Cephalon, Inc. et al v. Slayback Pharma Limited Liability Company
Filing
394
OPINION Signed by Judge Colm F. Connolly on 4/27/2020. (nmf)
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE
CEPHALON, INC., et al.,
Plaintiffs,
v.
Civil Action No. 17-1154-CFC
CONSOLIDATED
SLAYBACK PHARMA LIMITED
LIABILITY CO., et al.,
Defendants.
John W. Shaw, Karen Keller, Nathan Hoeschen, SHAW KELLER LLP,
Wilmington, Delaware; David I. Berl, Adam Harber, Elise Baumgarten, Shaun
Mahaffy, Ben Picozzi, Matthew Lachman, WILLIAMS & CONNOLLY LLP,
Washington, District of Columbia
Counsel for Plaintiffs
Eve Ormerod, Neal Belgam, SMITH, KATZENSTEIN, & JENKINS LLP,
Wilmington, Delaware; Beth Finkelstein, Constance Buttner, Frank Rodriguez,
James Barabas, BUDD LARNER, P.C., Short Hills, New Jersey
Counsel for Slayback Pharma Limited Liability Company
Jeremy Cole, Damien Tancredi, Jeffrey Cohen, PLASTER GREENBURG, P.C.,
Wilmington, Delaware; John Cravero, Sherry Rollo, Steven Feldman, HAHN
LOESER & PARKS LLP, Chicago, Illinois
Counsel for Apotex Inc.
Brian Farnan, Michael Farnan, FARNAN LLP, Wilmington, Delaware; Arun
Mohan, SCHIFF HARDIN LLP, New York, New York; Helen Ji, Kevin Nelson,
Imron Aly, SCHIFF HARDIN LLP, Chicago, Illinois
Counsel for Fresenius Kabi USA, LLC
James Lennon, DEVLIN LAW FIRM LLC, Wilmington, Delaware; David Steuer,
Nicole Stafford, Shyamkrishna Palaiyanur, WILSON SONSINI GOODRICH &
ROSATI, Austin, Texas; Rhyea Malik WILSON SONSINI GOODRICH &
ROSATI, San Diego, California
Counsel for Mylan Laboratories Limited
OPINION
April 27, 2020
Wilmington, Delaware
11
UNITED STATES DISTRICT JUDGE
Plaintiffs Teva Pharmaceuticals International GmbH, Cephalon, Inc., and
Eagle Pharmaceuticals, Inc. have sued Defendants Apotex Inc. and Apotex Corp.,
Fresenius Kabi USA, LLC, Mylan Laboratories Ltd., and Slayback Pharma LLC
under the Hatch-Waxman Act, 35 U.S.C. § 271( e)(2)(A). Defendants seek to bring
to market generic versions of Plaintiffs' Bendeka®, a drug indicated for the
treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell nonHodgkin lymphoma (NHL). D.I. 1 ,r,r 1, 12. 1 Plaintiffs allege infringement of U.S.
Patent Nos. 9,265,831 (the #831 patent), 9,572,797 (the #797 patent), 9,144,568
(the #568 patent) and 9,597,399 (the #399 patent) by all defendants and
infringement of U.S. Patent No. 9,572,887 (the #887 patent) by Slayback.
Defendants have stipulated to infringement of the asserted claims with two
exceptions outlined below. Defendants argue that all asserted claims of the
asserted patents are invalid.
I held a seven-day bench trial, and, as required by Federal Rule of Civil
Procedure 52(a)(l), I have set forth separately below my findings of fact and
conclusions of law.
1
All docket citations are to the docket for C.A. No. 17-1154 unless stated
otherwise.
I.
BACKGROUND
Plaintiffs sell Bendeka® under New Drug Application No. 208194. D.I. 1 ~
13. Eagle is the owner and assignee of the asserted patents and has listed them in
connection with Bendeka® in the Orange Book maintained by the Food and Drug
Administration (FDA). Teva Pharms. Int'! GmbH v. Apotex Inc., No. 17-1164 (D.
Del. 2017), D.I. 1 ~~ 27-35. Cephalon holds an exclusive license to the asserted
patents and has assigned to Teva its rights under the license, including the right to
sue for infringement. Id., D.I. 1 ~~ 38-39.
Bendeka®'s active ingredient is bendamustine hydrochloride (referred to by
the parties as bendamustine ), a nitrogen mustard chemotherapy drug that was first
developed in East Germany in the 1960s. D.I. 334 at 2; D.I. 364 ~ 1.
In 2008, Cephalon launched the first U.S. bendamustine product, Treanda®.
Tr. 403: 18-22. Cephalon initially sold Treanda® in a lyophilized, or freeze-dried,
form. Tr. 404:7-11, 1357:13-19. Lyophilized drugs must be reconstituted into an
injectable liquid before they can be administered to patients. Tr. 404:7-18,
405:8-06:4. Aware that bendamustine's toxicity makes it potentially dangerous
for medical staff to reconstitute the drug, Eagle began in 2009 to develop a liquid
bendamustine formulation that ultimately became Bendeka®. Tr. 83:7-84:13,
86:3-19.
2
In November 2014, Cephalon launched its own liquid version of Treanda®.
Tr. 981:25-82:2, 1657:10-11.
In 2015, Teva acquired Cephalon, Tr. 1660:10-14, and Cephalon thereafter
commercialized Bendeka® as permitted by its exclusive license agreement with
Eagle, PTX-0408; Tr. 1660:10-24, 1795:4-9.
On December 7, 2015, the FDA approved Bendeka®, D.I. 307-11152, and
on January 27, 2016, Teva launched Bendeka®, DTX-0500; Tr. 984:17-85:23,
'
1006:6-07:5. Bendeka® subsequently received orphan drug exclusivity, a sevenyear period during which the FDA is precluded from approving any other
manufacturer's application to market the same drug to treat the same rare disease.
Eagle Pharm., Inc. v. Azar, 2018 WL 3838265, at *1 (D.D.C. June 8, 2018), aff'd,
952 F.3d 323 (D.C. Cir. 2020); Tr. 1725:15-19.
In March of 2016, Teva stopped selling liquid Treanda®. DTX-0500_0001;
Tr. 1623 :7-8.
In July and August of 2017, Defendants each filed an Abbreviated New
Drug Application (ANDA) with Paragraph IV certifications under§ 505G) of the
Federal Food, Drug and Cosmetic Act to gain FDA-approval for the commercial
manufacture, use, and sale of a generic version ofBendeka®. E.g., D.I. 1115. In
August of 2017, Plaintiffs filed these suits alleging that Defendants' ANDA filings
with Paragraph IV certifications constituted acts of infringement. E.g., D.I. 1.
3
These cases were consolidated for all purposes. See December 13, 2017 Order.
At trial, Plaintiffs accused all Defendants other than Slayback of infringing
six formulation claims in two of the asserted patents: claims 2, 3, and 5 of the #831
patent; and claims 9 and 11 of the #797 patent. Plaintiffs also alleged infringement
of six administration claims in four of the asserted patents: claims 11, 18, and 22 of
the #568 patent and claim 15 of the #399 patent (by all Defendants); claim 13 of
the #399 patent (by Apotex only); and claim 13 of the #887 patent (by Slayback
only). Defendants countered that (1) the asserted formulation and administration
claims are invalid for obviousness under 35 U.S.C. § 103; (2) the asserted
formulation claims are invalid for indefiniteness under 35 U.S.C. § 112; (3) the
asserted formulation claims are invalid for lack of enablement under 35 U.S.C. §
112; and (4) claim 9 of the #797 patent is invalid for lack of written description.
Defendants stipulated that they infringe or induce infringement of each of the
asserted claims with two exceptions: Apotex, Fresenius Kabi, and Mylan argue that
(1) their ANDA products do not contain "a stabilizing amount of an antioxidant" as
the asserted formulation claims require; and (2) they do not induce infringement of
claim 9 of the #797 patent.
II.
OBVIOUSNESS
A.
Legal Standards for Obviousness
Under§ 103 of the Patent Act, codified at 35 U.S.C. § 1 et seq., a patent
4
"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 [POSITA] to which said subject matter pertains." 35 U.S.C. § 103. As
the Supreme Court explained in the seminal case, Graham v. John Deere Co., 3 83
U.S. 1 (1966), under§ 103, "[a]n invention which has been made, and which is
new in the sense that the same thing has not been made before, may still not be
patentable if the difference between the new thing and what was known before is
not considered sufficiently great to warrant a patent." Id. at 14. Section 103
ensures that "the results of ordinary innovation are not the subject of exclusive
rights under the patent laws." KSR Intern. Co. v. Teleflex Inc., 550 U.S. 398, 427
(2007). "Were it otherwise patents might stifle rather than promote, the progress
of useful arts." Id. (citing U.S. Const. art. I, § 8, cl. 8).
The Court reaffirmed in KSR that the "framework" set out in the following
paragraph from Graham governs the application of § 103, id. at 406:
While the ultimate question of patent validity is one of
law, the[§] 103 condition [ofpatentability], ... lends
itself to several basic 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
5
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. As indicia of
obviousness or nonobviousness, these inquiries may have
relevancy.
Graham, 383 U.S. at 14-15 (citations omitted).
It is clear that under this framework, a district court must consider in an
obviousness inquiry the three primary factors identified by the Court in Graham:
(1) the scope and content of the prior art, (2) the differences between the prior art
and the claims at issue, and (3) the level of ordinary skill in the pertinent art. Less
clear is the role, if any, secondary considerations should play in the analysis.
The logical-some would say necessary-implication of the Court's use of
the word "secondary" in Graham and its holding that the secondary considerations
"might be utilized" and "may have relevancy" is that a district court is permittedbut not required in all cases-to examine such considerations in evaluating an
obviousness-based invalidity challenge. The Court seemed to confirm as much in
KSR, when it noted that "Graham set forth a broad inquiry and invited courts,
where appropriate, to look at any secondary considerations that would prove
instructive." KSR, 550 U.S. at 415 (emphasis added).
But a district court ignores Graham's "invitation" to examine secondary
considerations at its peril. One legal scholar, Harmon, has observed that under
Federal Circuit law "[w]e are able now safely to strike the 'may' in the ...
6
sentence" in Graham in which the Court stated that secondary "indicia of
obviousness and nonobviousness ... may have relevancy." Robert Harmon,
Cynthia Homan, Laura Lydigsen, Patents and the Federal Circuit 245 (13th ed.
2017). Harmon correctly notes that "[t]he Federal Circuit has emphatically and
repeatedly held that objective evidence of non-obviousness [i.e., the "secondary
considerations" identified in Graham] must be taken into account always and not
just when the decisionmaker is in doubt." Id. In Stratoflex, Inc. v. Aeroquip Corp.,
713 F.2d 1530 (Fed. Cir. 1983), for example, the Federal Circuit held that
"evidence rising out of the so-called 'secondary considerations' must always when
present be considered en route to a determination of obviousness." Id. at 1538.
And in In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent
Litigation, 676 F.3d 1063 (Fed. Cir. 2012), the Federal Circuit reaffirmed that
holding, id. at 1079, and went on to say that the Supreme Court in Graham "did
not relegate ... to 'secondary status"' the "objective factors" the Supreme Court
had explicitly identified in Graham as "secondary considerations," id. at 1078.
It is true that less than a month after In re Cyclobenzaprine, a different
Federal Circuit panel held in Otsuka Pharmaceutical Co. v. Sandoz, Inc., 678 F.3d
1280 (Fed. Cir. 2012) that because it found that the defendants had "failed to prove
that [the challenged patent claim] would have been prima facie obvious over the
asserted prior art," it "need not address" the "objective evidence" of commercial
7
success, long-felt need, and the failure of others. Id. at 1296. But the safer course
for a district court faced with an obviousness challenge ( and looking to avoid
reversal by the Federal Circuit) is to treat Graham's "invitation" to look at
secondary considerations like a subpoena.
