*1 pre consideration of the issues Court’s to assist appeals.
sented in these order issues, the entire its consideration
records, along par with the briefs of the
ties, shall be transmitted to the Florida Jax,
Supreme Court. Intervest Const. of Co.,
Inc. v. Gen. Fid. Ins. F.3d (11th Cir.2011).
QUESTIONS CERTIFIED. CO., Ltd.,
SENJU PHARMACEUTICAL
Kyorin Co., Ltd., Al Pharmaceutical
lergan, Inc., Plaintiffs-Appellants
v. LIMITED, Lupin
LUPIN
Pharmaceuticals, Inc.,
Defendants-Appellees. Co., Inc.,
Hi-Tech Pharmacal
Defendant-Appellee.
No. 2013-1630. Appeals,
United States Court of
Federal Circuit.
March *2 Gibson, Perry, Dunn &
Mark Andrew DC, LLP, argued Washington, Crutcher represented Also plaintiffs-appellants. for Thomas, Irvine, CA, Lucas by Jeffrey T. DC; Townsend, Washington, Richard C. West, Kelly, Stephen Frank Jonah G. D. Obion, McClelland, Baxter, Spivak, Maier Neustadt, LLP, Alexandria, & VA. Mazzochi, Rakoczy M. Molino Deanne LLP, IL, argued Chicago, Siwik Mazzochi Limited, defendants-appellees Lupin for Pharmaceuticals, repre- Inc. Also Lupin Rakoczy, A. Paul J. by sented William Wadhwa, Molino, Anuj Kumar John Poliv- ick, Murray. Brian Peter n Castellano, LLP, Keller Jeffrey T. Shaw DE, defendant-ap- for Wilmington, argued Co., Pharmacal Inc. Also pellee Hi-Tech Keller; by Karen E. Steven represented Lord, LLP, York, Roth, D. Locke New NY. NEWMAN, PLAGER,
Before and MOORE, Judges. Circuit Opinion for the court filed Circuit Judge PLAGER. filed
Dissenting opinion Circuit Judge NEWMAN.
PLAGER, Judge. Circuit patent brought This is a case under the Act, Hateh-Waxman Pub.L. No. (“the Act”), appeal from the Stat. 1585 on for the Dis- United States District Court Act, to the trict of Delaware. Pursuant Senju Pharmaceutical plaintiffs-appellants Co., Ltd., Co., Ltd., Kyorin Pharmaceutical (collectively “Senju”) Allergan, Inc. Lupin defendants-appellees sued Limited (collec- Pharmaceuticals, Inc. Lupin Pharmacal tively “Lupin”) and Hi-Tech (“Hi-Tech”) Co., infringement of Inc. of reexamined asserted claims 6 and 12-16 (“the 6,333,045 pat- Patent No. .U.S. ent”). seeking counterclaimed Defendants Zymar®. declaratory judgment non-infringe- gatifloxacin product court, invalidity. Zymar® The district was listed in the FDA’s ment record Robinson, adjudged the Judge Sue L. Approved Drug Products With Thera- infringed but invalid for obvious- peutic Equivalence, what is known as the invalidity judg- appeal Plaintiffs ness. “Orange Book.” *3 ment.1 suit, In this first the district court 2010 ruled that the asserted claims were I. Introduction infringed, but that claims 1-3 and 6-9 were gatiflox- The at issue relates to invention as over the art. prior invalid obvious acin, eye aqueous liquid pharmaceutical However, found defendant added disodium drop composition, with Apotex failed to demonstrate that claims 6 (“EDTA”). prior pat- Seven edetate and 7 were invalid for lack of enablement alleged ents are as the basis for the obvi- inequitable and failed to demonstrate con determination, containing ousness each Inc., Senju duct. Pharm. v. Apotex Co. chemistry the claimed some of the same (D.Del.2010) 404, F.Supp.2d (“Apo 717 433 addition, there are several invention. ”).1tex prior patent infringement involving suits trial, or, Following a motion for a new chemistry the same and the same '045 alternatively, judgment to amend and find relevant, though are patent; these suits 7, ings regarding reopened claim the court vary. parties some extent the issues and the case to consider additional evidence suits, infringement includ- Three of Thereafter, regarding claim 7. the court in one, this have all been tried before and ing by 2011 found claim 7 obvious clear and judge district decided same convincing Senju evidence. Pharm. Co. v. District of Delaware. Inc., 196, Apotex F.Supp.2d underlying issues in this case—con- The (D.Del.2011) 2”). (“Apotex appeal On infringement structive under Hatch-Wax- 7, judgment regarding claim this court man, by alleged non-infringe- countered judgment invalidity in a affirmed invalidity ment and for obviousness—are summary affirmance, Senju Pharm. v.Co. Yet, familiar issues. the combina- (Fed.Cir. Inc., Apotex Fed.Appx. chemistry litiga- tion of the and the 2012) ”); (“Apotex parts I the other produced complex argu- tion has here a rulings judge’s appealed. district were not parties. ments both address below We only arguments in detail those we Meanwhile, 2011, fi- February before saliency regard to the believe have judgment litiga- nal was entered in that outcome. tion, Senju plaintiffs petitioned (“PTO”) for Patent and Trademark Office suits, the first
Regarding
law
patent.
of the '045
ex-parte re-examination
in 2007. Pursuant
to the Hatch-
began
art,
Plaintiffs
the ar-
Act,
submitted
generic
a manufacturer of
Waxman
guments
upon by
par-
the court and
relied
drugs, Apotex
Apotex Corp.
Inc. and
However,
ties,
opinion.
and the court’s
(“Apotex”), filed an Abbreviated New
(“ANDA”)
plaintiffs
notify
did not
either the defen-
Drug Application
with the Food
(“FDA”),
seeking
seeking
they
dants or the court that
were
Drug
Administration
re-examination;
shortly
until
Allergan’s
it was not
generic
to market
versions
adopted by
intervening rights, which in
in which it
relate to issues of
1. Hi-Tech filed brief
joined
Lupin's
we need not address in
reference and
most of
brief.
view of the outcome
opinion.
arguments
brief
Hi-Tech's additional
cally alleged infringement of the reexam-
completed,
before the re-examination
12-16,
was informed.
claims 6 and
this time based on
that the trial court
ined
202-653,
ANDA Nos.
