Senju Pharmaceutical Co. Ltd. et al v. Lupin Limited et al
Filing
190
OPINION. Signed by Judge Sue L. Robinson on 8/9/2013. (nmfn)
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE
SENJU PHARMACEUTICAL CO.,
LTO., KYORIN PHARMACEUTICAL
CO., LTD., AND ALLERGAN, INC.,
)
)
)
)
Plaintiffs,
v.
)
)
)
)
LUPIN LIMITED AND LUPIN
PHARMACEUTICALS, INC.,
)
)
)
Defendants.
SENJU PHARMACEUTICAL CO.,
LTO., KYORIN PHARMACEUTICAL
CO., LTO., AND ALLERGAN, INC.,
Plaintiffs,
v.
)
)
)
)
)
)
)
)
)
HI-TECH PHARMACAL CO., INC.,
Defendants.
)
)
)
Civ. No. 11-271-SLR (Consol.)
Jack B. Blumenfeld, Esquire and Maryellen Noreika of Morris, Nichols, Arsht & Tunnell
LLP, Wilmington, Delaware. Counsel for Plaintiffs. Of Counsel: Richard D. Kelly,
Esquire, Stephen G. Baxter, Esquire, Frank J. West, Esquire, Akihiro Yamazaki,
Esquire, and Tia D. Fenton, Esquire of Obion, Spivak, McClelland, Maier & Neustadt,
P.C.
John C. Phillips, Jr., Esquire and Megan C. Haney, Esquire of Phillips, Goldman &
Spence, P.A., Wilmington, Delaware. Counsel for Defendants Lupin Ltd. and
Lupin Pharmaceuticals, Inc. Of Counsel: William A. Rakoczy, Esquire, Paul J. Molino,
Esquire, Deanne M. Mazzochi, Esquire, Anuj K. Wadhwa, Esquire, John D. Polivick,
Esquire, and Brian P. Murray, Esquire of Rakoczy Molino Mazzochi Siwik LLP.
Karen E. Keller, Esquire and Jeffrey T. Castellano, Esquire of Shaw Keller LLP,
Wilmington, Delaware. Counsel for Defendant Hi-Tech Pharmacal Co. Inc.
OPINION
Dated: August 9, 2013
Wilmington, Delaware
~N,
I. INTRODUCTION
This patent infringement litigation is a consolidation of four separate actions by
Senju Pharmaceutical Co., Ltd. ("Senju"), Kyorin Pharmaceutical Co., Ltd. ("Kyorin"),
and Allergan Inc. ("AIIergan") (collectively, "plaintiffs") asserting infringement of
reexamined claims 6 and 12-16 of U.S. Patent No. 6,333,045 ("the '045 patent") 1
against Lupin Limited and Lupin Pharmaceuticals, Inc. ("LPI") (collectively, "Lupin"), and
Hi-Tech Pharmacal Co. Inc. ("Hi-Tech") (all three collectively "defendants"). 2 (D.I. 33,
35; 11-439 D.l. 8; 11-926 D.l. 11; 11-1059 D.l. 9) Defendants answered and Lupin
counterclaimed seeking a declaratory judgment of non-infringement and invalidity. (D.I.
138,139,143, 144) Plaintiffs answered the counterclaims. (D.I.146, 147)
On October 8, 2012, Lupin moved for judgment on the pleadings alleging that
the narrower reexamined claims of the '045 patent were invalid for obviousness and
plaintiffs should be collaterally estopped from relitigating these claims based on the
court's finding in Apotex 1/. 3 (D.I. 105) The court found that, although Lupin might later
1
Piaintiffs also alleged infringement of original claim 7; however, the Federal
Circuit upheld the court's finding that claim 7 was invalid for obviousness. See Senju
Pharmaceutical, Co., Ltd. v. Apotex, Inc., No. 2012-1179 (Fed. Cir. Oct. 5, 2012).
2
The above caption case, filed March 31, 2011, was consolidated with Civ. Nos.
11-439, filed May 18, 2011, against Lupin, as well as 11-926, filed October 11, 2011
and 11-1059, filed October 31, 2011, against Hi-Tech. (D.I. 47) All D.l. #references
are to Civ. No. 11-271, unless indicated by "Civ. No. D.l. #." Plaintiffs also alleged
infringement by United States Patent No. 5,880,283; however, the parties stipulated to
dismiss all claims and counterclaims related to this patent. (D.I. 84, 97)
3
. 0n
June 21, 2010, the court entered judgment in Apotex I that original claims
1-3, 6, 7, and 9 of U.S. Patent No. 6,333,045 were infringed, but invalid. See Senju
Pharm Co. Ltd. v. Apotex Inc., 717 F. Supp. 2d 404 (D. Del. 201 0) (Apotex /), aff'd,
1
succeed in showing that the reexamined claims were invalid, plaintiffs did not fully
litigate a claim with a limitation of 0.01 w/v% disodium edetate ("EDTA") and, therefore,
collateral estoppel could not apply. 4 (D.I. 135)
The '045 patent is directed to aqueous liquid pharmaceutical compositions
comprising gatifloxacin and disodium edetate, as well as various methods utilizing these
compositions. (D. I. 33 at ex. A) Plaintiffs allege infringement by Lupin's Abbreviated
New Drug Application ("ANDA") Nos. 202-653, 0.5 w/v% gatifloxacin ("Lupin 0.5%") and
202-709, 0.3 w/v% gatifloxacin ("Lupin 0.3%"), as well as Hi-Tech's ANDA Nos. 203189,
0.5 w/v% gatifloxacin ("Hi-Tech 0.5%") and 203190, 0.3 w/v% gatifloxacin ("Hi-Tech
0.3%"), 5 which seek FDA approval to market and sell generic copies of plaintiffs' FDA
approved 0.3 w/v% gatifloxacin ophthalmic solution (sold under the trademark
"Zymar®") and/or 0.5 w/v% gatifloxacin ophthalmic solution (sold under the trademark
"Zymaxid®"), which are the commercial embodiments of reexamined claims 6 and
12-16 of the '045 patent. (See JTX 4 (Lupin 0.5%); JTX 5 (Lupin 0.3%); JTX 6 (Hi-Tech
0.5%); JTX 7 (Hi-Tech 0.3%))
The court held a claim construction hearing on December 19, 2012. A bench
trial was conducted from January 14-17,2012, principally to resolve the issues of
Senju Pharmaceutical, Co., Ltd. v. Apotex, Inc., No. 2012-1179 (Fed. Cir. Oct. 5, 2012)
(as to claim 7). After the reexamination certificate issued, plaintiffs filed Apotex II,
based on reexamined claims 6 and 12-16. See Senju Ph arm Co. Ltd. v. Apotex Inc.,
891 F. Supp. 2d 656 (D. Del. 2012) (Apotex II). The court granted Apotex Inc.'s motion
for judgment on the pleadings finding that claim preclusion applied. (/d. at 662)
4
The court declines to entertain defendants' renewed collateral estoppel
argument. (D.I. 188 at 49-21)
5
Collectively "the 0.3% products" and "the 0.5% products."
2
infringement and invalidity, which have been fully briefed post-trial. (D. I. 163, 172, 178,
179, 182, 183) Having considered the documentary evidence and testimony, the court
makes the following findings of fact and conclusions of law pursuant to Fed. R. Civ. P.
52( a).