Obviousness is assessed based on the perspective of a POSITA at the time of
the invention. Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352, 1360 (Fed. Cir.
2011 ). The court therefore needs to guard against "hindsight bias" that infers from
the inventor's success in making the patented invention that the invention was
obvious. In re Cyclobenzaprine, 676 F.3d at 1079. The ultimate question in the
obviousness analysis is "whether there was an apparent reason [for a POSITA] to
combine [at the time of the invention] the known elements in the fashion claimed
by the patent at issue." KSR, 550 U.S. at 418. "The analysis is objective." Id. at
406. Thus, a court must determine whether a POSITA "would have had reason to
combine the teaching of the prior art references to achieve the claimed invention,
and ... would have had a reasonable expectation of success from doing so." In re
Cyclobenzaprine, 676 F.3d at 1069.
The party challenging the patent's validity bears the burden of proving
obviousness by clear and convincing evidence. Id. at 1068-69. In weighing the
Graham factors to decide whether the party has met that burden, the district court
must be guided by common sense. Wyers v. Master Lock Co., 616 F.3d 1231,
8
1238 (Fed. Cir. 2010). Indeed, "the legal determination of obviousness may
include recourse to logic, judgment, and common sense, in lieu of expert
testimony." Id. at 1239. In KSR, the Supreme Court warned lower courts to avoid
"[r]igid prever1tative rules that deny factfinders common sense" and to employ
instead "an expansive and flexible approach" under the Graham framework. KSR,
550 U.S. at 415. Thus, the district court may "reorder[] in any particular case" the
"sequence" in which it considers the Graham factors. Id. at 407. And although a
court should consider carefully the published prior art, "[t]he obviousness analysis
cannot be confined by ... overemphasis on the importance of published articles
and the explicit content of patents." Id. at 419.
"[A]ny need or problem known in the field of endeavor at the time of the
invention and addressed by the patent can provide a reason for combining the
elements in the manner claimed." KSR, 550 U.S. at 420. And "[t]he combination
of familiar elements according to known methods is likely to be obvious when it
does no more than yield predictable results." Id. at 416. "[T]he fact that a
combination was obvious to try might show that it was obvious under§ 103." Id.
at 421. But a combination is obvious to try only "[w]hen there is a design need or
market pressure to solve a problem and there are a finite number of identified,
predictable solutions" in the prior art at the time of the invention. Id. And the
court must also be mindful that "when the prior art teaches away from combing
9
certain known elements, discovery of a successful means of combining them is
more likely to be nonobvious." Id. at 416.
B.
Obviousness of the Asserted Formulation Claims
1.
Findings of Fact
a.
The Priority Date
The parties agree that the date of invention (i.e., the priority date) for the
asserted formulation claims is January 28, 2010. Tr. 403:4-6, 1352:16-21,
2015:3-16; #831 patent at (60); #797 patent at (60).
b.
Definition of the Relevant POSITA
The parties agree that a POSITA would have had the skills, education, and
expertise of a team of individuals working together to formulate a liquid injectable
drug product. Such a team would have included individuals with doctoral degrees
in chemistry, biochemistry, pharmaceutics, pharmaceutical sciences, chemical
engineering, biochemical engineering or related fields, with at least two years of
post-graduate experience in developing liquid injectable drug products, or master's
or bachelor's degrees in similar fields of study, with a commensurate increase in
their years of postgraduate experience. Such a team also would have been familiar
with a variety of issues relevant to developing liquid injectable drug formulations,
including, among other things, solubility, stability, pharmacokinetics,
pharmacodynamics, and other pharmaceutical characteristics. Such a team also
10
would have included persons with expertise in analytical chemistry, including the
detection and measurement of chemical degradants. The team also would have had
access to an individual with a medical degree with experience in treating patients
with CLL and NHL. PDX-4-2; Tr. 562:1-63:6, 1036:7-37:11, 1353:6-20,
2014:22-15:2.
c.
Content of the Asserted Formulation Claims
The asserted formulation claims teach a non-aqueous liquid composition that
contains (1) bendamustine (or a pharmaceutically acceptable salt thereof); (2)
about 5% to about 10% by volume of the solvent propylene glycol (PG); (3) the
solvent polyethylene glycol (PEG); (4) one of the following ratios of PEG to PG:
about 95:5, about 90:10, about 85:15, about 80:20, and about 75:25; and (5) a
stabilizing amount of an antioxidant. #831 patent at claims 2, 3, 5; #797 patent at
claims 9, 11. Two claims also specify components and quantities: (1) claim 11 of
the #797 patent requires that "the antioxidant is thioglycerol or
monothioglycerol," 2 and (2) claim 5 of the #831 patent requires that "the
bendamustine concentration is from about 25 mg/mL to about 50 mg/mL." Certain
claims also recite stability limitations such as "less than or equal to 0.11 % PG
esters at about 1 month of storage at about 5°C." #831 patent at claims 2, 3, 5;
#797 patent at claims 9, 11.
2
Thioglycerol or monothioglycerol are used synonymously. Tr. 519:10-15.
11
d.
Bendamustine, PEG, and PG
Bendamustine has two relevant functional groups at opposing ends of its
chemical structure: a nitrogen mustard group and a carboxylic acid group. Tr.
422:23-23: 13, 430: 19-31 :6, 1038:5-7.
Nucleophiles-such as water, PG, and PEG--degrade bendamustine at its
nitrogen mustard group through reactions in which an aziridinium ring forms. Tr.
407:12-19, 564:10-66:12, 1038:13-21, 1043:23-46:12, 1381:11-18; DTX-0073
at 4:33-37; PTX-1010 at TEVABEND00296748. Compounds like PEG and PG
that have hydroxyl (OH) groups also degrade bendamustine at its carboxylic acid
group through a process called esterification where the carboxylic acid group
reacts with the OH groups to form degradants called esters. Tr. 431 :4-13.
When PEG is combined with bendamustine, a process called PEG oxidation
accelerates the esterification reaction. Tr. 484: 15-85: 11, 1416:11-18: 12; PTX0669 at TEVABEND00294275; PTX-0623 at TEVABEND00289470. PEG thus
causes more degradation at bendamustine's carboxylic acid group than the same
amount of PG would cause. Tr. 1054:5-59:11; PTX-0999 at
TEVAVEND00292 l 31; PTX-0997 at TEVABEND0029195 5.
Because water causes bendamustine to degrade at its nitrogen mustard
group, the prior art bendamustine formulations used a lyophilized (freeze-dried)
form of bendamustine that required a human operator to reconstitute it using water
12
shortly before administering it to a patient. DTX-0094 0010; Tr. 404:7-18,
405:8-06:4, 408:17-09:1, 410:4-5, 1357:13-19. Reconstitution by human
manipulation had two known disadvantages in 2010: it increased the risk of
contamination, Tr. 406:16-20; and, because bendamustine is a cytotoxic
compound, it posed a potential danger to the operator, Tr. 84:2-13, 406:23-07:3;
DTX-0056_0001; DTX-0056 at 2:33-67; DTX-0094_001 l.
e.
Content of the Prior Art
Defendants argue that five prior art references would have motivated a
POSITA to arrive at the asserted formulation claims with a reasonable expectation
of success: Olthoff, Drager, Alam, Rowe, and Boylan. D.I. 378 at 31.
1)
Olthoff (DTX-0094)
Olthoff, a 1983 East German patent, claimed a stable, non-aqueous liquid
injection solution of between 25 and 100 mg/mL bendamustine dissolved in a
solvent consisting of 100% PG. DTX-0094_0016; Tr. 448:20-25. Olthoffs
objective was to "produce a stable and ready-to-use injection solution out of
N[itrogen]-mustard compounds, avoiding the technical solution of a dry ampoule
[i.e., lyophilization]." DTX-0094_0012; Tr. 409:18-10:5. Olthoff disclosed that
bendamustine has "a[n] extraordinarily high chemical stability for the production
of injection solutions in" monovalent alcohols, glycols and polyols. DTX0094_0012; Tr. 410:6-11 :8. Olthoff specifically proposed dissolving
13
bendamustine in "polyols, particularly 1,2-propylene glycol [i.e., PG]." DTX0094_0014; Tr. 412:6-14. Polyols are another name for compounds that have
multiple OH groups. Tr. 412:17-18, 413:11-13. Both PEG and PG are polyols.
Id.
Olthoff's examples did not use an antioxidant. DTX-0094_0013, _0015; Tr.
1457:5-12.
In the decades between Olthoff's publication and the priority date, its
formulations were never used. DTX-0073 at 2:19-29.
2)
Drager (DTX-0073)
About 30 years after Olthoff was published, Drager, a U.S. patent, issued in
2013. Tr. 434:6-20; D.I. 307-1
,r 223.
(Drager's priority date is September 25,
2008 making it prior art to the asserted formulation claims.) Like Olthoff, Drager
described stable "liquid pharmaceutical formulations comprising bendamustine."
DTX-0073 at 2:33-35, Abstract; Tr. 433:23-25. But Drager determined that the
"results described in [Olthoff] were not reproducible." DTX-0073 at 2:62-64.
Drager' s data showed that bendamustine in 99% PG degraded almost completely
after eight weeks at 25°C and more than 20% at 5°C after one year. DTX-0073 at
Fig. 3; Tr. 1378:9-80:5. The reason for that degradation, according to Drager, was
that (1) PG causes bendamustine to degrade at the nitrogen mustard group, DTX0073 at 4:19-24, 4:33-37; Tr. 602:13-15, and (2) PG's OH groups cause
14
bendamustine to degrade at the carboxylic acid group through esterification, DTX0073 at 5:12-14; Tr. 602:3-6.
As a solution to the degradation problem, Drager disclosed the use of aprotic
solvents, i.e., solvents containing no OH groups, in a liquid bendamustine
formulation. DTX-0073 at 3 :21-25; Tr. 5 81: 19-82: 12. Drager showed that
dissolving bendamustine in 100% DMA, an aprotic solvent, results in no
degradation ofbendamustine at the carboxylic acid group. DTX-0073 at Table II;
Tr. 432:22-33:7, 435:11-36:9.
Drager also taught that protic solvents-i.e., solvents, including PEG and
PG, that have OH groups-are acceptable to use with bendamustine but only when
combined with aprotic solvents. DTX-0073 at 3:3-10, 3:36-48, 4:18-24; Tr.
601: 11-17. Drager showed that the formulation containing 66% DMA and 34%
PG is stable. DTX-0073 at Table II; Tr. 436:16-37:15.
3)
Alam (DTX-0056)
Alam, a U.S. Patent issued on November 7, 1989, disclosed stable liquid
formulations of cyclophosphamide, a compound that, like bendamustine, has a
nitrogen mustard group. DTX-0056 at Abstract, 1 :5-8; Tr. 422:3-9, 424:6-12.
Alam tested cyclophosphamide's stability in mixtures of three polyols-PG, PEG
and glycerol-and found that the formulation containing PEG and PG had "less
degradation than the others." Tr. 424:2-25:5, 428:6-12, 1421:18-24; DTX-0056
15
at Tables 1-5. Alam disclosed using PG at a ratio of from about 10% to about
90% and PEG at a ratio of from about 90% to about 10%. DTX-0056 at 4:6-12;
Tr. 425:6-14.
Bendamustine and cyclophosphamide have two structural differences that
bear on how they degrade when they are mixed with PEG and PG. First, because
cyclophosphamide does not have a carboxylic acid group, cyclophosphamide does
not experience esterification, i.e., it does not react with compounds such as PEG
and PG that have OH groups to form esters. Tr. 430:22-31:1, 1077:25-78:6.
