been reasons, the nonlinear For the same Unexpected D. Results bioavailability does not re- of ibandronate argues that the district court prima showing but the of obvious- facie by granting summary judgment of erred ness of a once dose of 150 because the evidence of record obviousness bioavailability has The increased level mg monthly showed that the 150 dose responsible not been shown to be for the mg daily effective than the 2.5 dose more efficacy treatment improved osteoporosis superior effectiveness of the and that the A study by of the 150 Ravn et mg monthly unexpected. showed, in that a example, al. Roche also contends that ibandronate’s concen- doubling near blood-serum bioavailability at dos- nonlinear the 150 mg daily a 5 tration of ibandronate with age unexpected level was an result. dose, mg daily to a 2.5 compared increase and no study, published produced no further BMD Roche’s MOBILE Other mg monthly that a 150 further reduction bone turnover. demonstrated confirms that mg daily “[d]ue is more effective than a 2.5 record evidence surface, binding to the bone respect improvement strong to BMD dose with systemically available spine hip the lumbar and most sites. effects demonstrated, bisphosphonate of a are almost MOBILE for exam- amount exclusively related to its concentration ple, improvement a mean BMD than serum level.” spine year [blood] of 4.9% after one for bone rather lumbar *9 regarding bioavailability is did reference or suggest The evidence show the relevance to the obvious- Boniva® combination single therefore of little of a dose and inquiry. ness once-a-month administration. suggested No reference the effectiveness Accordingly, uphold judgment we the safety and of this combination. Nonethe- district court that claims 1-8 of the the less, my colleagues declare this treatment and claims 1-10 of the '957 patent '634 My colleagues’ obvious to them. primary light would have been obvious reason, thirty is the times prior the art and are therefore invalid. mg, dose of 5 does not mention that AFFIRMED. FDA approve refused to the 5 due to its toxic Surely side effects. this NEWMAN, Judge, dissenting. Circuit away leads from the obviousness of a sin- Hoffmann-LaRoche’s once-a-month Bo- gle thirty larger. times osteopo- niva® ibandronate medication for respectfully I dissent. required years rosis twelve of research testing and clinical and evaluation to dem- Discussion efficacy onstrate when dosed once a its unexpected The patented results safety high monthly month and its at this method are conceded panel majori- dosage. prior investigations The of inter- ty. summary The evidence on judgment dosing, publications mittent and the de- many sought was that others and failed to success, scribing protocols of lesser missed find an efficacious intermittent treatment protocol produced this successful prior schedule. The art by my relied on Indeed, art prior weighs method. this colleagues surrounded but missed the obviousness, heavily against despite ex- prior Roche method. The shows exploration, protocol tensive this successful safety likely compromised is to be high was not discovered. doses, efficacy likely and that to be of this patent sup- Invalidation is not compromised at extended intervals. ported by convincing clear and evidence. Nonetheless, this court now holds that ruling The court’s of obviousness violates was obvious to do what no one did or even principles of Graham v. Deere John suggested; my colleagues simply disre- Co., 383 U.S. 86 S.Ct. 15 L.Ed.2d gard preferences toxicity warnings and (1966) (all considered, factors must be procedures and discard the of the success, including commercial failure of art. need). others, long-felt and The court’s The art shows intermittent thera-
reasoning guidance violates the of KSR pies ranging every day to once Inc., 398, 421, Int’l Co. v. 550 U.S. Teleflex a week to twice a week to twice a month to (2007) (the 1727,167 127 S.Ct. L.Ed.2d 705 plus varying three months initial obvious-to-try requires standard a limit- loading range in a periods, dosag- wide specified ed number of alternatives offer- replete warnings es. The art is with light a likelihood of success in toxicity patient noncompliance. sense), prior art and common this court majority acknowledges panel judicial invoking hindsight instead to re- the nonlinear Roche’s MOBILE subject construct patented matter. (discussed bioavailability infra) data dem- many Nowhere amid the studies of bis- onstrate that the 150 treat- results, phosphonate osteoporosis produced unexpected treatments over ment but irrelevant; now, conditions, range dosages a wide deems this the court *10 scriv- success, patent of the expansive statements deems Roche’s knowledge ener. to have been method successful Roche’s along. all