II. FINDINGS OF FACT
A. The Parties
Senju and Kyorin are corporations organized under the laws of Japan with
principal places of business in Osaka and Tokyo, Japan, respectively. (D.I. 33 at ,-r 2, 3)
Senju develops pharmaceutical products that have applications regarding the eye, ear,
nose, throat and skin. Kyorin engages in the development of pharmaceuticals directed
to infectious, immunological, allergic and metabolic diseases. Allergan is a Delaware
corporation, having its principal place of business in Irvine, California. (/d. at ,-r 4) The
business of Allergan is directed to the development and sale of pharmaceuticals,
biologies and medical devices.
Lupin Limited is an Indian corporation with a place of business in Mumbai, India.
(D. I. 37 at ,-r 5) Lupin develops and manufactures pharmaceutical products, including
generic drug products. LPI is a Virginia corporation, having a place of business in
Baltimore, Maryland.
(/d. at ,-r 7) LPI distributes and sells pharmaceutical products.
Hi-Tech Pharmacal, Inc is a Delaware corporation with a place of business at 369
Bayview Avenue, Amityville, NY 11701. (11-926 D.l. 1 ,-r 5; 11-926 D.l. 14 ,-r 5) Hi-Tech
manufactures, sells and/or offers to sell generic products in the United States.
B. The Patent
3
On December 25, 2001, the original '045 patent, entitled "Aqueous Liquid
Pharmaceutical Composition Comprised of Gatifloxacin," was issued listing Shinichi
Yasueda and Katsuhiro lnada as inventors and Senju and Kyorin as assignees. (0.1.
33, ex. A) On February 25, 2011, plaintiffs filed a request for reexamination of claims
1-3, 6, 8 and 9 of the '045 patent and on October 25, 2011, the examiner allowed the
following reexamined claims, each of which is at issue:
6. A method for raising corneal permeability of an aqueous
pharmaceutical Gatifloxacin eye drop solution comprising
Gatifloxacin or its salt, having a pH of from above 5 to about
6 containing from about 0.3 to about 0.8 w/v% Gatifloxacin
or its salt, which comprises incorporating about 0.01 w/v%
disodium edetate into [eye drops containing Gatifloxacin or
its salt] said Gatifloxacin eye drop solution.
12. An aqueous liquid pharmaceutical eye drop composition
which comprises from about 0.3 to about 0.8 w/v%
Gatifloxacin or its salt, about 0.01 w/v% disodium edetate,
and wherein the aqueous liquid pharmaceutical composition
has a pH of from about 5 to about 6.
13. The aqueous liquid pharmaceutical eye drop
composition according to claim 12, comprising about 0.3
w/v% Gatifloxacin or its salt.
14. The aqueous liquid pharmaceutical eye drop
composition according to claim 12, comprising about 0.5
w/v% Gatifloxacin or its salt.
15. The aqueous liquid pharmaceutical eye drop
composition according to claim 12, comprising at least one
isotonic agent selected from the group consisting of sodium
chloride, potassium chloride, glycerin, mannitol and glucose.
16. The aqueous liquid pharmaceutical eye drop
composition according to claim 14, wherein the at least one
isotonic agent is sodium chloride.
'045 patent, 1:25-2:24.
4
C. The Asserted Prior Art
1. Gatifloxacin
Fluoroquinolones, otherwise known as quinolone carboxylic acids or simply
"quinolones," are a class of broad spectrum antibacterial compounds 6 that share a
common core chemical structure. (See U.S. Patent No. 4,980,470 ("the '470 patent"),
abstract; D.1. 166 at 595:22-596:15) The '470 patent, 7 which was before the examiner
during the prosecution of the '045 patent, claims gatifloxacin 8 and its acid derivatives.
The properties of this fourth generation quinolone are revealed following a discussion of
previously discovered quinolones, to wit, norfloxacin, ofloxacin and ciprofloxacin. ('470
patent, 1:32-61) The '470 patent teaches that gatifloxacin represents an improvement
over the prior art quinolones in that it exhibits a broader antibacterial activity, higher
selective toxicity and safe oral and parenteral administration. (1 :62-2:7) In a passing
reference to chemical structure, the '470 patent explains that each of the disclosed
quinolones have "similar substituents." (1 :41-43) Defendants' expert, Dr. Sherman,
testified that the prior art quinolones and gatifloxacin are structurally similar. (D .I. 166 at
595:22-596:15) Dr. Sherman further testified that gatifloxacin is a polar compound due
to its ability to readily ionize and because it contains several polar moieties. (!d. at
596:16-597:2)
6
Quinolones demonstrate high activity against both gram-negative and grampositive bacteria. ('470 patent, 1 :32-35)
7
The '470 patent issued to Kyorin on December 25, 1990. (JTX 12)
8
The IUPAC, or systematic, name for gatifloxacin is 1-cyclopropyl-6-fluoro-1 ,4dihydro-8-methoxy-7(3-methyl-1-piperazinyl)-4-oxo-3-quinoline carboxylic acid.
5
2. Disodium edetate
Disodium edetate is the disodium salt of ethylenediamine tetraacetic acid
(commonly known as "EDTA"). 9 (D. I. 166 at 600:25-601 :4) EDTA, a multi-purpose
excipient, 10 is widely known as a chelating agent. 11 (/d. at 589:10-590:12) In Griffith, 12 a
September 1967 article, EDTA was found to prevent coloration in a variety of active
pharmaceutical ingredients by "sequestering" metal ions through a chelating
mechanism. (DTX-981; D. I. 166 at 610-612) Griffith teaches that disodium edetate, in
concentrations of between 0.005 and 0.02 w/v%, prevented coloration of papaverine
hydrochloride and that, in concentrations between 0.005 and 0.04 w/v%, it similarly
prevented coloration in other pharmaceutical agents. (DTX-981)
EDTA is also known to increase corneal permeability of certain polar
compounds. (See JTX 9) A layer of epithelial cells, bound tightly together by calcium
ions, forms a protective barrier that prevents foreign molecules from entering the eye.
9
Because the principles of solution chemistry render EDTA and disodium edetate
functionally equivalent, and insofar as the parties make no distinguishing arguments on
these grounds, the court treats a prior art disclosure of a property of one compound as
the disclosure of the property with respect to both, and refers to these compounds
interchangeably.
10
The 1986 Handbook of Pharmaceutical Excipients discloses that EDTA, in
addition to its chelating function, may act as an antibacterial synergyst/preservative
enhancer. (DTX 1097)
11
A chelating agent can complex with certain undesirable ions (generally metals),
thereby removing them from solution. (D. I. 166 at 589-90)
12
"Griffith" is D.E. Griffith, Improvement of the Color Stability of Parenteral
Solutions of Papaverine Hydrochloride, 56 Journal of Pharm. Sciences, 1197-98
(1967). (DTX-981)
6
(/d. at 111) In Grass (1985), 13 considered during the prosecution and reexamination of
the '045 patent, the authors sought to determine the effect of EDTA on the permeability
of organic and inorganic compounds with respect to the corneal epithelia. 14 (/d. at 11 0)
Grass (1985) teaches that EDTA can reduce the number of calcium ions through
chelation, thus creating small channels between corneal epithelial cells. (See id.)