Second, in bendamustine, the nitrogen mustard group is attached to a benzene ring,
while in cyclophosphamide, the group is attached to a phosphoramide. Tr.
1075:4-25. Because it is attached to a benzene ring in bendamustine, a POSITA
would have expected nucleophiles such as PEG and PG to accelerate degradation
at the nitrogen mustard group via the formation of an unstable aziridinium ring.
Tr. 1037:19-41:16, 1058:12-17, 1060:2-9; PTX-0376 at
JDG_BENDA_00002265; PTX-1010 at TEVABEND00296748. But in
cyclophosphamide, the phosphoramide deactivates the nitrogen mustard group and
cyclophosphamide consequently does not degrade by forming the aziridinium ring
in a liquid formulation before administration. Tr. 1076: 1-77 :24; PTX-0991 at
TEVABEND00290978; PTX-0993 at TEVABEND00291516.
Neither Alam nor Drager used an antioxidant in their exemplary or preferred
16
formulations. Tr. 1458:2-58:23.
4)
Rowe, Handbook of Pharmaceutical Excipients
(DTX-0160)
Rowe's Handbook of Pharmaceutical Excipients disclosed that PEG is
susceptible to oxidation and that one can use an antioxidant to prevent such
oxidation. DTX-0160_0011; Tr. 486:7-24.
5)
Boylan (DTX-0063)
Boylan disclosed a list of "some of the most commonly used antioxidants in
pharmaceutical injectable formulations" including monothioglycerol.
DTX-0063_0019, 0020; Tr. 487:12-18. Boylan also disclosed usual
concentrations for each of the listed antioxidants. DTX-0063 0020; Tr.
487:18-19. Monothioglycerol is FDA-approved. Tr. 340:20-23.
2.
Conclusions of Law
I find that Defendants have not established by clear and convincing evidence
that a POSITA would have had reason to combine the limitations recited in the
asserted patents' formulation claims. Although Defendants persuaded me that a
POSITA would have had reason to try to develop a non-aqueous liquid
bendamustine formulation, they failed to establish by clear and convincing
evidence that a POSITA would have used in that formulation the PEG and PG
solvents, PEG:PG ratios, antioxidant, concentrations of bendamustine, or PG ester
stability limitations recited in the asserted claims. I do not find Plaintiffs' evidence
17
of secondary considerations to establish nonobviousness, but I find Defendants'
failure of proof with respect to Graham's primary factors in this case to be
dispositive and that therefore the formulation claims are not invalid under § 103.
a.
Non-Aqueous Liquid Bendamustine Formulation
Every asserted formulation claim requires a non-aqueous liquid formulation.
Due to bendamustine's instability in water, the prior art used a lyophilized form of
bendamustine. Tr. 404:9-18, 1357:13-19. But, as discussed above, lyophilization
had known disadvantages. To avoid lyophilization while still avoiding the use of
water, a POSITA would have been motivated to create a non-aqueous liquid
bendamustine product. In fact, as can be seen in Olthoff and Drager, other
inventors sought to create non-aqueous liquid bendamustine formulations before
the priority date.
b.
Use of PEG and PG
The claimed non-aqueous liquid bendamustine formulations contain the
solvents PEG and PG. Defendants argue that Olthoff, Drager, and Alam would
have motivated a POSITA to use PEG and PG with bendamustine. D.I. 378 at 13,
16.
1)
Olthoff and Drager
Viewed in isolation, Olthoff would have led a POSITA to use PEG and PG
in a liquid bendamustine formulation. D.I. 378 at 13; DTX-0094_0014; Tr.
18
412:3-18, 413 :4-13. Olthoff provided a short, finite list of solvent options that
included PEG and PG. Specifically, Olthoff reported that bendamustine is stable
in monovalent alcohols and polyols, DTX-0094_0012-13; Tr. 410:6-11 :8,
1084:13-86:11; and the disclosure of"polyols" would have given a POSITAjust
three polyol options: PEG, PG, and glycerol, Tr. 413:4-13. Plaintiffs dispute that
assertion, D.I. 371 at 20-23, but Plaintiffs' expert himself limited polyols to those
three options in a patent application that he submitted in 2009, see DTX0764_0011 ("Preferably the water soluble plasticizer is selected from the group
consisting of polyols (glycerin [i.e., glycerol], propylene glycol, polyethylene
glycols) .... "). His response when confronted with that disclosure at trial was:
"Yes, but I didn't -- at that time I didn't know that I would be sitting here today."
Tr. 1575:2-76:1. Moreover, while I agree with Plaintiffs that Olthoff would have
taught a POSITA also to consider monovalent alcohols, D.I. 371 at 21, Plaintiffs
only list four monovalent alcohols that a POSITA would have considered using
with bendamustine, D.I. 361
~
73. Olthoff thus would have left a POSITA with
three polyols and four monovalent alcohols as options. By providing a finite list,
Olthoff would have made using PEG and PG obvious to try because a POSITA
would face only "a finite number of identified, predictable solutions." KSR, 550
U.S. 398 at 421.
Drager, however, teaches away from Olthoffs teaching of using polyols
19
such as PEG and PG alone with bendamustine. As noted, Drager determined that
the "results described in [Olthoff] were not reproducible." DTX-0073 at 2:62-64,
3: 1-2. And Drager' s data showed that bendamustine in 99% PG degraded almost
completely after eight weeks at 25°C and more than 20% at 5°C after one year.
DTX-0073 at Fig. 3; Tr. 1378:9-80:5. As Plaintiffs' expert, Dr. Siepmann,
credibly testified, a POSITA would have considered 20% degradation after just
one year at 5°C to be "not good." Tr. 1379:25-80:5.
Drager disclosed combining bendamustine with aprotic solvents as a means
of reducing such degradation. DTX-0073 at 3:3-10, 3:21-25; Tr. 581:19-82:12.
Drager also allowed for combining bendamustine with a mixture of aprotic
solvents and protic solvents, including PEG and PG. DTX-0073 at 3 :3-10,
3 :36-48, 4:18-24; Tr. 601 :11-17. But Drager stated that the concentration of
protic solvents should be kept at 90%-and preferably lower-to limit
degradation. DTX-0073 at 3:49-4:25; Tr. 1393:3-22. Drager specifically showed
that a formulation containing 66% DMA and 34% PG is stable. DTX-0073 at
Table II; Tr. 436:16-37:15.
Defendants assert that Drager taught the use of aprotic solvents because they
have no OH groups and that, therefore, Drager would have motivated a POSITA to
use solvents with a low number of OH-groups. Tr. 431 :20-23, 437:8-15. They
argue that "[w]hile Drager claimed a formulation containing a polar aprotic solvent
20
(DMA) and a polar protic solvent (PG), a POS[IT]A would be motivated to
remove DMA from the formulation because DMA has been known to cause
problems in formulations." D.I. 379 ~ 65; D.I. 378 at 14-15. According to
Defendants, because DMA was the only aprotic solvent listed by Drager that is
"used in FDA products," D.I. 378 at 15, a POSITA would turn to protic solvents
like PEG that have a relatively low number of OH groups. D.I. 379 ~ 67; D.I. 378
at 21.
Drager, however, teaches away from the use of only protic solvents.
Therefore, Drager would not have motivated a POSITA to replace DMA with a
low-OH protic solvent. Defendants and their expert conceded that neither Drager' s
disclosures nor its examples taught using exclusively protic solvents. Tr. 583: 183: 10, 1886:17-19. Instead, Drager taught the use of an aprotic solvent with
bendamustine to avoid degradation by nucleophiles like PEG and PG. Moreover,
Drager disclosed numerous alternative aprotic solvents that could potentially
replace DMA. DTX-0073 at 3:9-14; Tr. 1395:7-14. And DMA was not the only
aprotic solvent in an FDA-approved product. The prior art reference Strickley, for
example, disclosed that the aprotic solvents NMP and DMSO had been
commercially used. PTX-0569 at JDG_BENDA_00003311-14; Tr. 1390:19-24.
A POSITA in 2010 reading Olthoff and Drager thus would have found that
Olthoff taught combining bendamustine with polyols including PEG and PG, but
21
that Drager taught away from using protic solvents, such as PEG and PG, alone
with bendamustine. "Where the prior art contains apparently conflicting teachings
(i.e., where some references teach the combination and others teach away from it)
each reference must be considered for its power to suggest solutions to an artisan
of ordinary skill ... consider[ing] the degree to which one reference might
accurately discredit another." Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157,
1165 (Fed. Cir. 2006) (internal quotation marks and citation omitted).
After considering the two references, I find that a POSITA would have
credited Drager's data and conclusions over those in Olthoff. Drager expressly
asserted that the "results described in [Olthoff] were not reproducible." DTX-0073
at 2:62-64. And Drager used high-performance liquid chromatography (HPLC) to
make its determinations while Olthoff used thin-layer-chromatography (TLC).
Plaintiffs assert, and Defendants do not dispute, that HPLC is more reliable than
TLC because of its superior sensitivity and ability to resolve impurities. Tr.
1074:4-75:3, 1086:17-20, 1380:14-25, 1511:5-11. Moreover, in the decades
between Olthoffs publication in 1983 and the priority date in 2010, Olthoffs
formulations were never used, suggesting that POSITAs generally did not rely on
Olthoff. DTX-0073 at 2:19-29. "The elapsed time between [Olthoff] and the
[asserted] patent's filing date evinces that the [asserted] patent's claimed invention
was not obvious to try." Leo Pharm. Prod., Ltd. v. Rea, 726 F.3d 1346, 1356 (Fed.
22
Cir. 2013). Thus, a POSITA looking at Olthoff and Drager would have followed
Drager' s teaching not to use protic solvents such as PG and PEG alone with
bendamustine.
2)
Alam
Defendants also argue that Alam' s disclosure of mixing cyclophosphamide
with PEG and PG would have motivated a POSITA to use those solvents with
bendamustine because both bendamustine and cyclophosphamide have nitrogen
mustard groups. D.I. 378 at 16. But two structural differences between
cyclophosphamide and bendamustine that effect how they degrade when they are
combined with PEG and PG would have discouraged a POSITA from relying on
Alam in formulating bendamustine. First, unlike bendamustine, cyclophosphamide
does not have a carboxylic acid group and thus does not undergo an esterification
reaction when it is combined with PEG or PG. Tr. 1077:25-78:6, 1421:1-5.
Second, because the nitrogen mustard group in bendamustine is attached to a
benzene ring, while in cyclophosphamide it is attached to a phosphoramide,
cyclophosphamide degrades differently at the nitrogen mustard group than
bendamustine does. Tr. 1077:4-1077:24; PTX-0991 at TEVABEND00290978;
PTX-0993 at TEVABEND00291516. Defendants' expert, Dr. Pinal, did not point
to any prior art references to support his contrary conclusion that "the nitrogen
group in the two molecules are exactly the same." Tr. 423:7-13, 504:21-05:5.
23
I find therefore that a POSITA in 2010 would not have viewed
cyclophosphamide as a relevant comparator for bendamustine reactions, Tr.
1078 :7-11, and would not have considered Alam in formulating a stable
bendamustine formulation, Tr. 1420:10-21:5.
****
In sum, Defendants have not proven by clear and convincing evidence that
Olthoff, Drager, and Alam would have motivated a POSITA to use PEG and PG to
create a non-aqueous liquid bendamustine formulation. Although Olthoff taught
using polyols such as PEG and PG with bendamustine, Drager teaches away from
the use of protic solvents such as PEG and PG alone with bendamustine and a
POSITA would credit Drager's teaching over Olthoff s. Moreover, a POSITA
looking to solve the degradation problem in bendamustine would not have
considered Alam in formulating a liquid bendamustine product because Alam
concerned a compound that degrades differently than bendamustine when
combined with PEG and PG.
c.