obvious side significant that “no Mockel states in clinical studies effects were observed recognized KSR Supreme Court dosages,” but high at using ibandronate “identify a challenger must that a pre- “high” exceeds his does not state a person prompted that would have reason limit, at that time the upper ferred field” to in the relevant ordinary skill oral single that “[a] FDA had determined invention. U.S. patented the at arrive mg is the maximum tolerable dose of 100 colleagues, 418, My 1727. 127 S.Ct. my ibandronate.” J.A. 8558. Yet dose of of the Roche any suggestion to find unable as ren- rely on this reference colleagues art, accept argu- protocol specific Roche’s once-a- dering obvious single of 150 that a dose ment dosage mg. month of 150 dose of 150 was obvious because mg. of 5 daily dose thirty is times A Lunar News to approve The FDA had refused to its of 5 due demonstrated dose that the field references also show Other of a dose toxicity. The success heightened bisphosphonate pro- seeking a better prohibited than the thirty larger times tocol, not problems were reasonably predicted. mg dose cannot be article,2 on The Lunar News solved. sense, art, nor common Neither majority places heavy reli- panel which the once-a- provides ance, broadly osteoporo- states that some of 150 at a month treatment intermittently. agents given can be sis and effective. would be safe directly iban- However it never associates Instead, therapy. oral
dronate with article states the then-current Lunar News A. The Prior Art projected “[t]he wisdom that mode 1. Patent The Mockel injection every once three ibandronate is Contrary 24321. to the months.” J.A. many My colleagues combine references unob- majority, supports this article panel ruling of obviousness. support their therapy, obvi- viousness of the not patent1 prop- the Mockel for the cite They ousness. than 150 single doses of more osition Mockel directed to “known.” were S. The Chen Patent formulations, not the concen- tablet coated similarly inapt. patent3 is pro- Mockel The Chen ingredients. tration of active ef- sought to minimize adverse examples of tab- Chen specific vides acids bisphosphonic with containing mg, a maximum of 50 fects associated lets by combining bisphosphonic acid upper limit is 100 preferred that the states dispersing acts as a medium could con- a carrier that mg, and that the formulations lists agent. for the Chen all shows no active up tain to about Mockel acids, bisphosphonic and states larger mg, than 50 al- known formulated any- dosages may be administered the usual though the reference contains 6,468,559 (filed 6,143,326 (filed Apr. Apr. Patent No. 3. U.S. 1. Patent No. U.S. 1997). 2000). Update: Bisphosphonates, News, Lunar (1999). Spring, 27-29 6. The Riis Article every between once two weeks where weeks, optimal with the every once twelve Several references address intermittent of once twelve weeks. frequency treatment, suggests but none once-month- provide any example using Chen does ly administration of 150 of oral iban- *11 ibandronate, suggest specif- a and does The court dronate. relies on the Riis arti- for iban- dosage dosage ic or interval cle,6 dosing patients which shows with 20 Nor does dronate-eontaining product. mg every day of ibandronate other for may lead to a parameters Chen state what twenty-four days, by a followed 9-week regimen. successful treatment, period returning of no then every mg day twenty-four
20
other
days,
treatment,
period
The
Patent
and 9-week
of no
Geddes
k-
etc. The court characterizes this as defini-
my
references on which
col-
The other
proof
dosing concept.”
tive
of the “total
helpful
are no more
to their
leagues rely
However,
suggestion
Riis makes no
is direct-
patent4
conclusion. The Geddes
high
the once-a-month
at the
dos-
therapy
bisphos-
to a combination
ed
age
by Roche could replace
used
Riis’ elab-
hormone,
phonate compound and a
procedure.
orate
may
bisphosphonate
be
states
general
Riis illustrates the
belief that
every day
from
to once a month.
dosed
complex dosing
some sort of
is needed if
not mention ibandronate or
Geddes does
daily
supplanted.
simplicity
doses are
may
effec-
dosage
suggest
or
that it
be
regimen
of the Boniva®
is nowhere to be
tive at 150
once a month.
found, although
regi
the need
a better
Graham,
recognized.