These channels allow polar molecules to penetrate through the cornea into the
aqueous humor of the eye. (See id.) In reporting the results of this study, Grass (1985)
describes how the addition of 0.5 w/v% disodium edetate to separate solutions of
glycerol and cromolyn resulted in increased corneal permeability in both solutions. (/d.
at 112) A lower unspecified concentration of EDTA was also shown to function in this
manner, albeit to a lesser extent. 15 (/d.) The authors of Grass (1985) conclude that the
propensity of EDTA to increase corneal permeability of polar compounds has a "direct
bearing upon ophthalmic solutions currently in use." 16 (JTX 12 at 112-13)
13
"Grass (1985)" is Grass et al., Effects of Calcium Chelating Agents on Corneal
Permeability, 26 Investigative Ophthalmology & Visual Science 110 (1985). (JTX 9)
14
The authors note that "the effects of chelating agents such as EDTA on the
permeability of inorganic and organic solutes have been well documented in other
epithelia, as well as the corneal endothelium, [but] no definitive studies examining the
effects of these compounds upon the corneal epithelia have been reported." (ld.)
15
1n one example, the authors inhibited corneal permeability of a solution of
glycerol and 0.5 w/v% EDTA by adding calcium to the solution. This calcium complexes
with the EDTA, leaving less EDTA to interact with the calcium ions in the corneal
epithelia.
16
Giycerol is a small polar compound, while cromolyn is a large pharmaceutically
active polar compound. (JTX 12 at 112; see also D.l. 166 at 495-97)
7
After building on this work, Dr. Grass authored two additional papers in 1988. 17
These papers tested lower concentrations of 0.1, 0.05 and 0.01 w/v% EDTA, finding
increased corneal permeability at these lower concentrations. (JTX 50; JTX 53)
Rojanasakul 18 built further on these teachings by testing EDTA concentrations as low as
0.00037 w/v% EDTA, and finding that even those very low concentrations increased
corneal permeability to some degree. (JTX 51 at 5, 12, fig.9)
3. Aqueous quinolone ophthalmic compositions comprising
disodium edetate
U.S. Patent No. 4,551,456 ("the '456 patent") issued on November 5, 1985, and
teaches that then-known quinolones 19 are both "compatible with ocular tissue" and
useful in treating bacterial ocular infections through topical administration. (JTX 10, the
'456 patent, 1:13-17) One of two exemplary ophthalmic compositions disclosed by the
'456 patent comprises an aqueous solution of 0.3 w/v% norfloxacin and 0.01 w/v%
disodium edetate. The '456 patent discloses EDTA in a list of 8 excipients described as
"conventional ingredient[s]" in ophthalmic compositions. (/d., col. 2:5-10)
U.S. Patent No. 4,780,465 ("the '465 patent") issued on October 25, 1988, and
17
"Grass (1988 I)" is Grass et al., Mechanisms of Corneal Drug Penetration 1: In
Vivo and In Vitro Kinetics, 77 Journal of Pharm. Sciences 3 (1988). (JTX 50) "Grass
(1988 II)" is Grass et al., Mechanisms of Corneal Drug Penetration II: Ultrastructural
Analysis of Potential Pathways for Drug Movement, 77 Journal of Pharm. Sciences, 15
(1988). (JTX 53) Collectively with Grass (1985), "Grass references."
18
"Rojanasakul" is Rojanasakul et al., Mechanisms of action of some penetration
Enhancers in the Cornea: Laser Scanning Confocal Microscopic and Electrophysiology
Studies, 66 lnt'l Journal of Pharm., 131 (1990). (JTX 51)
19
The quinolones discussed by the '456 patent include norfloxacin, ofloxacin,
perfloxacin, enoxacin and ciprofloxacin. (!d. at col. 1:30-36)
8
discloses aqueous compositions for the quinolone lomefloxacin; it likewise
characterizes disodium edetate as a conventional excipient. (JTX 11, the '465 patent,
2:31-46) The '465 patent addresses the low solubility exhibited by lomefloxacin
solutions containing sodium chloride, another common eye drop excipient. (3:7-20)
The inventors of the '465 patent solve these solubility issues irrespective of the
presence of disodium edetate in the composition. Two exemplary ophthalmic
compositions described in the '465 patent, similar to the ophthalmic composition
disclosed by the '456 patent, contain 0.3 w/ v% lomefloxacin and 0.01 w/v% disodium
edetate. (4:1-23)
Consistent with the '456 and '465 patents, the '470 patent discloses that
pharmaceutical formulations of gatifloxacin follow "the routes well known ... "with
respect to "oral [] and parenteral [ ]" administration, including "liquids [and] eye drops ..
. ." (470 patent at col. 7:21-26) While the '470 patent does not provide any guidance
regarding these formulations, the 1995 Physician's Desk Reference ("the PDR")
provides several example formulations of then available quinolone ophthalmic solutions.
(See DTX 1098)
Ill. CONCLUSIONS OF LAW
A. Claim Construction
1. Standard
Claim construction is a matter of law. Phillips v. A WH Corp., 415 F.3d 1303,
1330 (Fed. Cir. 2005) (en bane). Claim construction focuses on intrinsic evidence- the
claims, specification and prosecution history - because intrinsic evidence is "the most
9
significant source of the legally operative meaning of disputed claim language."
Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996); Markman v.
Westview Instruments, Inc., 52 F.3d 967, 979 (Fed. Cir. 1995) (en bane), aff'd, 517 U.S.
370 (1996). Claims must be interpreted from the perspective of one of ordinary skill in
the relevant art at the time of the invention. Phillips, 415 F.3d at 1313.
Claim construction starts with the claims, id. at 1312, and remains centered on
the words of the claims throughout. Interactive Gift Express, Inc. v. Compuserve, Inc.,
256 F.3d 1323, 1331 (Fed. Cir. 2001 ). In the absence of an express intent to impart
different meaning to claim terms, the terms are presumed to have their ordinary
meaning. /d. Claims, however, must be read in view of the specification and
prosecution history. Indeed, the specification is often "the single best guide to the
meaning of a disputed term." Phillips, 415 F.3d at 1315.
2. Analysis
The court construes the preamble of claim 6, "[a] method for raising corneal
permeability of an aqueous pharmaceutical Gatifloxacin eye drop solution," to mean
"[s]howing an increased concentration of gatifloxacin in the aqueous humor.'120 The
specification supports this construction, clarifying that it is the pharmacological agent,
gatifloxacin, whose corneal permeability is sought to be increased. ('045 patent, 1:2733, 1:61-2:4) The examiner cited the increase in corneal permeability of gatifloxacin
using the 0.01% EDTA as reason for allowance of the reexamined claim. (JTX 3 at
20
Defendants' position that this construction does not distinguish eye drops from
ear or nose drops is not convincing as increasing corneal permeability is logically limited
to the eye. Also, the claim ends with "said Gatifloxacin eye drop solution."
10
ALL0013974)
A. Infringement
1. Standard
A patent is infringed when a person "without authority makes, uses or sells any
patented invention, within the United States ... during the term of the patent." 35
U.S.C. § 271 (a). A two-step analysis is employed in making an infringement
determination. See Markman v. Westview Instruments, Inc., 52 F.3d 967, 976 (Fed.
Cir. 1995). First, the court must construe the asserted claims to ascertain their meaning
and scope. See id. Construction of the claims is a question of law subject to de novo
review. See Cybor Corp. v. FAS Techs., 138 F.3d 1448, 1454 (Fed. Cir. 1998). The
trier of fact must then compare the properly construed claims with the accused
infringing product. See Markman, 52 F.3d at 976. This second step is a question of
fact. See Bai v. L & L Wings, Inc., 160 F.3d 1350, 1353 (Fed. Cir. 1998).