Use of Claimed PEG:PG Ratios
Every asserted formulation claim requires a PEG:PG ratio that falls between
95:5 and 75:25. Defendants argue that the claimed PEG:PG ratios would have
been obvious "in light of Alam's express disclosure of the entire range from 10:90
to 90:10." D.I. 378 at 19-20. But as explained above, the prior art would not have
24
motivated a POSITA to use PEG and PG in the first place. Also, even if a
POSITA had chosen to use PEG and PG, it would not have relied on Alam. because
Alam. concerned a com.pound that degrades differently than bendam.ustine in
reaction to PEG and PG. Finally, the claimed formulations use m.ore PEG than PG
whereas Alam. preferred using m.ore PG than PEG, DTX-0056 at 4:6-12, and a
POSITA in 2010 would have known that PEG would cause m.ore degradation at
bendam.ustine's nitrogen mustard group than PG due to PEG oxidation. Tr.
1054:5-59:11; PTX-0999 at TEVAVEND00292131; PTX-0997 at
TEVABEND00291955. Thus, Alam. did not m.ake obvious the PEG:PG ratios
recited in the asserted formulation claims.
d.
Use of An Antioxidant
Every asserted claim. requires an antioxidant and one asserted claim. requires
that the antioxidant be m.onothioglycerol. Assuming a POSITA had chosen to use
a 90% PEG and 10% PG bendam.ustine formulation, that POSITA would have
been motivated to curb PEG oxidation: a process in which PEG accelerates the
esterification reaction. Tr. 484:15-85:11, 1416:11-18:12; PTX-0669 at
TEVABEND00294275; PTX-0623 at TEVABEND00289470.
Defendants argue that Boylan and Rowe would have motivated a POSITA to
solve the oxidation problem. with an antioxidant. D.I. 378 at 22-23. They assert
that Rowe taught a POSITA to inhibit the oxidation of PEG with the inclusion of a
25
suitable antioxidant and that Boylan taught using specific antioxidants, including
monothioglycerol. D.I. 378 at 23; Tr. 486:7-24, 488:7-9, 505:11-06:7, 543:2-5;
DTX-0160_0011; DTX-0063 _ 0020. Defendants also note that monothioglycerol
is "very commonly used," and is FDA-approved for injectable products. D.I. 378
at 23. 3
Other prior art references, however, teach away from the use of antioxidants.
See Tr. 1452:20-53:21; Note for Guidance, European Agency for the Evaluation of
Medicinal Products, PTX-0629 at TEVABEND00290713, TEVABEND00290720
("Antioxidants should only be in?luded in a formulation if it has been proven [t]hat
their use cannot be avoided."); Pharmaceutical Preformulation and Formulation,
Interpharm, PTX-0391 at JDG_BENDA_00000415 (stating that antioxidant use "is
now in decline" and that " [a] preferred method of preventing oxidation [over
antioxidants] is simply to exclude oxygen"). Moreover, none of the four approved
injectable products in the prior art that contained PEG included an antioxidant. Tr.
600:4-6, 1454:24-55:17; PTX-0722 (Ativan); PTX-0718 (Busulfex); PTX-0720
(Robaxin); PTX-0569 at JDG_BENDA_00003308 (VePesid). In addition, the
3
Defendants also assert that Drager taught "the use of antioxidants in the
formulation." D.I. 378 at 22. They did not, however, request a finding of fact on
this point and none ofDrager's preferred or exemplary formulations contained an
antioxidant. Drager mentioned that the invention may include other excipients
such as an antioxidant, DTX-0073 at 7: 1-18, claim 5, but it did not encourage a
POSITA to use an antioxidant.
26
liquid bendamustine examples in Defendants' prior art references do not include
antioxidants: Olthoffs liquid bendamustine formulation with PG had no
antioxidant, DTX-0094 at JDG_BENDA_00002313; Tr. 1457:5-12, and neither
Alam nor Drager used an antioxidant in their exemplary formulations, Tr. 1458:258:23. Accordingly, I find that Defendants did not establish by clear and
convincing evidence that the combination of Boylan and Rowe would have
motivated a POSITA to use an antioxidant.
e.
Use of the Claimed Bendamustine Concentrations
Claim 5 of the #831 patent requires a bendamustine concentration of "from
about 25 mg/mL to about 50 mg/mL." DTX-0006_0009. Defendants argue that
"[t]here was nothing special or unobvious about [that] concentration range" in
view of the Treanda® Label and Olthoff. D.I. 378 at 25.
First, Defendants assert that the lyophilized Treanda® Label would have
motivated a POSITA to use the claimed concentrations because a POSITA would
have multiplied the 120 mg/m2 dose for NHL patients disclosed in the lyophilized
Treanda® Label, DTX-0848_0001, by the average body-surface-area of a human,
2.0 m2, to get a 240 mg total dosage, D.I. 378 at 25-26. According to Defendants,
the POSITA then would have placed that dose in a common vial size of either 5
mL or 10 mL to arrive at a concentration of either 24 or 48 mg/mL. D.I. 378 at 26.
Defendants, however, offered no evidence establishing why a POSITA would have
27
combined a dosage for a lyophilized bendamustine formulation with a particular
vial size when making a liquid bendamustine formulation.
Second, Defendants argue that Olthoff would have motivated a POSITA to
reach the claimed concentration because "Olthoff disclosed and claimed [PG-only]
liquid bendamustine formulations containing 'concentrations of25 mg/m[L] to 100
mg/m[L],"' D.I. 378 at 25, and Olthoff disclosed that bendamustine's solubility in
PG was very high, 125 mg/mL, D.I. 378 at 26. Defendants assert that "[w]hile the
prior art did not disclose bendamustine's solubility in PEG, ... solubility is an
inherent (i.e. intrinsic) property" that can be discovered through routine testing,
and given the high 125 mg/mL solubility in PG, a POSITA "would understand that
by adding PEG to PG, the solubility would drop from 125 to a lower value, and
that at ten percent PG and 90 percent PEG, it would be possible to make a solution
with a concentration of 25 milligrams per milliliter." D.I. 378 at 26-27.
But as explained above, Defendants have not established a motivation to use
PEG and PG in the first place. Thus, even assuming that a POSITA could have
found bendamustine's solubility in PEG through routine testing, Defendants did
not establish by clear and convincing evidence that a POSITA would have been
motivated to conduct such testing. As Plaintiffs note, Defendants' expert "testified
only that the POS [IT]A would have considered it 'possible' to dissolve 25 mg/mL
bendamustine in 90: 10 PEG:PG at room temperature, far short of establishing
28
motivation" to use PEG. D.I. 371 at 43.
Moreover, Defendants fail to explain why a POSITA would believe that
bendamustine would have a lower solubility in PEG and PG as opposed to in PG
alone based only on bendamustine's high solubility in PG. In choosing a
concentration, a POSITA would have required that the bendamustine concentration
remain below the formulation's bendamustine solubility limit so that the
bendamustine would completely dissolve and dangerous precipitation would not
occur. Tr. 591: 19-92:7, 593 :23-94:4, 1434: 13-35 :9, 1435: 10-25, 1472: 12-14;
PTX-0667 at TEVABEND00293319. Because a POSITA would want to avoid
such precipitation, it would likely not combine bendamustine with a 90% PEG and
10% PG formulation based on bendamustine's solubility in PG alone.
f.
PG Ester Stability Limitations
Finally, certain asserted formulation claims contain a stability limitation, i.e.,
a maximum amount of degradants called PG esters that the composition can have
after storage for a set time period at a set temperature. For example, claims 2, 3,
and 5 of the #831 patent recite compositions having "less than or equal to O.11 %
PG esters at about 1 month of storage at about 5°C." #831 patent at claims 2, 3, 5.
Defendants argue that the stability limitations are an inherent property
because at least one obvious formulation in the asserted claims would naturally
result in the required PG ester levels. D.I. 378 at 27. But "[t]o prove that a claim
29
limitation is inherent in the prior art, [the challenger] must show ... [not only] that
the limitation at issue is necessarily present, or the natural result of the
combination of elements," but also that the combination of elements that naturally
result in the limitation is "explicitly disclosed by the prior art." Par Pharm., Inc. v.
Twi Pharm., Inc., 120 F. Supp. 3d 468, 473 (D. Md.), aff'd, 624 F. App'x 756
(Fed. Cir. 2015) (emphasis added) (internal quotation marks omitted); see also D.I.
378 at 28 ("Once an embodiment is shown to be obvious, any corresponding data
can be used to show that the stability property is inherent." (emphasis added)).
Because I find that the combination of elements that Defendants allege inherently
result in the stability limitations is not obvious, such limitations are not obvious
through inherency.
g.
Secondary Considerations
The parties adduced at trial evidence of only one secondary consideration
that bears on the formulation claims-commercial success. D.I. 371 at 79-80.
Plaintiffs argue that "[s]ales ofBendeka® exceed $2 billion," and that "Bendeka®
halted the downward trend in bendamustine sales, despite increasing competition."
D.I. 371 at 79. But such evidence does not support a finding of nonobviousness.
First, Bendeka® sells at a lower price than the prior art lyophilized Treanda®
product. Tr. 1641 :25-42:3, 1680:2-12, 1798:8-99:2. Second, Plaintiffs' cluster
30
of exclusivities has blocked others from entering the market. 4 Tr. 1723 :24-26: 1,
1730:3-7. "Where market entry by others was precluded ... the inference of
nonobviousness of the asserted claims, from evidence of commercial success, is
weak." Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 740 (Fed. Cir. 2013)
(internal quotation marks, alterations, and citations omitted).
****
Although the evidence of commercial success does not support a finding of
nonobviousness, I still find that Defendants have not shown by clear and
convincing evidence that the prior art they cited would have motivated a POSITA
to reach the claimed formulations. As discussed above, a POSITA would have
credited Drager over Olthoff, and Drager teaches away from the use of protic
solvents such as PG and PEG alone with bendamustine. Moreover, a POSITA
would not have relied on Alam in formulating bendamustine. Finally, clear and
convincing evidence does not show that a POSITA would have relied on Boylan
and Rowe as motivation to use an antioxidant because of the references that teach
4
Cephalon had an exclusive license from Fujisawa to develop bendamustine in the
U.S. DTX-1230_0001, _0002, _0019; Tr. 1226:24-27:1, 1263:21-25,
1233:18-34:25. Also, in 2008, lyophilized Treanda® obtained seven years of
orphan drug exclusivity (ODE) and an additional six months of pediatric
exclusivity. Tr. 1723:24-26:1. Bendeka® also received ODE. Eagle Pharm.,
2018 WL 3 83 8265, at *1. Thus, Bendeka® received seven years of exclusivity
that would prevent generics from entering the market until 2022. Tr.
1723 :24-26: 1.
31
away from the use of antioxidants in injectable formulations. And the Treanda®
Label and Olthoff would not have motivated a POSITA to reach the claimed
concentrations.
C.
Obviousness of the Asserted Administration Claims
1.
Findings of Fact
a.
The Priority Date
The parties agree that the priority dates for the asserted administrations
claims are (1) March 20, 2012 for claim 22 of the #568 patent, and (2) July 10,
2012 for the remaining administration claims. D.I. 332; Tr. 2015:10-16.
b.
Definition of the Relevant POSITA
The parties agree that a POSITA would have had the skills, education, and
expertise of a team of individuals working together to develop a safe and effective
administration protocol for a cytotoxic parenteral5 drug product. Such a team
would have included individuals with doctoral degrees in pharmaceutics,
pharmaceutical sciences, pharmacology, pharmacokinetics, pharmacodynamics, or
related fields, with at least two years of post-graduate experience in developing
protocols for pharmaceutical administration, or master's or bachelor's degrees in
similar fields of study, with a commensurate increase in their years of post-
5
In the pharmaceutical field, "parenteral" typically refers to products that are
administered by injection. Tr. 407:6-8.