men was well
See
Application
5.The
Patent
Schofield
18,
(objective
383 U.S.
be article,7 further the loading Schofield states that By comparison, the Recker twenty greater is about two to times sets forth in its introduction the which 2004, than maintenance dose. Schofield state of the art in states that “oral possible as a active fre- bisphosphonates mentions ibandronate must be administered methods, daily weekly)” and in ac- agent appropriate quently (e.g., for use in its or “stringent dosing recom- provides dosages specified peri- but no or cordance with ods for ibandronate. mendations.” (filed Postmenopausal Osteoporosis, 16 J. Bone 4. U.S. Patent No. Mar. 1996). Res., (1997). Min. 1871-78 Application 5. U.S. Patent Pub. al., Insufficiently 7. R. Recker et Intra- Dosed (filed 17, 2002). Dec. No.2003/0118634 Injections Ibandronate are Associated venous Efficacy Suboptimal in Post- al., with 6. BJ Riis et Comparison Ibandronate: A Antifracture (2004). menopausal Osteoporosis, 34 Bone 890 Dosing Daily Dosing Oral Versus Intermittent mg, to 100 dosing of art to week court reads Only this mg per which to 50 range render obvious preferred suggest the time. the art at suggest eluded show or Daifotis does not week. monthly dos- dosage, or that
any monthly Nonetheless the effective. ing might be Study The Ravn the Daifotis 35 majority selects panel to overcome attempts The court that 35 dosage, calculates per week by applying shortcomings month, mg per is about times weeks of Riis to concept the total dose with Riis and combines this calculation Ravn reference. test- Ravn8 ranges in the Roche combina- find obvious the Ravn to range dosag- using a daily treatment ed *12 tion of and schedule. day mg per and concluded es Yet the court most effective Bioavailability Explanation dose, despite its The B. Ravn’s 5.0 selects preference toxicity and Ravn’s increased the results colleagues agree that My up to Roche’s to scale for the lower product were achieved with the Boniva® suggest a does not mg dose. Ravn expert In her suggested predicted. or once-monthly dose of 150 Dr. Daifotis discussed the scientific report publi- that the Riis noteworthy It is also explain found to basis that had later been Ravn, cation, in time than is later which this treatment obtained with the successful not the 5.0 mg dosage, the 2.5 selected presented pub- protocol. Dr. Daifotis for intermittent dosage, as a framework by Reginster10 et scientific article lished dosing. showing disproportionate uptake al. stream, an un- into the blood Patent 9. The Daifotis result. Dr. Daifotis predicted and unusual explains unexpected testified this cites a majority also panel The mg dose. The efficacy of Roche’s 150 Dr. Daifotis9 as expert to Roche’s issued following graphical contains the record of obviousness evidence mean area under the portrayal, where the described dosing. Dr. Daifotis (AUC) average indicates the concen- curve ranging from twice week schedules in the blood: month, tration of ibandronate recommended once-a- twice al., Monthly al., Reginster et Oral 10. Jean-Yves Bone Mass and P. Ravn et Effect of Doses Ibandro- Bone Markers Well-Tolerated and Ibandronate is of Different Efficacious Bisphosphonate Prevention New nate: A Postmenopausal Results From the Women: Osteoporo- Postmenopausal and Treatment Monthly Study, Oral Pilot 90 J. of Clin. Endoc- Double-Blind, Randomized, Pla- A 1-Year sis: (2005). rin. & Metab. 5018-24 Study, Dose-Finding 15 Bone cebo-Controlled (1996). 527-33 6,432,932 (hied Sep. No. 9. U.S. Patent 1999).