"Direct infringement requires a party to perform each and every step or element
of a claimed method or product." BMC Res., Inc. v. Paymentech, L.P., 498 F.3d 1373,
1378 (Fed. Cir. 2007), overruled on other grounds by 692 F.3d 1301 (Fed. Cir. 2012).
"If any claim limitation is absent from the accused device, there is no literal infringement
as a matter of law." Bayer AG v. Elan Pharm. Research Corp., 212 F.3d 1241, 1247
(Fed. Cir. 2000). If an accused product does not infringe an independent claim, it also
does not infringe any claim depending thereon. See Wahpeton Canvas Co. v. Frontier,
Inc., 870 F.2d 1546, 1553 (Fed. Cir. 1989). However, "[o]ne may infringe an
independent claim and not infringe a claim dependent on that claim." Monsanto Co. v.
11
Syngenta Seeds, Inc., 503 F.3d 1352, 1359 (Fed. Cir. 2007) (quoting Wahpeton
Canvas, 870 F.2d at 1552) (internal quotations omitted). A product that does not
literally infringe a patent claim may still infringe under the doctrine of equivalents if the
differences between an individual limitation of the claimed invention and an element of
the accused product are insubstantial. See Warner-Jenkinson Co. v. Hilton Davis
Chern. Co., 520 U.S. 17, 24 (1997). The patent owner has the burden of proving
infringement and must meet its burden by a preponderance of the evidence. See
SmithKiine Diagnostics, Inc. v. Helena Lab. Corp., 859 F.2d 878, 889 (Fed. Cir. 1988)
(citations omitted).
For there to be infringement under the doctrine of equivalents, the accused
product or process must embody every limitation of a claim, either literally or by an
equivalent. Warner-Jenkinson, 520 U.S. at 41. An element is equivalent if the
differences between the element and the claim limitation are "insubstantial." Zelinski v.
Brunswick Corp., 185 F.3d 1311, 1316 (Fed. Cir. 1999). One test used to determine
"insubstantiality" is whether the element performs substantially the same function in
substantially the same way to obtain substantially the same result as the claim
limitation. See Graver Tank & Mfg. Co. v. Linde Air Products Co., 339 U.S. 605, 608
(1950). This test is commonly referred to as the "function-way-result" test. The mere
showing that an accused device is equivalent overall to the claimed invention is
insufficient to establish infringement under the doctrine of equivalents. The patent
owner has the burden of proving infringement under the doctrine of equivalents and
must meet its burden by a preponderance of the evidence. See Smith Kline
12
Diagnostics, Inc. v. Helena Lab. Corp., 859 F.2d 878, 889 (Fed. Cir. 1988) (citations
omitted).
2. Discussion
a. Claims 12-16
Plaintiffs presented evidence at trial showing that the ANDA products meet each
element of claim 12 and its dependant claims. Although patent infringement and
invalidity are separate and distinct issues, defendants presented no evidence of noninfringement at trial and their experts testified that they were not asked to opine on
infringement of reexamined claims 12-16. (D.I. 172 at 33; D.l. 166 at 527:19-529:4 (Dr.
Grass); D.l. 166 at 654:13-655:8 (Dr. Sherman)); Medtronic, Inc. v. Cardiac
Pacemakers, Inc., 721 F.2d 1563, 1583 (Fed. Cir. 1983) ("Though an invalid claim
cannot give rise to liability for infringement, whether it is infringed is an entirely separate
question capable of determination without regard to its validity.").
In response to plaintiffs' motion for judgment as a matter of law on the issue of
infringement, defendants' counsel argued for the first time that the pH ranges described
by the ANDA specifications actually allow the products to exceed a pH of 6. (D.I. 167 at
777:18-22) Therefore, "because it is possible for the parties to manufacture a product
that's ... compliant with their ANDA specifications ... where there is not an overlap of
the infringing range called for by the patent," some of defendants' products do not
infringe. (/d. at 777:24-778:7) This argument only applies to Lupin 0.3% (pH 5.7-6.3)
and Hi-Tech 0.3% (pH 5.5-6.5). 21 (JTX 5 LUGA669; JTX 7 at HITECHPHARM3007,
21
The Lupin 0.5% has a pH range of 5.1 to 5.7 (JTX 4 at LUGA4517) and HiTech
0.5% has a pH range of 5.3 and 5.5 (JTX 6 at HITECHPHARM182).
13
3128) The court will not entertain this argument which, although creative, was not
asserted by defendants prior to trial. There was no expert opinion offered to support it,
nor was it vetted through discovery. 22 The court concludes that plaintiffs have
demonstrated that the ANDA products infringe the composition claims 12-16 of the '045
patent.
b. Claim 6
Method claim 6 is directed towards an eye drop solution having all the claimed
components of claim 12. 23 As the court has construed the language, this claim further
requires plaintiffs to show that the solution "show[s] an increased concentration of
gatifloxacin in the aqueous humor." Plaintiffs are not required to test defendants'
proposed ANDA products, but instead "may prove infringement by any method of
analysis that is probative of the fact of infringement, and circumstantial evidence may
be sufficient." Martek Biosciences Corp. v. Nutrinova, Inc., 579 F.3d 1363, 1372 (Fed.
Cir. 2009). Plaintiffs submit that in vivo rabbit eye corneal permeability testing by Senju
("the Senju studies") demonstrates that the addition of 0.01% EDTA increases corneal
permeability of gatifloxacin in the proposed 0.3 w/v% and 0.5 w/v% products. The
Senju studies, performed prior to the filing of the ANDAs, compared the corneal
permeability of a 0.3 w/v% gatifloxacin eye drop solution with another solution identical
22
Moreover, this argument is largely contradicted by the evidence of record. The
testimony and ANDAs show that 6.0 is the target pH for both the Lupin 0.3% and
HiTech 0.3%, which would meet the claim element of about 5 to about 6. (See e.g. D. I.
165 at 239:8-240:19, 261:14-262:11; D.l. 165 at 288:3-21; JTX 5 at LUGA141, 661;
JTX 7 at HITECHPHARM3040, 3086)
23
As found above, defendants' products contain all the components of the
product claims.
14
but for the additional inclusion of EDTA. (JTX 15; JTX 16) The results of these studies
demonstrated that the gatifloxacin concentrations in the aqueous humor were
significantly higher for the solution containing EDTA. (D.I. 165 at 336-339)
Defendants provide several reasons why this evidence cannot demonstrate that
the ANDA products infringe claim 6. Defendants argue that, in contrast to the ANDA
products, the formulations in the Senju studies did not contain benzalkonium chloride
("BAK"). (JTX 15 at 2; JTX 16 at 2-3) This results in a material difference, according to
defendants, because BAK is a known corneal permeability enhancer. (D.I. 165 at
411:10-17 (Dr. Stella); D.l. 166 at 523:13-16; 650:5-653:15 (Drs. Grass and Sherman);
see also DTX 1063; DTX 1064; DTX 1352) Plaintiffs maintain, based on internal
testing, that the inclusion of 0.005 w/v% BAK would not increase, or would minimally
increase, the corneal permeability of gatifloxacin. (D.I. 164 95:6-14; D. I. 165 at 346:24347:6) Consistent with both parties' experts, the court agrees that the inclusion of BAK
would not negate the increase in corneal permeability caused by 0.01 w/v% EDTA.