32
graduate experience. Such a team would have been familiar with a variety of
issues relevant to administering liquid injectable drug products, including, among
other things, toxicity, solubility, pharmacokinetics, and pharmacodynamics. Such
a team would have included at least one individual with a medical degree with
experience in treating patients with CLL and NHL. PDX-2-4; Tr. 1112:4-20,
1293:22-94:9, 1233:1-17, 2014:22-15:2.
c.
Content of the Asserted Administration Claims
The asserted administration claims recite methods of treating CLL or NHL 6
with a liquid bendamustine composition. #568 patent at claims 11, 18, 22; #887
patent at claim 13. Certain claims require administering the bendamustine
composition on days one and two of a 21-day cycle for NHL, #568 patent at claim
18, or on days one and two of a 28-day cycle for CLL, #568 patent at claim 11.
One claim requires a bendamustine dose of"about 25 mg/m2 to about 120 mg/m2 ."
#887 patent at claim 13.
The asserted administration claims also specify administration times, the
longest time being "about 15 minutes or less." See e.g., #568 patent at claim 22;
#887 patent at claim 13. They also specify administration volumes that are all 100
mL or less. See e.g., #399 patent at claim 13. Finally, certain claims specify post-
6
Two claims recite, more generally, a "method of treating cancer or malignant
disease." #399 patent at claims 13, 15.
33
dilution bendamustine concentrations ranging from 0.05 mg/mL to 12.5 mg/mL.
See e.g., #568 patent at claims 11, 18.
d.
Content of the Prior Art
Defendants argue that eight prior art references would have motivated a
POSITA to combine the elements of the claimed administration with a reasonable
expectation of success: Palepu 2011, the Treanda® Label, Preiss 1985, Preiss
1998, Schoffski 2000a, Schoffski 2000b, Barth, and Glimelius. 7 D.I. 378 at 53.
1)
Palepu 2011 (DTX-0984)
Palepu 2011 is the published application that led to the asserted formulation
patents. Tr. 546:25-47:17. The parties have stipulated that Palepu 2011 disclosed
the formulations claimed in the asserted formulation and administration claims.
D.I. 320 if 6.
2)
Treanda® Label (DTX-0993 and DTX-1202)
The Treanda® Label, published in April 2009, D.I. 307-1
,r 247, disclosed
two FDA-approved liquid bendamustine composition dosing schedules: (1) for
CLL, intravenous (IV) infusion at a dose of 100 mg/m2 over 30 minutes on days
7 Defendants
also cite Olthoff to argue that the asserted administration claims were
obvious, but the arguments regarding Olthoff were advanced only by Dr. Yates, an
admitted non-formulator, and an expert that all Defendants but Apotex rejected.
Tr. 918:11-17, 920:19-22:13. Dr. Yates is a professional witness with limited
relevant experience who has testified repeatedly for Apotex. Tr. 908:17-13:12. I
did not find his testimony credible and do not rely on it.
34
one and two of a 28-day cycle for up to six cycles, Tr. 648:3-9; DTX-0993_0001;
DTX-1202_001; and (2) for NHL, IV infusion at a dose of 120 mg/m2 over 60
minutes on days one and two of a 21-day cycle for up to eight cycles, DTX0993_0001; DTX-1202_001; Tr. 648:3-9.
The Treanda® Label required the administration of Treanda® in a volume
of 500 mL, Tr. 652:13-16; DTX-1202_002, with a post-dilution bendamustine
concentration of0.2-0.6 mg/mL bendamustine, DTX-0993_0002; DTX-1202_003;
Tr. 652:21-23.
3)
Preiss 1985 (DTX-0320; DTX-0985)
Preiss 1985 disclosed the results of a pharmacokinetic analysis of
bendamustine. DTX-0320 0002; Tr. 658:25-59:2, 1119:18-20. A
pharmacokinetic analysis is a preliminary study in which a new drug is
administered to a small number of patients to determine the Cmax and area under
the curve (AUC). The Cmax is the peak concentration of the drug in the
bloodstream; the AUC is the patient's total exposure to the drug. Tr. 659:3-15,
847:8-24, 1114:2-7, 1120:18-25. Pharmacokinetic studies are not designed to
assess a drug's safety. Tr. 724:7-12, 1120:8-25.
Preiss 1985 administered bendamustine intravenously for three minutes to
seven patients with various cancers. DTX-0320_0002; Tr. 659:23-60:2,
723:16-24:3. Preiss 1985 administered an average total dose of280 to 375 mg.
35
Preiss 1985 reported "only rather mild side effects" at those doses. DTX0320_0006; Tr. 664:6-20, 1123:9-22.
4)
Preiss 1998 (DTX-0991)
Preiss 1998 investigated bendamustine's clinical pharmacology and defined
bendamustine's maximum tolerated dose (MTD) and dose limiting toxicities
(DLT). DTX-0991_0002; Tr. 674:16-25. The MTD of a drug is a tolerable dose
without severe or life-threatening toxicities; it differs from a recommended dose
for clinical use. Tr. 1126: 9-11. DLTs are severe or life-threatening side effects.
Tr. 674:23-75:1, 1126:12-23. Preiss 1998 administered bendamustine to more
than 50 patients with various cancers. DTX-0991_002. Preiss 1998 was not
designed to evaluate the safety of an infusion protocol. Tr. 730:22-31: 1,
731 :8-21.
Preiss 1998 administered three-to-ten-minute one-time infusions of
bendamustine in doses ranging from 54 to 226 mg/m2 • It also administered threeto-ten-minute infusions on four consecutive days in doses ranging from 20 to 88
mg/m2 • DTX-0987_005. Preiss 1998 concluded that "only mild toxicity occurred
even at high doses(> 200mg/m2 b-hydrochloride per cycle)." DTX-0991_0004;
Tr. 676:19-25. Preiss 1998 reported "disorientation" and a "vegetative neurotoxic
effect" after the one-time infusions of 175 mg/m2 and 215 mg/m2 doses. DTX991_0004, _0005.
36
5)
Schoffski 2000a (DTX-0987)
Schoffski 2000a administered bendamustine over 30 minutes and compared
its results to the three-to-ten-minute infusions disclosed in Preiss 1998. DTX0987_0002,_0005; Tr. 678:4-14. Schoffski 2000a reported that some side effects
from its 30-minute infusions were comparable to those observed with the three-toten-minute infusions in Preiss 1998. DTX-0987_0005,_0006; Tr. 678:10-79:5.
6)
Schoffski 2000b (DTX-0988)
Schoffski 2000b administered 60 to 80 mg/m2 ofbendamustine in 30
minutes. DTX-0988_0001-03; Tr. 679:20-22. Schoffski 2000b observed side
effects that were comparable to those observed in Schoffski 2000a. DTX0988_0005. Schoffski 2000b's authors did not "observe confusion or other signs
of neurotoxicity when giving the drug as a repeated 30-min i.v. infusion." DTX0988 0005.
7)
Barth 2010 (DTX-1004)
Barth suggested administering bendamustine in a solvent volume of 100 to
250 mL. DTX-1004_0005; Tr. 658:12-20, 681:21-83:8. Barth explained that
[t]he 30-minute short infusion [ofbendamustine] that is
practiced in Germany can be readily achieved with
infusion volumes of 100 to 250 m[L] 0.9% NaCl.
It is unclear why the American prescribing
information specifies 500 m[L] 0.9% NaCl or a final
concentration of 0.2-0.6 mg/m[L] .... A short infusion
with such volume is difficult to implement.
37
DTX-1004_0005; Tr. 682:9-83:2. Barth did not disclose any study or data. DTX1004_0005; Tr. 1157:22-59:18.
8)
Glimelius (DTX-0079)
Glimelius disclosed the administration of 5-Fluorouracil to treat colorectal
cancer as an infusion lasting ten to 20 minutes using a 50 to 100 mL mini-bag.
DTX-0079_0001, _0002. Mini-bags are small standard size bags. Tr. 554:2-9.
2.
Conclusions of Law
Defendants did not establish by clear and convincing evidence that a
POSITA would have been motivated to combine the prior art references to arrive at
the claimed administrations with a reasonable expectation of success. Although
the prior art would have motivated a POSITA to reach the claimed formulation,
dose, and dosing schedule, and although Plaintiffs' proffered secondary indicia of
nonobviousness were of little or no probative value, I find that the prior art would
not have motivated a POSITA to reach the remaining claim limitations, and thus
the claims as a whole are not obvious.
a.
Formulation, Dose, and Dosing Schedule
The parties agree that Palepu 2011, the published application that led to the
asserted formulation patents, disclosed before the priority date the formulations
found in the asserted administration claims. D.I. 320 ,r 6. But Plaintiffs argue that
Defendants have not shown that a POSITA would have been motivated to select
38
Palepu 2011 's formulations for the administrations recited in the asserted claims.
D.I. 371 at 48. Palepu 2011 itself, however, established a motivation to use its
formulations: it touted advantages of its disclosed formulations including "that
they have substantially improved long term stability when compared to currently
available formulations" and that they "are advantageously ready to use or ready for
further dilution" and thus "[r]econstitution of lyophilized powder is not required."
DTX-0984_0002 at [0007]; Tr. 889:8-90:3. It is undisputed that a POSITA would
have wanted to use a stable and ready-to-use formulation as part of an improved
administration method.
A POSITA also would have been motivated to combine Palepu 2011 with
the Treanda® Label to come up with the claimed doses and dosing schedule.
Palepu 2011 instructed administering its formulations in accordance with the
Treanda® dosing schedule. DTX-0984_0004 at [0044]; Tr. 856:8-9. And the
Treanda® Label taught similar doses and the same dosing schedules as those in the
asserted administration claims. DTX-0993_0001; DTX-1202_0001; Tr.
654:18-21, 695:10-20. The required dose found in the claims is about 25 mg/m2
to about 120 mg/m2 and the Treanda® Label requires doses of 100 mg/m2 or 120
mg/m2 • #887 patent at claim 13; DTX-0993_0001; DTX-1202_0001. Also, the
dosing schedule recited in the claims is the same as the Treanda® Label's
schedule: (1) for CLL, infusion on days one and two of a 28-day cycle, #568 patent
39
at claim 18; DTX-0993_0001; DTX-1202_001; Tr. 648:3-9; and (2) for NHL, IV
infusion on days one and two of a 21-day cycle, #5 68 patent at claim 11; DTX0993_0001; DTX-1202_001; Tr. 648:3-9.
That said, the asserted administration claims require administering each
bendamustine dose in faster times, in lower volumes, and at higher post-dilution
concentrations than the Treanda® Label requires. The question thus remains
whether a POSITA would have been motivated to reach the claimed administration
times, volumes, and concentrations.
b.
Administration Times, Volumes, and Post-Dilution
Concentrations
All asserted claims require administering bendamustine in 15 minutes or
less, with some requiring ten minutes or less. All asserted claims also require
administering bendamustine in a volume of 100 mL or less, with some claims
requiring about 50 mL. Finally, all but one of the asserted administration claims
require post-dilution bendamustine concentrations ranging from 0.05 to 12.5
mg/mL. 8
Defendants argue that the claimed administration times were obvious under
the Preiss and Schoffski studies; that the claimed administration volumes are
8
Claim 13 of the #887 patent, the only claim asserted against Slayback, does not
have a concentration limitation. D.I. 362 at 3.
40
obvious under the Preiss studies, Barth, and Glimelius; 9 and that the claimed postdilution concentrations are obvious under the Preiss studies and the Treanda®
Label. Defendants also contend that Eagle's post-invention statements corroborate
Defendants' assertion that the Preiss studies would have motivated a POSITA to
use shorter administration times, lower volumes, and higher concentrations.