Lupin’s earlier-filed
reexamination,
initial
the PTO
On
202-709,
gatifloxaein and
0.3
0.5 w/v%
the district court
agreed with
gatifloxaein, as well as Hi-Tech’s
have been obvious
original claims would
203189,
gatifloxaein
0.5
ANDA Nos.
patents.
of the cited
Subse-
light
gatifloxaein.
2011, the PTO issued a
in October
quently,
Lupin
sought
and Hi-Tech defendants had
pat-
for the '045
certificate
reexamination
generic
FDA
to market
approval
and sell
claims 1-3 and
ent which cancelled
Senju’s FDA
copies
approved gatifloxa-
claim
and added
amended
allowed
ophthalmic
cin
solution.
Senju filed another suit
plaintiff
Then
Lupin
judgment
plead-
moved for
on the
*4
infringement of
against Apotex, alleging
ings, alleging that
the narrower reexam-
seeking
claims and
a de-
the reexamined
patent
ined claims of the '045
were invalid
claratory judgment
infringement
based
obviousness,
plaintiffs
and that
should
filing
on the
ANDA
at issue
same
collaterally estopped
relitigating
be
from
Apotex responded to the
litigation.
first
findings
claims based on the court’s
these
by seeking dismissal on the
new action
that,
3. The district court ruled
Apotex
judicata,
claim
grounds
preclusion
of res
or
Lupin might
at trial
although
later
succeed
(“claim”
referring
proce-
here
to the civil
showing
the reexamined claims
patent
meaning).
law
concept,
dure
not the
obviousness, Senju
were invalid for
Ultimately the district court sided with Apotex
litigations
fully
1
2
had not
&
Senju
Apotex
gave judgment against
a claim
litigated
limitation of 0.01
preclusion:
claim
grounds
on the
“the
and, therefore,
collateral es-
w/v%
patent-at-issue
did
reexamination
toppel
apply.3
would not
J.A. 7.
against
not create a new cause of action
earlier,
patent
As noted
the '045
is di-
previous
the same
defendants and accused
aqueous liquid pharmaceutical
rected
Senju
Apotex
Pharm.
v.
product.”
Co.
compositions comprising gatifloxaein and
(D.Del.2012)
Inc.,
656,
F.Supp.2d
662
EDTA,
utilizing
as well as various methods
3”).
(“Apotex
appeal,
judgment
On
compositions.
patent’s
The '045
upheld
opinion by
in an extensive
21,
original
filing
April
date is
2000.
U.S.
Circuit, Senju
Apo
Pharm.
v.
Federal
Co.
The reexamined claims at issue are:
(Fed.Cir.2014)
Inc.,
tex
district present art to the claims as unexpected results proffer of evidence though methodology is errone- of these even such consider each unavailing. We will Appellant of law. Br. 63- ous as matter in turn. arguments Planning Corp. v. (citing Interconnect 64 1. Obviousness (Fed.Cir.1985)). Feil, addressing the substantive obvi- Before respond appellants’ pur- Appellees by the district analysis conducted ousness 6 and 12-16 was suit of reexamined claims court, Senju’s arguments re- we address merely attempt bypass a failed the dis- methodology the district garding the invalidity judgment Apotex trict court’s First, ar- analysis. appellants in used its appellants teachings improperly uti- gue that the district court court’s meth- cannot now claim the district findings from its deci- lized its obviousness odology failings. the reason for their is which to Apotex 1 as the basis from sion argue that the district court did Appellees case, in this begin invalidity inquiries by declining repeat the identical err essentially lessening appellees’ burden reasoning findings for identical factual convincing evidence proving clear Ap- appellants appealed Apotex never claims asserted in the that the reexamined pellees appellants’ singular note that focus been present case would have obvious. at trial was the 0.01 EDTA for cor- that the district court’s Appellants argue neal and that nev- findings Apotex factual should have rejected in arguments Apotex er raised the invalidity played inquiry no role arguments or outside this issue. new currently asserted this case because Thus, appellees argue, the district court new limitations reexamined claims contain ap- “find” anew facts properly declined to only a subset of the and disclose narrow pellants dispute did not at trial or those invention, original 'claimed commensurate already appealed Apotex found and not objective unexpected evidence of re- undisputed. such facts are Nev- because *6 sults. ertheless, out that the appellees point dis- findings trict court made new fact properly that the district court Appellants argue 'claims a specific to the reexamined as regard- upon findings Apotex relied from whole, EDTA beyond even the 0.01 ing pH range EDTA concentrations and to w/v% trial, appellants pursued repeating issue at in conclude that the new limitations the analysis for each complete a obviousness distinguish reexamined claims do the asserted, and appellants supporting claim prior the art. claimed inventions from findings all of its with evidence of record analyzed They argue that the court the from case. fashion, piecemeal violating the claims requirement in section 103 of the Patent position In of their the support analyze Act that courts the obviousness of predecessor district court used the an a invention “as whole.” See U.S.C. prior present art to the claims and 103(a). § analyze to the reexamined claims failed holistically, appellants cite Interconnect
Appellants argue
the district
In
analysis effectively ap- Planning Corp.,
The earliest of the the the polar penetrate through molecules to 5, 1985, patent, issued on November aqueous eye. cornea into the humor of the quinolones teaches that then-known are the specifically reports Grass 1985 “compatible both with ocular tissue” and separate addition of 0.5 EDTA to in treating useful bacterial ocular infec- glycerol cromolyn of and resulted solutions through topical tions administration. permeability patent, 1:13-17. The '456 increased corneal both also dis- exemplary ophthalmic unspecified A composi- closes solutions. lower concentrá- al., is, Investigative Ophthalmology & 4. "Grass 1985” is Grass et Cal- 26 Visual Effects of (1985). Chelating Agents cium on Comeal Science 110 J.A. 2707-10. Permeabili- 1344 abstract peer-reviewed function erence is a shown to of EDTA was also