(D.I. 165 at 347:12-16; D.l. 166 at 662:4-15)
Defendants criticize the Senju studies, arguing that the triplicate dosing protocol
used in JTX 15 cannot provide reliable data for the addition of 0.01 w/v% EDTA and
that, because of the low "n" number and the high degree of variability in the results, JTX
16 is not reliable. Further, defendants' expert opined that the studies were not
hypothesis driven (the purpose of JTX 15 was to show that 0.01 w/v% EDTA prevents
discoloration) and were not subject to peer review. Weighing these criticisms against
the opinions of defendants' experts, Dr. Grass and Dr. Sherman, that these side-byside comparison studies were a "fair" means of assessing the effect of EDTA on the
15
corneal permeability of gatifloxacin (D.I. 166 at 658:9-20, 491:1 0-22; D.l. 167 at 839:2124), the court finds, similarly to Apotex /, that the Senju studies are probative and
concludes that it is appropriate for the purposes of infringement to equate the 0.3%
accused products with the 0.3 w/v% gatifloxacin solution containing disodium edetate
from the Senju studies.
As to the 0.5% products, plaintiffs' expert testified that a parallel comparison of a
0.5 w/v% solution with and without 0.01 w/v% EDTA showed an increase in corneal
permeability. (JTX 14; D. I. 165 at 408:12-409:1, 410:4-19) Defendants' expert, Dr.
Sherman, agreed at deposition that, based on the prior art, he had no reason to think
that the 0.01 w/v% EDTA would not increase corneal permeability. (D.I. 166 at 656:17658:3) Although defendants argue that there is no evidence for Dr. Stella to reliably
opine that the 0.05 %w/v solutions infringe, the court disagrees. Based on the
testimony presented, there is support for the proposition that the use of EDTA in the
0.5% products also shows an increase in corneal permeability.
Defendants argue that Hi-Tech's addition of gatifloxacin to a solution containing
EDTA precludes literal infringement of claim 6, which requires addition of EDTA to a
gatifloxacin eye drop solution. (D.I. 179 at 28-29) Plaintiffs respond that the claim does
not require the addition of EDTA in any particular order and that Hi-Tech's order of
addition results in a bioequivalent solution and infringement under the doctrine of
equivalence. 24 "Unless the steps of a method actually recite an order, the steps are not
24
Defendants' argument that plaintiffs waived any doctrine of equivalents
argument is undermined by Dr. Stella's expert report, where he opines, although briefly,
"that the case law permits the steps of a process (e.g. order of addition) to be changed
and infringement to be found" and "that whether the addition of disodium edetate
16
ordinarily construed to require one." Interactive Gift Express, Inc. v. Compuserve Inc.,
256 F.3d 1323, 1342-43 (Fed. Cir. 2001 ). To determine whether the steps of a method
claim that do not otherwise recite an order, must nonetheless be performed in the order
in which they are written, a court should look to the claim language to determine if, as a
matter of logic or grammar, the steps must be performed in the order written and next
look to the rest of the specification to determine whether it "directly or implicitly requires
such a narrow construction." /d. at 1343 (finding that neither the claim or specification
required the steps be performed in order and holding that the claim was not limited to
embodiments that performed the steps in order, but covered real-time transactions);
Lora/ Fairchild Corp. v. Sony Electronics Corp., 181 F.3d 1313, 1321 (Fed. Cir. 1999)
(holding that the claim language itself indicated that the steps had to be performed in
their written order because the second step required the alignment of a second
structure with a first structure formed by the prior step); Mantech Envtl. Corp. v. Hudson
Envtl. Servs., Inc., 152 F.3d 1368, 1375-76 (Fed. Cir. 1998) (holding that the steps of a
method claim had to be performed in their written order because each subsequent step
referenced something logically indicating the prior step had been performed).
In this case, claim 6 "comprises incorporating about 0.01 w/v% disodium edetate
into said Gatifloxacin eye drop solution." The examples in the specification recite
formulations and specify that "aqueous liquid preparations of Gatifloxacin were
occurs before or after the addition of Gatifloxacin, the same increased corneal
permeability would be obtained over that identical solution but without disodium
edetate, and would [sic] it would be achieved in the same manner by including disodium
edetate in a eye drop solution containing Gatifloxacin." (0.1. 182, ex. 2 at,-r,-r 134,141,
158, 162)
17
prepared" without describing or attributing any importance to the order of addition of the
ingredients. ('045 patent, 4:24-27, tb1.3, 5:39-8:1 0) In one example, the gatifloxacin
and EDTA were added at the same time. (/d. at 4:63-66) The court concludes that no
order of addition is necessarily described or required.
For completeness, the court turns its attention to the doctrine of equivalents
argument, wherein plaintiffs contend that
Hi-Tech's inclusion of 0.01 w/v% EDTA prior to the addition
of gatifloxacin has no effect on the final product's qualities
and performs the same function (increasing corneal
permeability of gatifloxacin), in the same way (by including
0.01 w/v% EDTA in the solution), and achieves the same
result (increased concentration of gatifloxacin in the
aqueous humor) as including 0.01 w/v% EDTA after the
addition of gatifloxacin.
(0.1. 182 at 21 (citing D. I. 165 at 356:24-358:7, 285:8-286:7; D. I. 172 at 45-48) While
"the bioequivalency of an accused product with a product produced from the patent at
issue is not sufficient to establish infringement by equivalents," bioequivalence "may be
relevant to the function prong of the function-way-result test. Abbott Laboratories v.
Sandoz, Inc., 566 F.3d 1282, 1298 (Fed. Cir. 2009). Here, Hi-Tech relied on the
similarity of its products to plaintiff's products to obtain a bioequivalence waiver. (0.1.
179 at 30) Hi-Tech dissolves EDTA in purified water for the ease of manufacturing. No
testimony was offered that the order of addition of the components is material to the
properties of the eye drop solutions. The purpose of the patent is the inclusion of
EDTA to increase the corneal permeability of gatifloxacin. Even if the court accepts
defendants' argument that the function of the "incorporating" step is to incorporate
EDTA into a gatifloxacin solution, the incorporation of EDTA into a solution is the
18
process step and this step is also accomplished in Hi-Tech's process, albeit that EDTA
is added before the gatifloxacin.
As discussed above, defendants' products contain each of the components of
claim 6. Further, the court is satisfied that the accused products additionally satisfy the
limitation of increasing the corneal permeability of gatifloxacin. Therefore, the court
concludes that plaintiffs have shown, by a preponderance of the evidence, that
defendants' ANDA products infringe claim 6. 25
c. Miscellaneous defenses to infringement
Lupin argues that its products are made in India; specifically, the "incorporation"
step is performed in India and, therefore, it cannot be found liable under 35 U.S.C. §
271 (a) or (g) for methods that do not occur in the United States. (JTX 4 at 77; JTX 5 at
75; D.l. 167 at 752:16-19; 761 :11-14) Plaintiffs respond seeking a declaration that
claim 6 is infringed under U.S.C. § 271 (a) because Lupin's products are made by the
process of claim 6. The court concludes that Lupin's sale within the United States of its
ANDA products will infringe under § 271 (g) as it will "import[] into the United States or
offer[] to sell ... within the United States a product which is made by a process
patented in the United States." 26
25
The court declines to entertain defendants' defense that their products do not
infringe because they are not seeking to use them to "raise corneal permeability." This
defense was raised for the first time in the pre-trial order and was not vetted through
discovery. (D. I. 136, ex. 5 at ,-r,-r 59-62)
26
Defendants' cited cases are inapposite. See Joy Technologies, Inc. v. Flakt,
Inc., 6 F.3d 770, 773-74 (Fed. Cir. 1993) (holding that the sale of equipment which
performs a patented process is not itself direct infringement of the process); NTP, Inc.
v. Research In Motion, Ltd., 418 F.3d 1282, 1323-24 (Fed. Cir. 2005) (determining that
email packets were not physical products, thus § 271 (g) could not apply).