1)
The Preiss Studies
Defendants argue that the Preiss studies support a finding that the claimed
administration times, volumes, and concentrations are obvious. First, Defendants
argue that a POSITA would have been motivated to administer bendamustine in 15
minutes or less because Preiss 1985 and Preiss 1998 disclosed that administration
of bendamustine in three-to-ten minutes was well-tolerated in humans and
Schoffski 2000a and 2000b disclosed that the safety results of 30-minute
bendamustine administrations were consistent with Preiss' s three-to-ten-minute
infusions. D.I. 378 at 39-40. Second, Defendants assert that the Preiss studies
render the claimed volumes of 100 mL or less obvious because, although the Preiss
references did not disclose a volume, a POSITA would have known based on
Preiss's three-to-ten-minute time constraint and typical infusion rates that the
9
Relying on the testimony ofDr. Yates, Defendants also cite Olthoff to argue that
the claimed volumes were obvious. D.I. 378 at 43. As noted above, I did not find
Dr. Yates's testimony to be credible and will not rely on it. Moreover, Olthoff's
example bendamustine formulation did not use PEG and, as explained above,
Drager discredited Olthoff's data. DTX-0094_0015; Tr. 923:14-24.
41
studies infused similar volumes. D.I. 378 at 42. Third, Defendants contend that
Preiss rendered the claimed concentrations of 0.05 to 12.5 mg/mL obvious because
Preiss 1985 likely used a concentration of 5.6 mg/mL. D.I. 378 at 46.
I find, however, that the Preiss studies would not have motivated a POSITA
to reach the claimed administration times, volumes, or concentrations because (1) a
POSITA would not have relied on the Preiss studies to determine a safe and
effective infusion time, volume, or concentration for bendamustine, (2) subsequent
prior art taught away from Preiss's three-to-ten-minute infusions, and (3)
Defendants only hypothesize that the Preiss studies used volumes and
concentrations similar to those in the claimed administrations.
a)
A POSITA would not have relied on the
Preiss studies to determine a safe
administration.
As an initial matter, Preiss 1985 and Preiss 1988 were not designed to
evaluate safety, and thus a POSITA would not have relied on the Preiss studies to
determine a safe infusion time, volume, or concentration. Tr. 724:7-12,
730:22-31:1, 731:8-21. Moreover, the Preiss studies did not provide enough data
points or information to allow a POSITA to rely on them for safety information.
Preiss 1985 tested only seven patients with various cancers, DTX-320_0002; Tr.
723:16-24:3, 1122:20-22; it did not discuss how it collected side effect
information, including the number or timing of observations, the side effects being
42
observed, or a grading system, Tr. 724:14-28:16; and it neither specified which of
the seven patients in the study had side effects nor distinguished between IV and
oral side effects, Tr. 728:8-20. A POSITA would not have concluded that side
effects would not be present in a larger population, Tr. 1121: 1-5, let alone the
relevant population, Tr. 1122:20-23 :8, based on a study that covered only seven
I
patients with various cancers and offered no explanation of how the side effects
were studied or which patients experienced the side effects. Preiss 1998 similarly
tested patients with various cancers, Tr. 1125:24-26:1, and it did not disclose when
the side effects it reported were monitored or how many times side effect
information was collected from patients. Thus, a POSITA would not have relied
on either Preiss study to determine the safety of a short bendamustine infusion. Tr.
1122: 14-19, 1123 :9-22.
In addition, the parties agree that the claimed administrations require
repeated cycles, D.I. 378 at 38; D.I. 371 at 59, but the Preiss studies did not
administer bendamustine in repeated cycles. 10 And according to Defendants'
expert, "bendamustine therapy side effects result from ... the number of cycles
given" and "these side effects are typically more severe in subsequent cycles
10
Defendants cited no reference that administered bendamustine in ten minutes or
less in repeated cycles. Tellingly, Defendants' references that did administer
bendamustine in repeated cycles all used 30-minute infusions. DTX-0987_0001;
DTX-0988_0001; DTX-1004_0002, _0005; DTX-0848; PTX-0268.
43
because there are cumulative effects on bone marrow." Tr. 736:11-37:20. A
POSITA would therefore not have relied on the Preiss studies to determine the
safety of a short infusion ofbendamustine administered in multiple cycles. Tr.
1133 :7-11. Moreover, neither Preiss study administered bendamustine over two
consecutive days as the claims require. Tr. 1129: 12-20.
The Schoffski articles also would not have motivated a POSITA to rely on
the Preiss studies to determine the safety of a short infusion time, lower infusion
volume, or higher infusion concentration. Schoffski 2000a reported that it
observed some side effects like those in Preiss 1998, but did not compare the
overall incidence or severity of side effects in the two infusion protocols.
DTX_0987_0006,_0007; Tr. 1138:21-39:19. Also, Schoffski 2000b stated that it
observed similar side effects to those observed in Schoffski 2000a, not that it
observed the same side effects as Preiss. And Schoffski 2000b stated that it did not
"observe confusion or other signs of neurotoxicity when giving the drug as a
repeated 30-min i.v. infusion," DTX-0988_005, while Preiss 1998 reported
"disorientation" and a "vegetative neurotoxic effect," DTX-0991 at
JDG- BENDA- 00006920-21.
b)
Subsequent prior art taught away from
the Preiss infusions.
Subsequent prior art also would have dissuaded a POSITA from relying on
the Preiss studies. A POSITA would not have stopped with Preiss 1985 and Preiss
44
1998; instead, it would have also considered later prior art references that used 30
to 60 minute infusions and a 500 mL volume. "Too often the obviousness analysis
is framed as an inquiry into whether a person of skill, with two (and only two)
references sitting on the table in front of him, would have been motivated to
combine ... the references in a way that renders the claimed invention obvious.
The real question is whether that skilled artisan would have plucked [those
references] out of the sea of prior art and combined [them]." WBIP, LLC v. Kohler
Co., 829 F.3d 1317, 1337 (Fed. Cir. 2016).
The Preiss researchers themselves conducted later studies and recommended
in subsequent papers an infusion of at least 30 minutes in 500 mL. DTX0987_0001; DTX-0988_0001; PTX-0268; DTX-0982_0009; Tr. 1145:13-46:7.
Preiss 2003-conducted by the same research group as Preiss 1985 and 1998reported administration over 30 minutes in repeated cycles. PTX-0268; Tr.
1141 :21-43: 15. Moreover, the Ribomustin Monograph-which set forth the
prescription information for the German bendamustine product Ribomustin and
was developed by a company that employed scientists involved in the Preiss and
Schoffski studies-recommended a 30 to 60 minute infusion in 500 mL because of
local toxicity concerns. DTX-0982 009; Tr. 1143:17-44:13, 1144:14-45:5,
1146:8-54:4.
45
c)
Defendants only hypothesize that the
Preiss studies used the claimed volumes
and concentrations.
Finally, Defendants only hypothesize that the Preiss studies used similar
volumes and concentrations as those recited in the asserted claims. With respect to
volume, Defendants assert that although the Preiss references did not disclose a
volume, "[b]ecause administration time and volume are related," a POSITA would
have known based on Preiss's three-to-ten-minute time constraint and typical
infusion rates that the studies infused small volumes. D.I. 378 at 42 (citations
omitted). With respect to concentration, Defendants contend that "Preiss 1985
administered bendamustine in a dose of 280-375 mg in a bolus, [i.e., a volume that
the] evidence showed likely meant 50 or 100 mL," and diluting 280 mg in 50 mL
would result in a concentration of 5.6 mg/mL. D.I. 378 at 46. Such speculations
about Preiss's infusion rate and volume, however, are only based on "conclusory
and unsupported expert testimony" and they do not support a finding of
obviousness by clear and convincing evidence. See TQ Delta, LLC v. CISCO Sys.,
Inc., 942 F.3d 1352, 1361 (Fed. Cir. 2019) ("In cases like InTouch, Active Video,
and DSS, we rejected obviousness determinations based on conclusory and
unsupported expert testimony.").
Defendants have thus failed to establish by clear and convincing evidence
that the Preiss studies support a finding that the claimed infusion times, volumes,
46
and concentrations were obvious. "Whether a skilled artisan would be motivated
to make a combination includes whether he would select particular references in
order to combine their elements," WBIP, 829 F.3d at 1337, and a POSITA in 2010
would not have selected the Preiss studies to determine a safe and effective
infusion for a bendamustine formulation.
2)
Barth and Glimelius
Defendants also argue that the administration volumes are obvious under
Barth and Glimelius. They note that Barth recommended a 100 to 250 mL
bendamustine infusion, D.I. 378 at 43, and that a "POS[IT]A would have known
from Glimelius (DTX-0079) that minibags, [standard infusion bag sizes of 50 or
100 mL], were typically used for infusions of 10-20 min;" D.I. 378 at 44 (citations
omitted).
Barth and Glimelius, however, would not have motivated a POSITA to use
the claimed volumes. First, Barth did not disclose any study or data; it only
suggested hypothetical smaller volumes. DTX-1004_0005; Tr. 1159:10-18. And
Barth's 100 to 250 mL suggestion did not cover the claimed volumes (all claims
require 100 mL or less). DTX-1004_0005; Tr. 1159:3-16. Second, Glimelius did
not disclose any bendamustine administration, Tr. 841 :3-42:22, and the mere
availability of a standard IV bag would not have given a POSITA motivation to
use a bag that size. IV bags of 50 mL were available before the priority date, but
47
had never been used to deliver bendamustine. D.I. 371 at 58.
3)
The Treanda® Label
Defendants also assert that the Treanda® Label would have motivated a
POSITA to use the claimed post-dilution concentrations. They argue that the
claimed concentrations are obvious as inherent because diluting the claimed doses
disclosed in the Treanda® Label in the claimed volume of liquid necessarily would
have resulted in the claimed concentrations ofbendamustine, PG, and PEG. D.I.
378 at 44. But because I find that the claimed volumes are not obvious, it does not
follow that the claimed concentrations are obvious as inherent. Defendants also
state that "on the lower end of the spectrum, the [claimed] concentration falls
within the 0.2-0.6 mg/mL concentration of the Treanda® Label." D.I. 378 at 45.
But the Treanda® concentrations only cover a small portion of the claimed range
of 0.05 to 12.5 mg/mL and thus they do not render the claimed concentrations
obvious.
4)
Eagle's Post-Invention Statements
Defendants further argue that, through post-invention statements, Plaintiffs
admitted that the prior art taught that short infusions in lower volumes were safe
and effective. Defendants point to the fact that Eagle relied on the conclusions
from the Preiss studies when it told the FDA that its Bendeka® protocol was safe.
D.I. 378 at 51.
48
It is true that, in support of its request for permission to test Bendeka®,
Eagle submitted to the FDA a Detailed Review of Literature that relied in part on
data from the Preiss and Schoffski references. DTX-1041 017 5. The literature
review stated: "Thus, the short duration infusion of bendamustine appears to be
well tolerated in this study and a dose of 215 milligrams has been reported in the
literature as the clinically tolerated dose for bolus administration of bendamustine."
DTX-1041_0175. Later, Eagle made similar statements to the FDA when drafting
its Investigator's Brochure to support its requested study that required
administering the Bendeka® formulation in ten minutes. DTX-1061 at 14.
Eagle's submissions to the FDA, however, also contained non-public, nonprior-art tests and analysis Eagle had conducted to show those short-infusion
protocols were safe to test in humans. DTX-1041_0025-26. And I find that
Eagle's post-invention discussion of the prior art that is intermingled with its own
non-public data that it developed in inventing the claimed administration does not
show that a POSITA who did not have Eagle's non-public data would have relied
on the Preiss studies. Conclusions drawn from a patentee's "disclosures to the
FDA" risk being "distorted by hind-sight bias," especially here where the FDA
submission was dated after the priority dates and thus was written "through the
lens of what [the inventor] had invented." Neptune Generics, LLC v. Eli Lilly &
Co., 921 F.3d 1372, 1377 (Fed. Cir. 2019).