tion Mitra, teachings studying manner, extent. reinforces the to a lesser in this albeit permea- of EDTA on impact the references, ap- four In addition to these bility. J.A. 2810-11. 1988-15, Grass raise the Grass pellees also First, references, argue that the seven 1988-116, appellants Rojanasakul7 and upon by relied claim limi- art references mainly the additional to address narrower, predate the claimed inven- district court reexamined tations which, “is itself eight years, tion at least and Grass claims. The Grass 1988-1 Appellant in evidence of nonobviousness.” references build on work (citing Corp. 25 Panduit v. Dennison (collectively, “Grass refer- Br. Grass (Fed.Cir. Co., Mfg. ences”), concentrations of testing lower 1987)). EDTA, Second, argue that the 0.1, 0.05, appellants finding and 0.01 w/v% teachings district court misconstrued the permeability at these increased corneal Specifically, respect art. Rojanasakul lower concentrations. argue that a pro- to claims studying is directed to reference moti- skilled artisan would not have been penetration mechanisms of various moting EDTA, cornea, enhancers, cherry-pick vated to individual limitations including '465, '456, patents for evalu- from the and '470 and developing well as to methods compositions viability. combine them to achieve ating damage tissue J.A. Appellants argue claims 12-16. that the This reference builds further on the 2788. selectively excerpt- teachings references test- district court erred Grass ing teachings from these three ing EDTA concentrations as low as EDTA, finding reverse-engineer references to the claimed even analysis, appellants In its ar- very low concentrations increased invention. degree. gue, the district court failed to consider permeability to some J.A. ordinary practitioner whether an would 2795-96. multiple make have had reason to Appellants also raise two additional ref- selections, combinations, and modifications erences, the Mitra reference and the analysis needed under its to arrive at the reference, Kompella as evidence of nonob- compositions. claimed viousness. The Mitra reference is com- drug Appellants also that the district prehensive ophthalmic review of de- improperly declined to consider evi- livery systems. J.A. 2768-72. The Mitra permeability the mecha- dence on corneal with refer- specifically reference studies Appel- claims. drug pen- composition nisms of EDTA for corneal ence to examining point concentrations at lants out that corneal is etration of the cor- relevant to these claims because which increases compositions embody the method Kompella nea occur. J.A. 2772. The ref- claimed al., al., 7."Rojanasakul” Rojanasakul et is et Mecha- "Grass 1988-1” is Grass Mechanisms Drug penetration Comeal Penetration 1: In Vivo and In action some Enhancers nisms Kinetics, Vitro 77 Journal of Pharm. Sciences Scanning Mi- in the Cornea: Laser Confocal (1988). J.A. 2773-84. Studies, croscopic Electrophysiology *8 Pharm., (1990). 131 J.A. Int'l Journal of al., "Grass 1988—II” is Grass et Mechanisms 2787-98. Drug Comeal Penetration II: Ultrastmctur- of al Pathways Analysis Dmg Potential for Sciences, Movement, 77 of Pharm. Journal (1988). J.A. 2800-08. purpose claim 6 and the anything permeabil- of reexamined disclose about corneal composition ity gatifloxacin and, therefore, and the functions of solutions cannot be provide limitations divorced from the no reason to arrive at the claimed inquiry. Appellant Reply compositions. Appellants obviousness Br. argue that Products, Leo Pharmaceutical (citing district court identify any failed to reasons Rea, Ltd. v. 1346, 1353, 726 F.3d 1356 for skilled artisan to prior combine the (Fed.Cir.2013)). Because, to according ap- invention, art to achieve the claimed find- pellants, prior ing only no disclosed 0.01 that a skilled artisan would have EDTA preferred purpose for the of been gatifloxacin motivated to use raising permeability, appellants ar- EDTA together and that the pH claimed gue they merely did more than EDTA seek concentration limitations are patent to ingredi- prior combination of known found art.
ents to achieve established functions. that, Appellees respond respect
Appellants argue only that the district court appellants did waive improperly found claims 12-16 obvious years publica- the issue of the between the '456, '465, finding without and tion of the art and the filing date of patents actually any gatifloxacin teach patent application the '045 being “itself formulations for ocular administration. evidence of by raising nonobviousness” Appellants argue that the district court this issue for the first time appeal, on but improperly Panduit case patent surmised that the '456 also that the appellants cite quinolones teaches that are useful in treat- in support position of their compara- is not infections, ing patent bacterial the '465 ble to the current case. Appellees point the Panduit excip- case, teaches that EDTA is a conventional out there were quinolone ient for use with the lomefloxa- no art references at issue that dis- cin, patent and the '470 that gati- suggested teaches closed or all of the claimed limitations, known floxacin formulations can be used structural while this case routes of oral and parenteral just administra- several art references do that. Panduit, tion, including liquid eye drops. Br. Appellee (citing 1577). conclusions, Based these improp- that the district court then respect appellants’ With main obvi-
erly gatifloxacin arguments, relied on the fact that is a appellees point ousness out quinolone family member of the composition of com- that because the claims do not pounds to pat- combine the '456 and '470 contain the corneal limitation ents and arrive at the idea of an ophthal- found method claim the corneal solution, gatifloxacin mic pulling teachings permeability teaching away arguments are concentrations and from irrelevant to claims 12-16. ar- Appellees patents gue only composition ap- the '456 and '465 and 0.01 that the element pellants missing from the '456 to arrive at deemed from the '456 and specific ranges recited in the formulation quinolone ophthalmic pat- claims. Essentially, appellants argue gatifloxa- that the express dis- ents was an mention of selectively excerpted teachings trict court cin improving however, patents any drug. Appellees argue, from each of the three improperly reverse-engineer patent, the claimed when combined with the '470 Appellants point invention. out that limitation of the claims is obvious. Addi- this is '456, improper hindsight tionally, appellees argue there was bias because the suffi- '465, patents and '470 themselves do not cient reason to combine the claims *9 years the opinion merely render asserted that recite three to the patents published. the Appel- claims obvious. 10-14). (citing lant Br. 19 n. 4 J.A. is This patent the '456 Appellees characterize insufficient discussion to consider ar- this using norfloxacin and structur- teaching court, gument raised ally topical ocular related antibodies therefore, is, argument waived. See formulations, patent taught the '465 while Inc., Prods., Indus., Sage v. Devon Inc. preparing ophthalmic fluoroquino- stable (Fed.Cir.1997) 1420, (finding 126 F.3d patents both compositions, lone con- exceptions that notable ... “[w]ith few taining ranges ingredient encompassing not consider appellate party’s courts do the those claimed. Both '456 and '465 theories, lodged appeal”). new first on topical patents taught also ocular formula- tions various For the of claims containing purpose features encom- the claims, appeal main passed by composition appellants’ the such as focus of brief was pH. and 5.2 permeability Because the inclusion of the corneal analysis as an limitation gatifloxacin improved validity viewed fluoroquinolone, argue these that appellees that one claims. We conclude the