19
B. Obviousness
1. Standard
"A patent may not be obtained ... if the differences between the subject matter
sought to be patented and the prior art are such that the subject matter as a whole
would have been obvious at the time the invention was made to a person having
ordinary skill in the art." 35 U.S.C. § 103(a). Obviousness is a question of law, which
depends on several underlying factual inquiries.
Under§ 103, the scope and content of the prior art are to be
determined; differences between the prior art and the claims
at issue are to be ascertained; and the level of ordinary skill
in the pertinent art resolved. Against this background the
obviousness or nonobviousness of the subject matter is
determined. Such secondary considerations as commercial
success, long felt but unsolved needs, failure of others, etc.,
might be utilized to give light to the circumstances
surrounding the origin of the subject matter sought to be
patented.
KSR lnt'l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007) (quoting Graham v. John Deere
Co., 383 U.S. 1, 17-18 (1966)).
"[A] patent composed of several elements is not proved obvious merely by
demonstrating that each of its elements was, independently, known in the prior art."
KSR, 550 U.S. at 418. Likewise, a defendant asserting obviousness in view of a
combination of references has the burden to show that a person of ordinary skill in the
relevant field had a reason to combine the elements in the manner claimed. /d. at
418-19. The Supreme Court has emphasized the need for courts to value "common
sense" over "rigid preventative rules" in determining whether a motivation to combine
existed. /d. at 419-20. "[A]ny need or problem known in the field of endeavor at the
20
time of invention and addressed by the patent can provide a reason for combining the
elements in the manner claimed." /d. at 420. In addition to showing that a person of
ordinary skill in the art would have had reason to attempt to make the composition or
device, or carry out the claimed process, a defendant must also demonstrate that "such
a person would have had a reasonable expectation of success in doing so."
PharmaStem Therapeutics, Inc. v. ViaCe/1, Inc., 491 F.3d 1342, 1360 (Fed. Cir. 2007).
"Because patents are presumed to be valid, see 35 U.S.C. § 282, an alleged infringer
seeking to invalidate a patent on obviousness grounds must establish its obviousness
by facts supported by clear and convincing evidence." Kao Corp. v. Unilever U.S., Inc.,
441 F.3d 963, 968 (Fed. Cir. 2006) (citation omitted). In conjunction with this burden,
the Federal Circuit has explained that,
[w]hen no prior art other than that which was considered by
the PTO examiner is relied on by the attacker, he has the
added burden of overcoming the deference that is due to a
qualified government agency presumed to have properly
done its job, which includes one or more examiners who are
assumed to have some expertise in interpreting the
references and to be familiar from their work with the level of
skill in the art and whose duty it is to issue only valid patents.
PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 1304 (Fed. Cir. 2008) (quoting
Am. Hoist & Derrick Co. v. Sowa & Sons, 725 F.2d 1350, 1359 (Fed. Cir. 1984)).
2. Discussion
The differences between the reexamined '045 patent claims and the prior art
may be summarized as: (1) using 0.3 w/v% to 0.8 w/v% gatifloxacin; (2) having a pH of
above 5 to about 6; and (3) using 0.01 w/v% EOTA to increase corneal permeability.
(0.1. 178 at 29; 0.1. 183 at 1) As the court recognized in its order on defendants' motion
21
for judgment on the pleadings, the court in Apotex I did not make specific findings for a
claim with a limitation of 0.01 w/v% EDTA. (D.I. 135 at 7) While plaintiffs remain
determined to reargue each limitation of the reexamined claims, the court will not
entertain each of these as new arguments separate from its findings in Apotex /.
a. Claims 12-16
The court adopts its previous analysis of the use of gatifloxacin and EDTA.
Specifically, the court concludes that "it would be obvious for one of ordinary skill to
substitute the gatifloxacin of the '470 patent for any of the quinolones described by the
'456 patent in the prior art quinolone compositions .... " Apotex /, 717 F. Supp. at 421.
Thus, the use of gatifloxacin for an ophthalmic solution is obvious in view of the '456
and '470 patent. /d. at 420-21. Moreover, the court again declines to accept the
characterization of the prior art disclosure of EDTA as among a laundry list of
excipients, as EDTA is listed among eight "conventional ingredients" in the '456 patent
and a similarly small group of excipients, making it not remotely approaching an infinite
genus. ('456 patent, 2:1-16; '465 patent, 2:36-49); see Apotex /, 717 F. Supp. at 420
(citing In re Baird, 16 F.3d 380, 382 (Fed. Cir. 1994)). The court also adopts its
conclusion that the use of gatifloxacin with EDTA would have been obvious to a person
of skill in the art. With this preliminary guidance, the court turns its attention to the
particular issues of the reexamined claims, specifically, narrower ranges for both
gatifloxacin and EDTA.
The use of 0.3 to 0.8 w/v% of gatifloxacin is outlined in the prior art. ('456
patent, 1:37-43 ("from about 0.03 to 3%"); '465 patent, 2:22-25 ("preferably about 0.3%
22
to 5% w/v"). The court concludes that the concentration range of gatifloxacin in the
reexamined claims is explicitly recited in the prior art. Moreover, the use of 0.01 w/v%
of EDTA was also known:
[T]he prior art reveals that disodium edetate is a
conventional excipient with beneficial properties used in
aqueous ophthalmic quinolone compositions. Multiple
commercial and noncommercial quinolone compositions
utilized disodium edetate in an amount of 0.01 w/v%, i.e.,
within the concentration range of 0.001 to 0.2 w/v% claimed
by the '045 patent.
Apotex I, 717 F. Supp. at 421. Specifically, the '456 patent discloses an exemplary
formulation of a 0.3% quinolone solution that incorporates 0.01 w/v% EDTA. (4:1-23)
Plaintiffs argue that the pH range from about 5 to about 6 distinguishes the
claims from the prior art. The court disagrees. The prior art ophthalmic quinolone
compositions included eye drops maintained at a pH of between 5 and 8. See Apotex I,
717 F. Supp. at 420. Specifically, the '456 patent teaches solutions with a pH of 5.2.
(3:35-37; see a/so D.l. 166 at 591:19-592:4; 629:17-630:7) The '465 patent teaches
solutions with pH ranges between 3 and 6.5 (2:32) and with the preferred range of 4 to
6.5 (2:32-33). (See a/so D.l. 166 at 593:1-6; 629:17-630:7; D.l. 167 at 799:1-2) The
target pH in the examples of the '465 patent is 6.0. (/d. at 3:24-4:34) Therefore, the pH
range does not distinguish the reexamined claims from the prior art.