49
In sum, Defendants failed to prove by clear and convincing evidence that a
POSITA reading the Preiss and Schoffski studies, Barth, Glimelius, and the
Treanda® Label would have found the claimed infusion times, volumes, and
concentrations obvious.
c.
Secondary Considerations
Plaintiffs offered at trial evidence of four secondary considerations that bear
on the administration claims: skepticism, long-felt need, commercial success, and
industry praise. I did not, however, find this evidence to be probative indicia of
nonobviousness for the following reasons.
1)
Skepticism
Plaintiffs argue that "industry participants" were skeptical of the claimed
invention. D.I. 371 at 77. But the skepticism they cite was apparently held by a
"couple of nurses, a pharmacist[,] and an oncology medical resident," DTX0959_ 000 l, and investors, D.I. 371 at 78. Such "lack of enthusiasm by a few is not
equivalent to skepticism." BTG Int'/ Ltd. v. Amneal Pharm. LLC, 923 F.3d 1063,
1076 (Fed. Cir. 2019).
Plaintiffs also contend that the FDA declined to allow testing of Eagle's IV
push method of administration because of safety concerns. D.I. 371 at 78. But the
IV push method is not the claimed invention; the invention is the ten-minute
infusion and the FDA told Eagle to proceed with its ten-minute infusion study.
50
PTX-0746 at EGL-BENDEKA_00146354; Tr. 1691:3-14; see also PTX-0747 at
EGL-BENDEKA_00146355 ("[Eagle] stated that they have decided not to
evaluate the IV push method administration. [Eagle] will use 120 mg/m2 over 10
minutes in their bridging study.").
2)
Long-Felt Need
Plaintiffs also argue that Bendeka®'s shorter infusion addressed a "long-felt
need to reduce chair time for chemotherapy, improving patient experience and
allowing more patients to be treated." D.I. 371 at 79. The parties offered
competing expert testimony on this point. I found credible only Defendant's
expert, Dr. Thirman, who testified that Bendeka® does not meaningfully reduce
chair time because patients receive IV fluids and other drugs simultaneously with
the administration ofBendeka® and the administration of those fluids and other
drugs lasts for much longer than 15 minutes. Tr. 188:20-89:9, 189:22-24,
1744:14-51:20, 1745:20-46:6, 1751:3-51:8, 1765:18-66:6, 1779:11-18; DTX0968_0001. For example, Bendamustine is frequently administered with a drug
called Rituxan that has an administration time of four to eight hours. Tr.
190:24-91:6, 191:2-6, 713:14-22, 1746:11-17, 1781:14-22. 11
11
Plaintiffs' expert, Dr. Agarwal, was not credible. He testified that, based on his
experience in a "community-based cancer center," Tr. 1288:19, there were "always
issues with the chair time" in the oncology field and that Bendeka® resolved the
chair time need, Tr. 13 04: 7-0 5: 19. My assessment of his lack of credibility was
informed by the logic and credible nature of Dr. Thirman's testimony and also by
51
Dr. Agarwal's dissembling with respect to his billing practices (which might
explain why he favored shorter chair times). Dr. Agarwal initially denied having
any idea how his patients are billed for his work: "I mean, I'm not, I'm not the
biller and I don't get paid by the amount I bill or anything .... My only concern is
the patient's safety and that's all I care about. ... I have no clue honestly about
billing, billing procedures." Tr. 1339:15-21. He volunteered that "billing, which
is a totally different department, I have no clue how they do it and I don't take a
look at it. I don't even know how to look at it." Tr. 1340:15-17. And when asked
how billing relates to infusion time, Dr. Agarwal claimed to have "no idea how the
billing codes work with the infusion." Tr. 1344: 13-17. But when asked by the
Court ifhe was "paid by salary," Dr. Agarwal responded: "So the way it works is,
what they [his practice group] wanted is eat what you kill. Basically, if I see more
patients, I get paid more. Ifl work harder, I get more. Ifl work less, I get paid
less." Tr. 1345 :7-11. He then continued to explain the billing process in detail:
So the way it works is, so we have like repeated billing
codes for repeated business, which are from level one to
level four, and that's very small. You just mark what
billing code you want to put. These are being audited by
McKesson and auditors, that you are not -- they look at
our notes. They decide if the doctor is overbilling or
underbilling with the code. We have another code for the
new patient.
****
So they have like one to four levels of visit. Depending
on how much time I spend with a patient, either from 15
minutes to 30 minutes, I can go from a level one visit to a
level four visit and that's what I mark on that. I think it's
level one to level five. Level five is a very complex visit
where I spend an hour or more with a patient, and most
of the visits are about level three or level four, but these
patients that are going to see me, I just bill level 3 or 4
and then I submit the payment and that is taken care of
by the billing and coding department.
Tr. 1345:19-46:1, 1346:13-23. Also, when Dr. Agarwal was asked ifhe was
"familiar with a term called infusion billing," he responded "Yes." Tr. 1338:2-4.
52
3)
Commercial Success
Plaintiffs further argue that Bendeka®'s commercial success is
demonstrated by ( 1) the fact that "Bendeka® halted the downward trend in
bendamustine sales, despite increasing competition," D.I. 371 at 79, and (2)
"Teva's choice to license Bendeka® and pay Eagle a portion of the profit for each
Bendeka® sale, when it could keep all profits from Treanda®," D.I. 361
,r 222.
But such evidence does not support a finding of nonobviousness. Plaintiffs have
not provided evidence to establish that Bendeka®'s sales and Teva's decision to
license Bendeka® were linked to Bendeka®' s patented advantages as opposed to
Bendeka®'s exclusivities. See D.I. 371 at 80 ("Eagle's patents expire shortly after
Teva's pre-existing patents."); Tr. 1725:25-26:2 (stating that with the Bendeka®
license, Teva has FDA exclusivity until 2022). Also, the "competition" that
Plaintiffs cite consists only of Eagle's Belrapzo®-a drug that shares Bendeka®'s
formulation, but lacks the short-infusion protocol. D.I. 361
,r 219.
Because Eagle
benefits from the sales of both Belrapzo® and Bendeka®, it may have an incentive
to market Bendeka® over Belrapzo®, Tr. 1652:19-53:2, and thus any evidence
that Bendeka® has higher sales has little if any probative value.
4)
Praise
Finally, Plaintiffs argue that "Bendeka®'s patented advantages ... have
received industry praise." D .I. 3 71 at 81. In support of this assertion, they cite ( 1)
53
Veteran's Administration (VA) newsletter that highlighted the advantages of
Bendeka® as compared to Treanda®, (2) a study that noted attributes ofBendeka®
that drive Bendeka®'s usage, and (3) Fresenius Kabi's pre-litigation statement that
Bendeka® reduced "[p ]atient chair time" and that Bendeka® could "have higher
pricing and still retain volume due to the benefits it offers." D.I. 371 at 81; D.I.
361
,r 226.
Here again, I find such evidence to have at best marginal probative
value. As an initial matter, the VA does not even use Bendeka®. Tr.
1777: 1-7 8: 16. Second, the study Plaintiffs cite was funded by Teva and provides
no connection between the claimed limitations and industry praise. Tr.
1305:25-07:4. Third, Fresenius Kabi's statement merely lists reduced chair time
as a fact and does not exhibit any praise related to the asserted claims.
****
In sum, the secondary consideration evidence does not support a finding of
nonobviousness. I still find, however, that the asserted administration claims are
not obvious. Defendants have not shown by clear and convincing evidence that
Palepu 2011, the Treanda® Label, Preiss 1985, Preiss 1998, Schoffski 2000a,
Schoffski 2000b, Barth, and Glimelius would have motivated a POSITA to arrive
at the claimed administrations with a reasonable expectation of success. A
POSITA would not have been motivated to follow Preiss's three-to-ten-minute
(and potentially lower volume and higher concentration) infusions because ( 1) a
54
POSITA would not have relied on the Preiss studies to determine a safe
bendamustine infusion protocol, (2) subsequent prior art taught away from the
three-to-ten-minute infusions, and (3) Defendants only guess that Preiss used
similar volumes and concentrations to those claimed. Moreover, Barth and
Glimelius would not have motivated a POSITA to administer bendamustine at
lower volumes because (1) Barth only disclosed hypothetical volumes that did not
even include the claimed volumes of 100 mL or less and (2) Glimelius did not
involve bendamustine. Finally, the claimed concentrations are not obvious as
inherent or under the prior art.
III.
INDEFINITENESS
Defendants argue that the asserted formulation claims are invalid because
they each require "a stabilizing amount of antioxidant"-a requirement Defendants
contend is indefinite. D.I. 371 at 2.
A.
Legal Standards for Indefiniteness
" [A] patent is invalid for indefiniteness if its claims, read in light of the
specification delineating the patent, and the prosecution history, fail to inform,
with reasonable certainty, those skilled in the art about the scope of the invention."
Nautilus, Inc. v. Biosig Instruments, Inc., 572 U.S. 898, 901 (2014).
"Indefiniteness is a matter of claim construction, and the same principles that
generally govern claim construction are applicable to determining whether
55
allegedly indefinite claim language is subject to construction." Praxair, Inc. v.
ATM], Inc., 543 F.3d 1306, 1319 (Fed. Cir. 2008), abrogated on other grounds by
Nautilus, 572 U.S. at 901 (rejecting Federal Circuit's "insolubly ambiguous"
standard for indefiniteness). As in claim construction, in making an indefiniteness
determination, the district court may make "any factual findings about extrinsic
evidence relevant to the question, such as evidence about knowledge of those
skilled in the art." See BASF Corp. v. Johnson Matthey Inc., 875 F.3d 1360, 1365
(Fed. Cir. 2017). "Any fact critical to a holding on indefiniteness ... must be
proven by the challenger by clear and convincing evidence." Cox Commc 'ns, Inc.
v. Sprint Commc'n Co. LP, 838 F.3d 1224, 1228 (Fed. Cir. 2016) (alteration in
original)).
B.
Discussion
Defendants argue that "the claims recite a 'stabilizing amount' [of
antioxidant] with no guidance, functional or otherwise, on what degree of stability
is required to obtain some unnamed objective." D.I. 380 at 3. But this argument
conflates (1) whether a given antioxidant amount improves bendamustine's
stability with (2) the extent to which that given antioxidant amount improves
stability. The written description defines a "stabilizing amount of antioxidant" as
an amount that "increase[s] or enhance[s] the stability of the bendamustine in the
compositions described herein," #831 patent at 3:49-54; Tr. 370:25-71:9. Thus,
56
the "objective" of the antioxidant amount is not "unnamed" but is instead "to
increase or enhance the stability of the bendamustine in the compositions"
described in the specification. 12
Defendants argue that the term is indefinite because "[t]he specification does
not explain how to determine whether stability has been 'increased' or
'enhanced."' D.I. 378 at 3. But as Plaintiffs' expert, Dr. Siepmann, credibly
testified, a POSITA would understand that a stabilizing amount of an antioxidant
includes any amount that decreases the amount ofbendamustine degradation after
any time period and at any temperature. Tr. 1485:4-87:10, 1502:8-12. And the
patents provide a POSITA with a method for measuring stability: using HPLC to
compare the amount of overall bendamustine degradation with and without the
antioxidant. Tr. 1485:14-86:11. Example 3 demonstrates that a POSITA would
compare the amount of bendamustine remaining in the same formulation, stored
under the same conditions, with and without the antioxidant, #831 patent at
12
Section 112(b) of Title 35 provides that "[t]he specification shall conclude with
one or more claims[.]" This language makes clear that the specification includes
the claims asserted in the patent, and the Federal Circuit has so held. See
Markman, 52 F.3d at 979 ("Claims must be read in view of the specification, of
which they are part"). The Federal Circuit and other courts, however, have also
used "specification" on occasion to refer to the written description of the patent as
distinct from the claims. See, e.g., id. ("To ascertain the meaning of claims, we
consider three sources: The claims, the specification, and the prosecution
history."). To avoid confusion, I refer to the portions of the specification that are
not claims as "the written description."