dis- ordinary in the art had trict found that properly skill would have court patent’s gati- permeability reason to combine '470 is not relevant in the discus- improve to of composition floxacin disclosure the '456 and sion claims 12-16 because patents’ '465 contain formulations. these claims do not the corneal limitation found in method Appellees also that these disclo- 6, claim discussed below. J.A. 24 n. 25. appellants sures combined with failure to dispute gatifloxacin that the art viewed do persuasive appellants’ as We not find improved fluoroquinolone, provides argument necessary to that it is consider ordinary reason why one of when analyzing skill would want to improve patents the '456 and '465 claims the claimed composi 12-16 because patent’s the '470 incorporating gatiflox- embody tions the method of reexamined point acin. out claim Appellees the '470 6. The Leo Pharmaceutical Prod ucts, Rea, patent’s eye drop gatifloxacin teaching is Ltd. v. 726 F.3d drug (Fed.Cir.2013), class directed to the same as the '456 case cite in sup provides patents port argument evidence of their examines a compo should work in the '456 sition claim that includes as a limitation patent’s composition. formulation. the function of the In com position patent, claims 12-16 of the '045 claims, 12-16, With respect we con- denoting there is no limitation the function clude that the district court properly held composition of the and we to im decline Appellants’ obvious. argu- port this limitation into claims. See relating eight year ment to the gap be- Phillips Corp., v. AWH tween art and the filing (Fed.Cir.2005) (stating have we is application unconvincing and repeatedly against confining warned properly Appellants raised. only show claims to particular embodiments in the support being for this issue raised description). written appeal single to this is a citation to the opinion Further, district court in which appellants there were several other fac- footnote, argue, in a that the district court tors Leo Pharmaceutical led the “acknowledged vintage conclude claims were th^t art,” nonobvious, citing portions including of the district court a lack of reasons
1347
ordinary
pointed
in the art to combine
out
one of
skill
the use of 0.01
prior
the asserted
art references. Leo was also
patent,
known from the '456
Pharrn.,
In
present
them would have been obvious one of claims 12—16were invalid as obvious. ordinary skill the art. Next, analyze we whether method claim The '045 and patents oph- '456 disclose general, would have been obvious. quinolone compositions thalmic in topical appellants argue that the district court formulations, gave ocular reasons to improperly found that all of the of features ordinary one of skill in the art to combine claim of patent the '045 are disclosed gatifloxacin with the disclosure of the '470 art, prior appellees and that failed to patent gatifloxacin because recognized prove invalidity of claim 6 clear and in the art an improved fluoroquinolone. convincing Specifically, appel- evidence. Appellants never art disputed argue nothing lants in the gatifloxacin improved viewed as an fluoro- reasonably suggested that the claimed lim- Thus, quinolone. it would have been obvi- itations of 0.01 EDTA at improve ous to patent the '456 and '465 improving gati- would have effect in formulations incorporating pa- the '470 floxacin’s corneal in vivo. In gatifloxacin. tent’s fact, appellants argue, art ex- Many appellants’ arguments pressly taught of on the these claimed limita- lack of reasons to teachings combine the tions would have no effect on corneal patents rely these three on the fact that permeability. they do not anything disclose about cor- Appellants argue that several gatifloxacin neal solutions. away references which teach from the above,
As discussed this is not a limitation invention, including claimed the Mitra and and, therefore, of claims 12-16 is not rele- references, Kompella notably are absent vant to the obviousness determination. invalidity analysis. from the district court’s
Lastly, the use gatifloxacin Appellants argue that the district court’s per- EDTA would have obvious to a boilerplate language stating been it had ordinary son of skill the art. EDTA is documentary “considered the evidence and among eight ingredi- testimony” listed “conventional discharge is insufficient to ents” in the '456 and a similar challenger’s proving burden of obvious- 2:1-16; group excipients. patent, Appellant Reply (citing ness. Br. 3 In re Further, patent, Cyclobenzaprine Hydrochloride 2:36-49. the use of Extend- Capsule Litig., 0.3 to 0.8 is outlined in ed-Release Patent art, (Fed.Cir.2012)). 1063, 1075, patent, Appel- such as in the '456 (“from 3%”), that, by addressing only 1:37-43 about 0.03 to and in lants those that, patent, (“preferably the '465 2:22-25 of the district about references view w/v”). court, obviousness, 0.3% to 5% As court pointed towards argue that the dis- Appellants all of the further weigh failed to district Rojanasakul trict court’s reliance on the question sides of the evidence on both misplaced. Appellants point *11 reference was invalidity. Rojanasakul did not measure the out that prior art argue that Appellants cor- any through of molecule passage high EDTA concentra- taught the use of membrane, rather, Rojanasakul meas- neal permeability, corneal tions to increase in resistance of changes ured the electrical concentrations, such low EDTA the use of tissue, using corneal electrical resistance For patent. in the '045 as those disclosed general proxy permea- for membrane as that in the appellants argue example, bility According appellants, to of ions. reference, used researchers Kompella deny Rojanasakul that appellees did not w/v%, of 0.5 EDTA at a concentration permeability did not measure the corneal in- patent, to fifty times that of the molecule, only attorney any relying of of several permeability crease corneal that a argument support position to beta-blockers, in- teaching ordinary also that in the art would person while of skill expected electrical resistance to cor- pH to 8.4—well above the have creasing transport gati- relate with the corneal of range improved cor- pH claimed 5-6— Further, Rojanasakul. floxaein based on Appellants further ar- permeability. neal appellants argue that the district court expressly reference gue that the Mitra Rojanasakul, misconstrued which uses improve corneal discouraged seeking “permeability” only to refer not to the EDTA using the claimed permeability of the corneal membrane permeability vivo, in that such reporting concentration eye, surface of the but also comprising the concentrations are “devoid of effects” permeability plasma membrane Thus, appellants in vitro experiments. Thus, in- surrounding individual cells. suggest a argue, Kompella both Mitra and Rojana- permeability crease disclosed high- development pointing line of towards to the asserted applicable sakul is not higher