The court concludes that the combination of the '456, '465 and '470 patents
discloses each limitation of the product claims. 27 Defendants have presented a prima
27
Piaintiffs contend that these references do not address improving corneal
permeability and, further, that the inventors of the '045 patent encountered challenges
and "methodically experimented with various formulations for efficacy and stability
before accidentally happening upon low concentrations of EDTA as a successful
23
facie case of obviousness with respect to claims 12-16. It would have been obvious for
one of ordinary skill to arrive at the products of the reexamined claims 12-16 of the '045
patent, with the reasonable expectation that it would result in an aqueous formulation,
by substituting the gatifloxacin of the '4 70 patent for any of the quinolones described by
the '456 patent, in the prior art quinolone compositions comprising disodium edetate, as
described in the '465 patent.
b. Claim 6
Defendants rely on the '456, '465, '470 patents, the Grass references, and
Rojanasakul to argue that the method of claim 6 is obvious, i.e., to show that using 0.01
w/v% EDTA would result in an increase in corneal permeability. Plaintiffs argue that the
prior art does not teach or suggest using the combination of 0.01 w/v% EDTA with a
gatifloxacin ophthalmic solution at a pH of from about 5 to about 6 to create a stable
solution with increased corneal permeability. The court begins with the reasoning from
Apotex I, namely, that
[w]ith respect to the ... [EDTA] concentration range of 0.001
to 0.2 w/v%, the record demonstrates that one skilled in the
art would understand [Grass (1985)] to suggest that EDTA
concentrations lower than 0.5 w/v% would be effective in
view of the increased corneal permeability of the 0.5 w/v%
EDTA formulation to which calcium was added. Accordingly,
one of ordinary skill would apply this teaching in conjunction
with the pre-existing quinolone formulations, which
incorporated between 0.05 and 0.1 w/v% EDTA, in arriving
at a gatifloxacin formulation characterized by increased
corneal permeability.
excipient that unexpectedly increased the corneal permeability of the gatifloxacin." (D.I.
178 at 30-34) The court declines to address this argument with respect to claims 12-16,
as the product claims do not include a limitation of increasing corneal permeability.
24
Apotex I, 717 F. Supp. 2d at 421-22. The court concluded that "the step of adding
[EDTA] (even at a concentration as low as 0.1 w/v%) to a solution of gatifloxacin eye
drops would demonstrate an increased concentration of gatifloxacin in the aqueous
humor."
Plaintiffs assert that the prior art teaches that the use of 0.01 w/v% EDTA fails to
increase corneal permeability of either of the polar compounds tested. (JTX 50 at tbl.
XIII and JTX 53 at 5, 9) The record reflects otherwise. The prior art teaches that
adding EDTA to any polar compound solution will increase corneal permeability dosedependently. (D.I. 166 at 505:11-22; see, e.g., the Grass references) After
experimenting with higher concentrations, Grass (1988 I) tested 0.1, 0.05, and 0.01
w/v% of EDTA, finding that each concentration raised corneal permeability; however,
the increases were not all statistically significant. (JTX 50 at tbl. XIII) Specifically using
0.01 w/v% EDTA, the researchers found a permeability coefficient for methanol of 99.5
(control was 91.3) and for glycerol, 4.53 (control was 4.47). 28 (/d.) Researchers
28
Table 50 is reproduced below:
p
105,a
95% CL
105·b
Name
Added Agent
Methanol
Control
91.3
9.4
-
Methanol
0.01% EDTA
99.5
6.0
0
Methanol
0.1% EDTA
108.9
14.0
0
Glycerol
Control
4.47
2.45
-
Glycerol
0.01% EDTA
4.53
1.61
0
Glycerol
0.05% EDTA
8.41
1.46
88
Glycerol
0.1% EDTA
18.2
7.4
307
X
"Permeability coefficient. b95% confidence limit.
25
X
Percent Change in Permeability over
Control
calculated the percent change in permeability over the control, which was zero for both
methanol and glycerol. (/d.) Plaintiffs focus on this percent change to conclude that the
data showed no increase in corneal permeability. Defendants concede that the percent
changes were not statistically significant; however, defendants' expert points out that a
person of ordinary skill would have recognized from the data that the 0.01 w/v% EDTA
would increase corneal permeability. (D. I. 166 at 622-624) This is also consistent with
further research, such as Rojanasakul, which tested concentrations of EDTA as low as
0.00037 w/v% and confirmed a dose dependent relationship between EDTA
concentration and corneal permeability. (JTX051 at 5, 12, fig.9; D. I. 166 at 513-515;
D. I. 167 at 689:20-25) The court concludes that the prior art suggests the use of
concentrations as low as 0.01 w/v% EDTA would be effective to increase corneal
permeability.
Finally, and contrary to plaintiffs' contentions, 29 the prior art ophthalmic quinolone
compositions included eye drops maintained at a pH of between 5 and 8; for example,
the '456 patent used a pH of 5.2 and the '465 patent a target pH of 6.0. The court
concludes that the prior art teaches the pH range of claim 6.
A finding of obviousness of claim 6 does not require that the prior art teach or
suggest the formation "of a stable, highly permeable gatifloxacin solution ... adding
0.01 w/v% EDTA to a gatifloxacin ophthalmic formulation at a pH of from about 5 to
29
Piaintiffs contend that gatifloxacin's corneal permeability dropped in tests where
the pH was lowered from 7 to 5 and that the prior art teaches the use of higher pH,
referencing Rojanasakul and Grass references using a pH of 7.4. (JTX 13 at 9; D.l. 164
at 94:20-23) Plaintiffs' contentions ignore the focus of the prior art and the '045 patent,
increasing corneal permeability using EDTA.
26
about 6." (D.I. 172 at 18) Instead, the law of obviousness looks to the subject matter
as a whole and the reason to combine the elements in the manner claimed. See 35
U.S.C. § 103(a); KSR, 550 U.S at 418-19. As the parties agree that corneal
permeability is a desirable property of an ophthalmic drug formulation, one of ordinary
skill would place value on references showing the use of EDTA and gatifloxacin. The
record demonstrates that a person of ordinary skill in the art would have been motivated
to use gatifloxacin and EDTA together. The pH and EDTA concentration limitations of
plaintiffs' claim 6 are found in the prior art. The court concludes that defendants have
met their burden of showing, by clear and convincing evidence, that method claim 6 is
obvious in light of the '456, '465, '470 patents, the Grass references, and Rojanasakul.
Plaintiffs argue that, even if defendants meet their prima facia case of
obviousness (which they have), claim 6 is not obvious because of the unexpected result
of "dramatically increased corneal permeability of gatifloxacin." 30 (D.I. 178 at 37)
Plaintiffs rely on their interpretation of Grass (1988 1), i.e., that zero increase in corneal
permeability would be expected when using 0.01 w/v% EDTA. (/d. at 37-38) The court
agrees with defendants' expert and finds this interpretation incorrect as explained
above. 31 Based on the dose dependent correlation (lower amounts of EDTA give lower
increases in corneal permeability), the raw data in Grass (1988 I) and the further
research in Rojanasakul show that the use of 0.01 w/v% EDTA would still show an
increase in corneal permeability.
30
While plaintiffs present this theory for all asserted claims, as previously noted
by the court, increased corneal permeability is not a limitation of product claims 12-16.
31
See analysis of infringement of claim 6 at Part B.2.b.