Dr. explained Daifotis a Study, “[t]his was bile 20 J. Bone Miner. Res. 1315-22 surprising finding (2005). concerning dispro- the Nothing prior the art renders portionate amount of ibandronate that be- expected, predicted, the result or obvious. comes available from oral administration of mg, amounts above about 50 and was Expert Testimony C. May
unknown as of 2002.” J.A. 20726-27 Also of record were the reports ¶ Dr. explained 108. Daifotis that “[t]he experts Roche’s Dr. Bilezikian and Dr. benefit of this surprising result was that a explained Harris. Roche opines each patient higher could receive than thought that, inventions, at person the time of the a possible amounts of drug active to be avail- skilled the art would not have had osteoclasts, able to inhibit while at the expectation succeeding reasonable adversely time not affecting safety pro- the safe, effective, a and well-tolerated once- a file of 150 dose of ibandronate.” J.A. ¶ of ibandronate in an 20732 115. large amount as as 150 Dr. Daifotis also clinical cited trial data showing mg monthly that a 150 dose of “requir[ed The trier of fact is consid- to] superior increasing ibandronate is at bone relating er all evidence to obviousness be- density in spine postmeno- the lumbar finding fore invalid on those women, pausal as compared to 100 grounds.” In Cyclobenzaprine Hydro- re month, given once a mg given on two Capsule chloride Extended-Release Patent (50/50) days single consecutive month (Fed.Cir.2012). 1063, Litig., 676 F.3d mg daily and a 2.5 It is noteworthy although generic the
The record producers contains other scientific arti- who are defendants herein also cles, al., e.g., Paul D. Monthly presented Miller et expert reports, expert pro- no Therapy Oral Ibandronate anything personal opin- Postmeno- vided other than a pausal Osteoporosis: 1-Year discovery the Mo- ion that the Roche was obvious. grasp. his or her technical need, options within failure of long-felt
The evidence success, it anticipated unre- If this to leads others, success and commercial not innovation expert provided product is butted, likely adverse and no sense. ordinary and common success but of skill from which any evidence confidently pre- could be product Boniva® 421, KSR, at 127 S.Ct. U.S. that it argument was dicted. Their Here, however, colleagues agree my even try” to “obvious have been would and that unpredicted, that the result was course, to possible it is Of Roche method. art, or in the suggestion was no there sorts of treatment all speculate about sense, this procedure in common newsletter,11 schedules, Krause as result. sought-after might produce specificity speculation without but Nonetheless, colleagues invalidate the my a reasonable likelihood achieving plan for try.” to successful treatment “obvious con- clear and provide not does success with oth experimentation The extensive on the of obviousness vincing evidence dosages demonstrates regimens er try.” to ground of “obvious try. to not that this selection was obvious Try need long-felt this to to meet D. Obvious failure find my colleagues’ weighs heavily against try, to to be obvious For an invention protocol, although ing that finite number of known be a there must field, is investigators obvious to art, reasonable choices in the in In re court. As stated obvious this for the of success choice 746, (Fed.Cir.1995), 54 F.3d Soni KSR, 127 S.Ct. 550 U.S. tried. this rule is principle behind “[t]he basic try found cannot be 1727. Obvious have which would straightforward hint that a gives no when the —that ordinary person to a surprising been re- might achieve the desired specific trial have art would not particular skill in the Kubin, *14 561 F.3d re sult. In KSR, As established been obvious.” O’Farrell, (Fed.Cir.2009) In re (quoting di alternatives and some absent limited (Fed.Cir.1988)). 894, Dr. 853 F.2d path, the successful “obvi rection toward testified, “monthly dosing of Daifotis try” applicable. not ous to as a feasible or alendronate was not seen if it for investigation; desirable endeavor suggest art does been, it.” explored would have had we might that it have a protocol, or 20717. J.A. Only expectation of reasonable success. try” requires success, of “obvious to The law can knowledge of Roche’s alter- a limited number of suggest- there be defined that which is not one reconstruct that the desired suggestion and a anything, large natives If art. ed likely through achieved result is be publication adds to amount of trial. The Court proposed stated: uncertainty, provides for it no direction holding The court’s potential success. or market design there is a need When discourage improvements today simply problem and there will pressure to solve if fields, by holding even identified, predict- crowded are finite number of succeed, patent investigation should solutions, ordinary skill such person able is not the known available. pursue has reason to good Krause, Roche, 2001. Carey 11. GlaxoSmithKline Pact, Reporter, Chem. Market December Drug my colleagues’ From invalidation of the advance, significant on this medical respectfully
I dissent.
LAKESHORE ENGINEERING
SERVICES, INC., Plaintiff-
Appellant,
v. STATES, Defendant-Appellee.
UNITED
No. 2013-5094. Appeals,
United States Court of
Federal Circuit.
April