pH er EDTA concentrations and claims. permeability— levels to increase corneal argue that none of Appellants because away and thus from the claimed invention. '456, '465, patents even men- Appellants argue also the Grass permeability, tion art corneal references do not render claim 6 obvious. provided not have a reason patents would argue that Grass Specifically, appellants improved for a artisan to seek cor- skilled study permeabili- 1985 did not the corneal EDTA permeability using neal low concen- ty any quinolone, nor or did Appellants argue trations. that if it was employ it concentrations and conditions re- gatifloxacin into simple incorporating as as sembling specified those reexamined formulations, appellees as con- existing Further, appellants argue claims. tend, likely invention would have been explicitly reported Grass that 0.01 1988-1 opposed within months as to the achieved EDTA has “0” effect on corneal eight years passed anyone before con- vitro, reporting the results permeability compositions. Appel- ceived the claimed statistically for 0.01 indistin- of EDTA lants the inclusion guishable Appellants argue from zero. among possible excipients mentioned improperly that the district court focused patents does not ren- the '456 and '465 in- raising on the 1988-1 raw data to find Grass der its eventual use though per- gatifloxacin unpatentable, creased even claims, at a mini- because the asserted centage change reported zero. mum, present way using along parties’ a new an exist- with the post-trial briefing, ing drug. discussed both these references. Thus, appellees argue, the references were Lastly, appellants argue that the presumptively considered. taught higher pH, the use of not lower pH, improve permeability. Ap- Further, appellees argue that neither pellants argue that uniformly the Kompella or Mitra references teach taught using pH higher levels than the away from the claimed invention. Accord- range citing claimed Grass 1985 ing to appellees, Kompella reference 7.4), (pH 7.4-7.6), (pH Grass 1988-1 Grass says nothing derogatory about 0.01 w/v% 7.4), 8.4), (pH Kompella (pH EDTA or lower ranges, never even *12 7.4). Rojanasakul (pH Appellants point testing or commenting on 0.01 w/v% out that only appellees the evidence have EDTA Appellees formulations. argue also change of a in permeability is a decrease in that the Mitra reference nowhere discour- lowering when pH, the not an ages investigation or dissuades the devel- in permeability increase with a decrease in opment of 0.01 EDTA formulations pH Thus, as claimed in patent. appel- for polar drugs, gatifloxacin, such as argue lants that the evidence confirms the ability readily has to ionize and contains surprising nature of the inventors’ discov- polar fact, several moieties. J.A. 10. ery that 0.01 % EDTA formulations appellees argue, appellants mischaracter- significantly increase concen- ize the disclosure Mitra that 0.2 and 5 humor, aqueous trations at even effects, mM EDTA doses are devoid of relatively low levels. omitting the important fact that the num- for these tests were with a different Appellees respond appellants’ that ex- bers EDTA, compound, even without that perts opinions defending offered no had transport no across the Ap- non-obviousness of the claim membranes. elements re- pellees argue supports that Mitra lating pH, gatifloxacin percentages, Grass’s use teachings range that agents, of isotonic of EDTA levels or the combination increased corneal ophthalmic permeability, recogniz- thereof in an formulation. In- stead, ing that an EDTA drug de- appellees argue, appellants’ expert combination serves some opined solely upon improving consideration question of whether bioavailability poorly penetrating drugs. ordinary expect one of skill would 2772). Appellee (citing Br. 16 J.A. EDTA to work increase corneal permeability. Thus the district court cor- Appellees add that taught Grass 1985 rectly found that all of the features of the the broad effect perme- of EDTA’s corneal patent asserted claims of the '045 are dis- ability-increasing properties, recognizing closed in the art. “chelating agents that since are rou- added
Appellees argue tinely ophthalmic the district court medications for stabil- obligated Kompella ity was not to cite the purposes,” the results of the Grass Mitra references in opinion. Appellee bearing upon tests would have a “direct (citing My Space, GraphOn Br. 45 Inc. v. ophthalmic currently solutions use” even (Fed.Cir. Corp., 1250, though 672 F.3d 1263-64 such solutions used 2012); Sys., Ap- Plant Genetic N.V. v. DeKalb “at lower concentrations.” amounts (Fed. 1335, 2709-10). 2707, Corp., pellee (citing Genetics 315 F.3d Br. 10-11 J.A. Cir.2003)). Appellees point Appellees out that also that appellants mis- explained district court that it considered characterize the Grass 1988-1 and Grass the documentary testimony, establishing evidence and 1988-11 references as a 0.01 6, we conclude to claim respect on With EDTA’s effect where threshold held this properly court Instead, that the district was zero. '456, light claim invalid as obvious appellees it is explained, expert Lupin’s - along '465, patents, and '470 the skilled art showed position that 1988-11, Grass Grass Grass exceedingly “EDTA works person that find Rojanasakul references.8 We “magically and did low concentrations” legal correct applied court that the district Br. Appellee number. specific at a start” standards, accepting that the 1695). further Appellees (citing J.A. validity; presumption was entitled to support no there is point out the under- had to establish appellees assigned that the “0” argument appellants’ by clear factual of obviousness lying proofs in Table EDTA numbers to the 0.01 w/v% evidence; and that convincing that the meas- means XIII of Grass 1988-1 all of the rele- considered properly Instead, appel- result is unreliable. ured Pharma Inc. v. See Sciele vant evidence. simply signifies “0” argue, this lees (Fed.Cir. Ltd., Lupin signifi- reach statistical the data did not 2012) (“Whether previous- a reference ordinary cance, though one of skill even PTO, the burden is ly considered raw data 1988-1 observed reading Grass *13 of convincing evidence the same: clear actual measured increase of confirming an invalidity.”). at even 0.01 permeability, w/v% specifi- did not Though the district court EDTA levels. in its cally Kompella to and Mitra cite Senju’s by appellees, As characterized neither is not fatal because opinion, this 'Rojanasakul in- respect to arguments reference ac- Kompella Mitra nor the attorney uncited charac- variety clude a utilizing a lower tually away teach from teachings the reference’s terizations about at the claimed EDTA concentration Appellees that trial witness offered. no find success level. While both references that Rojanasakul’s teaching point to concentrations, they EDTA do higher capaci- resistance and changes in electrical that lower not indication provide