27
Plaintiffs' arguments that the magnitude of the increase in corneal permeability
with 0.01 w/v% EDTA is unexpected are equally unavailing. 32 Plaintiffs assert that the
small increase shown in the Grass (1988 I) data would lead a researcher to predict a
smaller increase, if any, in corneal permeability. (D.I. 178 at 44) Therefore, according
to plaintiffs, the 40% increase in corneal permeability measured over two hours in JTX
15 (using three instillations at 15 minute intervals) and the 29% increase in JTX 16
(single instillation) are "completely unexpected effect[s]." (/d.) Dr. Stella did not use a
statistical analysis to arrive at this conclusion, but relied on the data points shown in the
studies. 33 (See 167 at 828: 13-22)
In contrast, defendants argue that, even accepting these percent increases, 34
modifying the pH from 7 to 6 leads to a 30% change in permeability. (D. I. 165 at 404
(Dr. Stella)) The '045 patent shows an increase in corneal permeability from 1.30 to
1.93 IJg/ml (67%) with the use of 0.05 w/v% EDTA. (D.I. 183 at 17 (citing JTX 1 at
tb1.2)) Based on the record and testimony offered, the court concludes that the
increase in corneal permeability shown by plaintiffs using a 0.01 w/v% EDTA is not
unexpected or surprising. 35 Instead, it is a product of routine optimization that would
32
Aithough defendants argue that this argument was first presented at trial, as
the "unexpected results" argument was vetted through discovery, the court will consider
the additional argument.
33
This is in contrast to plaintiffs' repeated arguments that the actual data points in
Grass (1988 I) should be ignored.
34
Piaintiffs did not account for the large error bars seen in the data. (D. I. 167 at
741 :6-13)
35
The court declines to consider plaintiffs' additional argument that the results
were unexpected because of the "relative size" of the gatifloxacin molecule, as it was
28
have been obvious to one of skill in the art. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d
1348, 1364, 1370 (Fed. Cir. 2007) (finding that "case law is clear that obviousness
cannot be avoided simply by a showing of some degree of unpredictability in the art so
long as there was a reasonable probability of success"). For the foregoing reasons, the
court finds that the asserted claims of the '045 patent are invalid for obviousness. 36
D. Intervening Rights
1. Standard
The doctrine of intervening rights recognizes the public's right to use what is not
specifically identified in a patent as originally filed. See, e.g., Seattle Box Co., Inc. v.
Indus. Crating and Packing Inc., 756 F.2d 1574, 1579 (Fed. Cir. 1985). Claims
amended during reexamination, if they are legally "identical" to the claims of the original
patent, 37 can be enforced for the period prior to the issuance of the reexamination
certificate. See, e.g., Minco, Inc. v. Combustion Eng'g, Inc., 95 F.3d 1109, 1115 (Fed.
Cir. 1996); Kaufman Co. v. Lantech, Inc., 807 F.2d 970, 976 (Fed. Cir. 1986). On the
other hand, an infringer who was engaged in allegedly infringing activities (or
"substantial preparation was made by the infringer" to do so) before a reexamination
certificate issued may continue to infringe said claims, if the court determines that the
presented for the first time at trial and is outside the scope of the expert report. (0.1.
178 at 42-43)
36
As the court found in the pre-trial conference that enablement was not properly
presented as a defense, the court declines to allow defendants to pursue this argument.
(0.1. 142 at 53:22-55:4)
37
"1dentical" does not mean verbatim, but rather means without substantive
change. See e.g., Westvaco Corp. v. lnt'l Paper Co., 991 F.2d 735, 741 (Fed. Cir.
1993).
29
reexamined claims are not "without substantive change" compared to the original
claims, and to the extent and under such terms as the court deems equitable for the
continued manufacture, use or sale of an allegedly infringing product. See, Seattle
Box, 756 F .2d at 1579. Therefore, the doctrine of intervening rights is a defense to
infringing activity occurring after reexamination. See, e.g., Forte/ Corp. v. Phone-Mate,
Inc., 825 F.2d 1577, 1580 (Fed. Cir. 1987).
Equitable intervening rights are based in the second sentence of the second
paragraph of 35 U.S.C. § 252 and concern the manufacture, use, or sale of specific
things after the issuance of a reissued or reexamined patent. Under equitable
intervening rights, an infringer may continue to manufacture, use or sell additional
products covered by the reissued or reexamined patent when the infringer made,
purchased, or used identical products, or made substantial preparation to make, use or
sell identical products, before the issuance of the reissued or reexamined patent. Thus,
under equitable intervening rights, a court may protect investments made before the
grant of the reissued or reexamined patent, if the equities dictate such a result. B/C
Leisure Prods., Inc. v. Windsurfing lnt'l/nc., 1 F.3d 1214, 1221 (Fed. Cir. 1993).
2. Analysis
The court agrees with defendants that the reexamined claims are new or
amended and substantively changed. See Bloom Eng'g Co., Inc. v. N Am. Mfg. Co.,
129 F.3d 1247, 1249-50 (Fed. Cir. 1997) (an amendment which narrows the scope of
the claim may be considered a "substantive change" sufficient to invoke the doctrine of
intervening rights). As the court has found the reexamined claims infringed, but invalid,
30
defendants' intervening rights defense is moot. As such, the court declines to
undertake an examination of this argument herein.
E. LPI is a proper party
LPI describes itself as "the U.S. wholly owned subsidiary of Lupin Limited, which
is among the top five pharmaceutical companies in India." Further, LPI "intends to bring
a portfolio of generics as well as branded products to the US market." See,
http://www.lupinpharmaceuticals.com/about.htm. With these statements, the court
declines to accept defendants' argument that LPI is not the ANDA applicant and will not
benefit economically. Clearly, LPI served as an agent on its parent company's behalf
and countersigned the ANDA application. (JTX 4; JTX 5) As its mission is to become a
"transnational pharmaceutical company," LPI cannot argue that it will not benefit
economically. Therefore, the court concludes that LPI is a proper party to the case at
bar.
F. Attorney Fees and Costs
Pursuant to 35 U.S.C. § 285, "[t]he court in exceptional cases may award
reasonable attorney fees to the prevailing party." In order to determine whether a case
is exceptional and, therefore, eligible for an award of attorney fees, the court undergoes
a two-step process. See Eon-Net LP v. F/agstar Bancorp, 653 F.3d 1314, 1323-24
(Fed. Cir. 2011 ). The district court must first "determine whether the prevailing party
has proved by clear and convincing evidence that the case is exceptional." ld. (citing
Forest Labs., Inc. v. Abbott Labs., 339 F.3d 1324, 1327 (Fed. Cir. 2003)). "Second, if
the district court finds the case to be exceptional, the court must then determine
31
whether an award of attorney fees is appropriate and, if fees are appropriate, the
amount of the award." /d. (citing Cybor Corp. v. FAS Techs., Inc., 138 F.3d 1448, 1460
(Fed. Cir. 1998)).
Plaintiffs assert that defendants increased the cost of litigation by refusing to
stipulate to infringement of the reexamined claims and maintaining that LPI was not a
proper party to the case. (0.1. 172 at 54-55) Defendants counter that plaintiffs should
have stipulated to the invalidity of claims 12-16. The court denied Lupin's motion for
judgment on the pleadings, wherein Lupin alleged that the narrower reexamined claims
of the '045 patent were invalid for obviousness and plaintiffs should be collaterally
estopped from relitigating these claims based on the finding in Apotex II. At the pre-trial
conference and at trial, both parties advanced theories not vetted through discovery
and beyond the scope of the expert reports. Thus, the court will not award attorney
fees to either party.
IV. CONCLUSION
For the foregoing reasons, the court finds that defendants infringe claims 6, 1216 and that claims 6, 12-16 of the '045 patent are invalid for obviousness. An
appropriate order shall issue.
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