changes in the tance correlate well with EDTA would not also work. concentrations space and membrane aqueous intercellular 2811, 2772. Because the district See J.A. integrity, respectively, support to surface directly required address Rojanasakul’s finding that the relevance of the references do not these references and changed being after electrical resistance teaching away from provide evidence exposed to EDTA levels as low as 0.00037 disclosure, the district the '045 admit that in- appellants Because in its w/v%. not commit clear error court did space between cells space tercellular is Inc., 672 F.3d at analysis. MySpace, See travels, gatifloxacin appel- “[wjhere through which the record ade (finding ordinary skill person lees that a judgment, the district quately supports the reasonably conclude obligation in the art could to recite court does not have impact (citing Lexion very reasoning”) low EDTA levels would of its every even detail Techs., Inc., ed., thereby promoting Northgate LLC v. junctions, the cellular M (Fed.Cir.2011)). 1352, 1359 F.3d transport gatifloxacin. spaces. The dis- intercellular regard appellants' "size-dependent” EDTA-created 8. With untimely argument theory, properly because excluded this it was trict court they alleged gati- provided no evidence untimely to address it further. and we decline through precluded movement size floxacin’s 1695; focus on the use of 0.01 Appellants permeability. J.A. testimony This EDTA permea- to increase corneal art, is consistent with other w/v% such as bility distinguishing as the feature of claim Rojanasakul, which confirmed a dose de- However, this feature does not suffi- pendent relationship between EDTA con- ciently distinguish claim 6 from the centration and corneal permeability, test- art. The asserted references demonstrate ing concentrations of EDTA as low as ordinary one skill the art would Thus, 0.00037 J.A. 2795-96. w/v%. using have known that EDTA w/v% suggests that the use of concen- would result in an increase in corneal trations as low as 0.01 EDTA would permeability. Specifically, we look to be effective to increase corneal permeabili- suggests Grass that EDTA ty concentrations lower than 0.5 would bottom, At analysis court’s be effective in view the increased cor- largely rests on a determination that Lu- neal permeability of the 0.5 EDTA pin’s experts were more credible than Sen- formulation to which calcium was added. ju’s experts. J.A. 30-31. Based on this J.A. 2710. This disclosure Grass 1985 determination, the district court found that would lead of ordinary apply one skill to 1988-1, along Grass with the other cited conjunction teaching pre- with the references, taught that 0.01 existing quinolone formulations, which in- would be effective increase corneal corporated between 0.05 and 0.1 w/v% permeability. J.A. 31. On the evidence EDTA, in arriving at a formu- us, before that determination the dis- lation characterized increased trict court falls well within the wide discre- See, permeability. e.g., J.A. 2712-13. tion the court weigh expert has to credibil- Contrary to appellants’ arguments that ity. Ordinarily, and compelling absent *14 art teaches that the use of 0.01 otherwise, reason an appellate court defers EDTA fails increase corneal w/v% credibility to such determinations. See permeability of polar either of the com- Vitro, CellzDirect, Inc., Celsis In Inc. v. tested, pounds actually teach- (Fed.Cir.2012). 664 F.3d adding es that EDTA to polar com- pound will permeability increase corneal Unexpected Results dose-dep'endently. example, For after ex- Appellants argue that the district court concentrations, perimenting higher engaged in an improper post analysis hoc 0.1, 0.05, Grass 1988-1 tested and 0.01 appellants’ unexpected evidence of re- EDTA, finding that each concentra- w/v% sults, concluding that the claims were obvi- tion raised permeability, corneal even fully considering ous before evidence of though not all of the increases were statis- unexpected and making results without tically significant. J.A. 2780. Appellants any finding of the results skilled artisan improperly focus on the percentage change expected. Appellants point would have control, permeability in over the which was out that a rec- complete administrative zero for both glycerol, methanol and including Senju studies and the conclude that the data showed no increase ord— Grass 1985 and Grass 1988-1 references— permeability. reality, though corneal was before the PTO at the reexamination percent changes statistically were not grant and that the decision to significant, appellees expert set forth testi- examiners’ “ mony that a new person ordinary skill would amended and ‘carries recognized presumption have from the it a that Examin- [each] data 0.01 with duty EDTA would increase er did his and knew what claims he w/v% EDTA that the claimed concentra- suggest (citing Br. 53 Appellant allowing.”’ was Int’l, Inc., aqueous in an increase tion would result v. 174 F.3d Corp. VSI Al-Site and cro- (Fed.Cir.1999) glycerol concentrations of (quoting Intervet humor Labs., Inc., uni- Additionally, Am., molyn. Inc. v. Kee-Vet than Thus, using pH higher levels (Fed.Cir.1989))). formly taught appel 1050, 1054 5-6, confirming the range in the claimed court erred argue, lants discov- nature of the inventor’s surprising factual to the PTO’s give weight failing EDTA formulations ery re that 0.01 unexpected validity findings on w/v% gatifloxacin increase concen- significantly sults. humor even at aqueous trations in the pre-litigation that two Appellants argue relatively pH levels. low (the by Senju in 2006 studies conducted respond that the district study”) Appellees meas- the “'904 study” “'901 only af- found the claims obvious properly concentrations compared ured and considering appellants’ unexpected re- the com- ter administering after gatifloxacin finding unpersuasive. it sults evidence and with and without pound solutions Senju setting persuasive forth a Despite EDTA, demonstrating expected USPTO, Examiner at the case before the of the claimed inven- surprising benefits before the district collapsed stud- their theories expound Appellants tion. testimony point out from Appellees court. undisputed results demonstrat- provide ies who testified that appellants’ expert EDTA addition of 0.01% ing study gatifloxacin- did not show the increase in results in a 27-40% produced EDTA cor- solution humor. The Grass 1988-1 aqueous benefits that were statis- reference, argue, permeability a neal reported tically significant compared to non- gly- percent change zero argue that the Appellees EDTA solution. of 0.01 upon cerol addition vitro, testimony from district court heard both taught and the 1988-11 article Grass credibility, and re- experts, weighed their that concentrations of EDTA about 0.01 a whole in vitro to show an viewed 1988-1 as before Grass were needed Lupin’s expert’s credible glycerol. finding more effect on corneal person would not opinions that even if Grass the skilled Appellants point out “no interpret teaching 1988-1 as interpreted teaching some Grass *15 EDTA. increase” occurred at 0.01 permeability in corneal miniscule increase EDTA, the gatifloxacin with 0.01 argue also that the raw data Appellees magnitude improvement sheer observed nu- in 1988-1 shows that reported Grass have Senju’s in '901 and '904 studies would merically, permeability the corneal levels surprising. unexpected been and control even with compared did increase Ap- EDTA formulations. appellees the 0.01 Appellants further the 27 and 40% pellees point in out that anyone no evidence that presented numbers in the raw permeability increase expected have a low concentration would for evidence of appellants rely in data produce significant EDTA to a increase in studies unexpected success occurred permeability. gatifloxacin’s (including control fact, all of the numbers argue, the remainder of where values) varied, references, large, unex- including widely Grass argue that 1985, Mitra, Appellees Rojanasakul, plained reinforce error bars. and of one unit can adjustment if a mere Senju’s '901 and surprising results in corneal studies, a difference produce of these references 30% as none Vitro, permeability, pH adjustments are rou- court. See Celsis In 664 F.3d at done, tinely appellants’ change 27-40% permeability with 0.01 w/v% We further conclude the dis magnitude EDTA has a achievable oth- trict properly court a applied presumption prac- er formulation tweaks and routine validity, considering both the evidence Further, appellees argue,
tice. of obviousness and the evidence of unex properly achieving found that results, pected appellees to find that set changes magnitude on this order of re- forth convincing clear and in evidence of “product optimiza- flected the of routine validity this case. See Sciele Pharma tion.” J.A. 33-34. Inc., 684 F.3d at agree 1260. We that it was not clear error for the district court to Appellees argue that the district court unexpected conclude that the results evi properly unexpected found the results evi- Senju upon dence that during relied reex unpersuasive dence because the results of amination, J.A. did not withstand the '901 and '904 studies were not statisti- scrutiny by Lupin’s experts and the dis cally significant merely reported nu- Ultimately, trict court. the district court merical increases that were unsurprising properly concluded that the pre theories light Appellees point of Grass 1988-1. during proved sented reexamination too only out that Dr. Grass acknowledged that challenged judicial weak when in a forum Senju study reports single time to rise to the level of unexpected results point study that the claimed was statisti- sufficient to a strong rebut case of obvious cally significant, Lupin’s but that statisti- ness. See Procter & v. cian Gamble Co. Teva point demonstrated this time was sta- USA, Inc., Pharms. tistically insignificant under a correct (Fed.Cir.2009). analysis. Appellees argue Senju’s nothing studies achieved better than We have unpersua- considered and find Grass 1988-1 which 0.01 sive appellants’ argu- the remainder of solutions were tested as single doses and ments. Concluding that the district court showed concentration depen- and time did judgment not err that the reex- dence permeability where the 30 minutes’ amined claims at issue are invalid obvi- quadrupled numbers or more than the 20 ousness, we -need not reach the issues of minute numbers. infringement estoppel. We conclude the district court III. Conclusion
properly considered of unexpect evidence judgment of the district court is results, ed J.A. and did not err affirmed. that, finding based on the record and testi AFFIRMED offered, mony the increase in corneal by plaintiffs using shown *16 NEWMAN, Judge, dissenting. Circuit 0.01 EDTA unexpected is not or surprising, product a op prior litigation, but is of routine In the district court held Senju’s timization that would have been ground obvious to claims invalid on the one of skill the art. J.A. 3334. These of obviousness. Before that decision determinations, many much like finality, Senju requested of the ob reached PTO re- determinations, examination, viousness were on presenting sig- based new claims of which, credibility judgments on on nificantly scope. the evi narrowed The PTO reex- us, 6,333,045 Senju’s dence before we defer to the district amined Patent No. U.S. (“the away claimed subject narrowed data lead from the patent”), held the that, These discovered liti- matter. inventors subsequent this patentable. using EDTA at a concentration of when no deference gation, gave w/v%, only not 0.01 formulation is ef- of claim review the restricted the PTO’s but, antibiotic, contrary as an to the fective at that scope unexpected results or the art, permeabili- prior increases the corneal inval- scope, the narrowed claims and held ty gatifloxacin. of ap- it grounds previously id on the same plied original to the claims.1 specifically I focus on reexamined claim 6: repeat
My colleagues panel raising perme- A method for corneal 6. they analysis: flawed do not consider aqueous ability pharmaceutical of Ga- claims, the unex- scope the reexamined of eye comprising tifloxacin solution drop pected the teach- scope, results at salt, having or Gatifloxacin its of ing-away prior respectfully art. I of containing above 5 to from about 6 from dissent, not been for these claims have about 0.3 about 0.8 Gatifloxacin shown to be invalid. salt, comprises incorporat- which or 0.01 ing about disodium edetate Discussion [eye drops containing into Gatifloxacin Senju that a The inventors discovered eye or its said drop salt] Gatifloxacin containing gati- antibiotic composition solution. permeability floxacin enhances corneal patent, col. 11. 25-col. 21. 5. when very combined with low amounts (EDTA) reexamination, During the PTO examin- ethylenediaminetetracetic at acid that no or er found reference combination specific Zy- This is pH. appellants’ suggests the of references teaches or im- me- product, mar® whose commercial and proved permeability corneal obtained us- the impetus dicinal success is for this at the ing EDTA low concentration of Act challenge Senju’s Hateh-Waxman prior experimental The patent. data w/v%. no show either effect at 0.01 or art is It contains The crowded. permeability enhanced at concentrations quinolones, family much data on above 0.01 w/v%. is a member. The improved No reference shows use chelating agents, also shows the such low concentrations EDTA, excipients such as that enhance EDTA; all are that the indications stability ophthalmic How- medications. concentration should be above 0.01 ever, w/v%. no combination of art refer- Senju discovery contradicts the obser- suggests very ences shows or the use of art. reported vations None- low of EDTA concentrations to enhance theless, panel majority holds that it for- of antibiotic that superior was obvious results would be gatifloxacin, other or of mulations by reducing obtained the concentration. quinolone. et al. The Grass Scientific Articles field, specific In this crowded combi- primary import nation and concentration here claimed is to the district Of court’s shown, published scientific are Dr. opinion publications three Co., Ltd., 9, 2013) Senju Lupin Aug. ("Dist.Ct.Op."). Pharm. Ltd. v. Civ. 11-271-SLR, (D.Del. No. WL 4101820 *17 Grass, George panel majori- finding contrary M. et al. The is to the record. The ty publications states that these render the most that Grass 1988-1 can be deemed to obvious. To con- claimed combination “suggest” is that the EDTA concentration trary, publications away teach from higher should be than 0.01 w/v%. Senju the direction taken inventors. The two other publications cited Grass al., et Grass Mechanisms of Corneal “teaching away” reinforce the
Drug Penetration I: In and In Vivo Vi- art: Kinetics, (1988) tro J. Pharm. Sci. 3 al., Grass et Effects of Calcium Che- 1988-T”): (“Grass lating Agents Permeability, on Corneal panel majority The states that the Grass Investigative Ophthalmology & Visu- 1988-1 reference shows that the three con- (1985) (“Grass 1985”): al Sci. 110 (0.1, EDTA centrations of tested 0.05 and Grass 1985 describes the effects of the w/v%) 0.01 are enhancing effective at cor- chelating agents EDTA Cromolyn and permeability. neal That is incorrect. corneal permeability glycerol pro- and Grass 1988-1 shows that EDTA at a con- gesterone in eyes. rabbit Grass 1985 re- produced centration of 0.01 a zero ports that EDTA at concentrations of 0.5 percent permeability, increase corneal glycerol increased concentration measured for both methanol glycerol. humour, aqueous and concludes that Grass 1988-1 also states that the in vitro the addition of high chelators at concentra- experiments performed exposures were at or frequent application may tions in- (3 hours) significantly longer than most crease permeability ep- corneal topical applications provide, would yet the ithelium. This reference shows enhanced reported data are that EDTA at 0.01 w/v% concentrations, at higher effects not the totally ineffective. low concentration claim 6. Grass 1988-1 discusses the work of oth- al., Grass et Mechanisms of Corneal er investigators, reports no corneal Drug Penetration II: Ultrastructural penetration of mannitol EDTA using at Analysis Pathways Drug of Potential of 0.2 concentrations and 5 mM. Grass Movement, (1988) Pharm. J. Sci. 15 permeability 1988-1 concludes that corneal (“Grass 1988-11”): increases with increased concentration of EDTA. directly away This leads from Grass 1988-11 describes electron micro- suggestion or expectation improved scope eyes studies of exposed rabbit permeability formulations glycerol, specifically EDTA and analyzing EDTA concentrations of as low as epithelial junctions cell after treat- 0.01 w/v%. EDTA glycerol. ment with Grass reports that the effects of EDTA appellees concede that Grass 1988-1 depend on statistically exposure shows no concentration and significant increase time, and that at concentrations of 0.01 the low concen- EDTA, tration of epithelial “the data did not tissue showed w/v%: significance.” expansion reach statistical no Appellee visible of the intercellular Yet, Br. at panel majority spaces, correlating affirms which is described as unsupported finding court’s with corneal permeability. The authors “prior art suggests interpret showing the use of that “in these results as concentrations as low as 0.01 EDTA vitro concentrations of above 0.01% would be effective to increase corneal caused increased of the cor- permeability.” Op. Dist. Ct. at *11. glycerol.” This nea to Grass 1988-11 at 22.
1356 permea- corneal of EDTA to enhance show tions the Grass references
Collectively, bility. must be used that EDTA suggest or to higher than
concentrations
References
Other
permeability.
corneal
effectively increase
by
relied on
Three other references
Drug Delivery
Opthalmic
Systems,
(U.S.
4,551,456;
Patent Nos.
district court
Dekker,
ed.,
(Ashim
Marcell
Mitra
K.
4,980,470)
4,780,465;
make no mention
Inc., 1993) (“Mitra”):
Those
improving
permeability.
of
as an anti-
describe
references
the re-
summarizes
The Mitra book
excipient,
EDTA a traditional
biotic and
field, and
knowledge in this
search
i.e.,
ingredient;
they
drug
as an inactive
using low concen-
experiments
that
states
suggestion
or
related
teaching
contain no
any
“devoid of
of EDTA were
trations
permeability.
to
(62),
a concentration de-
suggesting
effects
Legal
The
Conclusion of Obviousness
at 188. Mitra states
pendence.” Mitra
“deserve in-
EDTA-drug combinations
that
not
foresight,
is a matter of
Obviousness
likely
that
seems
vestigation,”
“[i]t
but
of obviousness
hindsight. A determination
ca-
high concentration of divalent
that the
suggestion,
reason or
requires some
prevent
film would
tions in the tear
sense,
prior art or
common
Id. Mitra
enhancing permeability.”
from
subject
likely to be effec-
claimed
matter is
drug transport
improving
that while
adds
purpose.
tive for its intended
KSR Int’l
success, “it
found some
across the cornea
Inc.,
398, 420-22,
Corp. v.
550 U.S.
Teleflex
that has
drug
is
the modification
(2007).
1727,
enough concentrations of one or more che-
lators or frequent application at short in-
tervals, preservatives may indeed enter segment
anterior tissue.” Gras at suggested
11. Grass “high enough concen-
trations,” very low concentrations. published contemporaneous state- ELECTRONICS, INC., HALO ments of interpreting scientists their ex- Plaintiff-Appellant periments weight warrant more than un- v. supported opinions appearing for the first in litigation. time Grass did not test the ELECTRONICS, INC., PULSE Pulse composition patented, reported here Corporation, Electronics Defen be a product now of medical choice. Appellants. dants-Cross Senju’s pre-litigation experiments fur- Nos. 2013-1656. support ther the conclusion that one Appeals, United States Court of skilled in the art expected would not have Federal Circuit. to enhance corneal using the method of claim 6. The district court ac- March knowledged that the claimed levels Senju’s EDTA were experiments shown produce significant increase
concentration of aque- Nevertheless, ous humour. the court ON PETITIONS FOR PANEL RE- Senju’s expert faulted because he did not HEARING AND REHEARING EN analysis use statistical to show that BANC. unexpected. analy- effects were Statistical times, helpful sis can indeed be Craig Countryman, but the E. Fish & Richard- P.C., perspective CA, of those Diego, petition skilled the art can- son San filed ignored. not be exception rehearing With the en banc for plaintiff-appel- witnesses, Lupin’s expert petition those skilled in lant. With him on the were Mi- Woodford, art interpreted Senju’s experiments chael Kane J. and William R. demonstrating unexpected Minneapolis, results. MN.