57
7:59-8:27; and the specifications describe measuring the remaining bendamustine
using HPLC, id. at 2:26-44, 2:57-3:4, 4:22-26; Tr. 1487:11-89:11. In addition to
providing exemplary test methods, the specification also lists "suitable antioxidant
amounts" and "antioxidants," and provides examples of "stabilizing" amounts.
#831 patent at 3:57-4:8, 7:59-9:2; Tr. 371:15-72:18, 1489:23-90:4.
In BASF, the Federal Circuit held the term "composition ... effective to
catalyze" not indefinite, even though the patent did not "recite a minimum level of
function needed to meet this 'effective' limitation" or "a particular measurement
method," because tests for determining whether a composition was catalyzing were
well-known. 875 F.3d at 1366-68. Here, the term "stabilizing amount of
antioxidant" is like the term "composition ... effective to catalyze" and Plaintiffs'
expert, like the expert in BASF, persuasively testified that a POSITA would know
how to determine whether an amount of antioxidant is stabilizing. Moreover,
unlike in BASF, the asserted patents here provide a test method.
Finally, Defendants cite the patentee's removal of antioxidant and stability
limitations during prosecution as support for their indefiniteness argument. D.I.
378 at 5-6. But the removal of those limitations undercuts Defendants' argument
because it confirms that the "examiner understood" the claims without those
limitations. See Sonix Tech. Co. v. Publ'ns Int'l, Ltd., 844 F.3d 1370, 1379-80
(Fed. Cir. 2017).
58
I thus find that the term "stabilizing amount of antioxidant" is not indefinite
and I construe it as: any amount of an antioxidant that decreases the amount of
bendamustine degradation after any time period and at any temperature.
IV.
ENABLEMENT
Defendants assert that the asserted formulation claims are invalid for lack of
enablement because the formulation patents disclosed neither the use of sodium
hydroxide (NaOH) or of "other undisclosed variables." D.I. 378 at 59.
A.
Legal Standards for Enablement
"Claims are not enabled when, at the effective filing date of the patent, one
of ordinary skill in the art could not practice their full scope without undue
experimentation." Wyeth & Cordis Corp. v. Abbott Labs., 720 F.3d 1380, 1384
(Fed. Cir. 2013) (citation omitted). "That some experimentation is necessary does
not preclude enablement; the amount of experimentation, however, must not be
unduly extensive." Atlas Powder Co. v. E.I. du Pont De Nemours & Co., 750 F.2d
1569, 1576 (Fed. Cir. 1984) (citations omitted). A challenger must prove
invalidity based on non-enablement by clear and convincing evidence. MagSil
Corp. v. Hitachi Glob. Storage Techs., Inc., 687 F.3d 1377, 1380 (Fed. Cir. 2012).
Enablement is a question of law based on underlying facts. Abbott Labs., 720 F.3d
at 13 84 (citations omitted).
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B.
Discussion
Defendants argue that the asserted formulation claims are not enabled
because the claims do not contain NaOH and "a pH adjuster like NaOH is
necessary to obtain the PG ester levels claimed in the [a]sserted [f]ormulation
[c]laims." D.I. 378 at 59. Defendants note that "Eagle's later-filed [#]879
application ... explains [that] 'the control samples, which did not include NaOH
did not provide long term storage stability,' and 'exhibited more than 28% total
esters compared to initial after six months of storage at 25° C. "' D.I. 378 at 60
( citation omitted).
Evidence that some claimed formulations did not result in the PG ester
limitations, however, does not establish that the claims are not enabled.
Defendants have not presented any evidence to show that a POSITA would have
had to undertake undue experimentation to alter the formulation to obtain the PG
ester limitations. That some formulations with the claimed ingredients do not
satisfy the PG ester limitations does not support non-enablement unless the number
of such formulations is significant enough to have required a POSITA to
experiment unduly. See Atlas Powder, 750 F.2d at 1576-77 ("Even if some of the
claimed combinations were inoperative, the claims are not necessarily invalid....
Of course, if the number of inoperative combinations becomes significant, and in
effect forces one of ordinary skill in the art to experiment unduly in order to
60
practice the claimed invention, the claims might indeed be invalid. That, however,
has not been shown to be the case here." (citations omitted)). Defendants
presented no evidence showing that the number of unsuccessful formulations is
significant enough to require undue experimentation. Accordingly, they failed to
establish by clear and convincing evidence that the asserted claims are invalid for
lack of enablement.
V.
WRITTEN DESCRIPTION
Apotex argues that claim 9 of the #797 patent is invalid for lack of written
description. D.I. 378 at 60. It asserts that "the absence of any mention of a pH
adjuster like NaOH in the [#]797 patent demonstrates that the inventors did not
have possession of it at that time, as confirmed by their later filing of another
patent application that discloses and claims it." D.I. 378 at 61 (citations omitted).
"But written description is about whether the skilled reader of the patent disclosure
can recognize that what was claimed corresponds to what was described .... "
Alcon Research Ltd. v. Barr Labs., Inc., 745 F.3d 1180, 1191 (Fed. Cir. 2014).
And Apotex never cites the intrinsic record to show that the asserted formulation
patents claim something that they do not describe in their written descriptions.
Instead, Apotex improperly cites extrinsic evidence-the later-filed Eagle patent
application. Apotex has thus failed to establish that claim 9 is invalid for lack of
written description.
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VI.
INFRINGEMENT
Defendants stipulated to infringement of the asserted claims with two
exceptions. Apotex, Fresenius Kabi, and Mylan argue that (1) they do not infringe
the asserted formulation claims because their ANDA products do not contain "a
stabilizing amount of an antioxidant" as the asserted formulation claims require,
D.I. 369 at 2; and (2) they do not directly infringe or induce infringement of claim
9 of the #797 patent, which requires that the "bendamustine-containing
composition ha[ve] less than or equal to 0.43 % total PG esters at about 3 months
of storage at a temperature of about 25°C," because their proposed labeling does
not direct physicians to store their ANDA products for about 3 months at about
25°C, D.I. 369 at 4-5.
A.
Legal Standards for Infringement
A defendant is liable for patent infringement if it files an ANDA "for a drug
claimed in a patent or the use of which is claimed in a patent." 35 U.S.C. §
271(e)(2)(A). To establish infringement based on the filing of an ANDA under§
271(e)(2)(A), a patentee must show that "if the drug were approved based upon the
ANDA, the manufacture, use, or sale of that drug would infringe the patent in the
conventional sense." Glaxo, Inc. v. Novopharm, Ltd., 110 F.3d 1562, 1569 (Fed.
Cir. 1997).
"Conventional" infringement includes direct infringement and inducement.
62
35 U.S.C. § 271 (a), (b ). Direct infringement requires that "every limitation set
forth in a claim ... be found in an accused product, exactly." Southwall Techs.,
Inc. v. Cardinal JG Co., 54 F.3d 1570, 1575 (Fed. Cir. 1995) (citation omitted).
Inducement requires a showing "that the accused inducer took an affirmative act to
encourage infringement with the knowledge that the induced acts constitute patent
infringement." Microsoft Corp. v. DataTern, Inc., 755 F.3d 899, 904 (Fed. Cir.
2014) (citation omitted). A plaintiff can prevail on a claim of inducement only if it
establishes direct infringement. See Limelight Networks, Inc. v. Akamai Techs.,
Inc., 572 U.S. 915, 921 (2014) ("[I]nducement liability may arise if, but only if,
there is direct infringement." (internal quotation marks, alterations, and citation
omitted)).
A patentee must prove infringement by a preponderance of the evidence.
Envirotech Corp. v. Al George, Inc., 730 F.2d 753, 758 (Fed. Cir. 1984). "A
patentee 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)
(internal quotation marks and citations omitted).
B.
Direct Infringement of the "Stabilizing Amount of Antioxidant"
Limitation
The asserted formulation claims require a "stabilizing amount of an
antioxidant," a term that I construed as any amount of an antioxidant that decreases
63
the amount ofbendamustine degradation after any time period and at any
temperature.
Defendants' ANDA products each contain 5 mg/mL of the antioxidant
monothioglycerol, see PTX-0474 at APOLIQBENDA_ANDA_0005427 (Apotex);
PTX-0486 at FK_BENDA_00003243, 3245 (Fresenius Kabi); PTX-0007 at
MYLBEN_000248 (Mylan); Tr. 372:19-74:13, and the formulation patents'
written description shows that 5 mg/mL of monothioglycerol is a stabilizing
amount. The written description identifies "5 mg/mL to about 20 mg/mL" as a
"preferable" stabilizing amount of antioxidant. #831 patent at 3 :49-68; #797
patent at 3:55-66. The written description also identifies "thioglycerol (also
known as monothioglycerol)" as a preferred antioxidant. #831 patent at 4: 1-8;
#797 patent at 4:6-16. Moreover, Example 3 demonstrates that adding "5
mg/m[L] oflipoic acid ... as a stabilizing antioxidant" to 20 mg/mL of
bendamustine in PEG decreased the amount ofbendamustine degradation after 15
days at 25°C and 40°C as compared to the same formulation without an
antioxidant. #831 patent at 7:59-8:27; #797 patent at 7:61-8:29; Tr.
371:15-72:18. Example 4 recites dissolving 50 mg/mL bendamustine in 90% PEG
and 10% PG, and adding "5 mg/m[L] of [mono]thioglycerol, a-lipoic acid or
dihydrolipoic acid," an amount that it describes as "a stabilizing amount of an
antioxidant." #831 patent at 8:29-65; #797 patent at 8:32-66.
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Circumstantial evidence can establish infringement; and here, the asserted
formulation patents' disclosures that 5 mg/mL of an antioxidant (and specifically
monothioglycerol) is stabilizing shows that the 5 mg/mL of monothioglycerol that
Defendants use in their ANDA products decreases the amount ofbendamustine
degradation as compared to the same formulation without an antioxidant.
Finally, Fresenius Kabi and Mylan represented to the FDA that 5 mg/mL
monothioglycerol was sufficient to ensure that the amount of bendamustine in their
ANDA products did not fall below specification limits. See PTX-0054 at
FK_BENDA_00000543 (Fresenius Kabi); PTX-0201 at MYL-BEN_005258
(Mylan); Tr. 374:14-77:1.
C.
Direct and Induced Infringement of Claim 9 of the #797 Patent
Claim 1 of the #797 patent recites a "method of treating leukemia,
Hodgkin's disease, or multiple myeloma" comprising "administering" the specified
"liquid bendamustine-containing composition." #797 patent at 12:43-46 (claim 1).
Claim 9 recites the method of claim 1, wherein the "bendamustine-containing
composition has less than or equal to 0.43% total PG esters at about 3 months of
storage at a temperature of about 25° C." #797 patent at claim 9. Defendants
stipulate that their ANDA Products have "less than or equal to 0.43% total PG
esters at about 3 months of storage at a temperature of about 25° C," but contend
that they do not directly infringe or induce infringement of claim 9 because their
65
proposed labeling does not recommend storing their ANDA Products for "about 3
months" at "a temperature of about 25° C." D.I. 307-4 ,r I.a; D.I. 320 ,r 3.
I find, however, that even though Defendants' labeling does not mention
storage, Defendants' ANDA products directly and indirectly infringe claim 9
because the PG ester limitation does not require the user to store the products for
three months at 25°C. Claim 9's PG ester limitation describes a characteristic of
the claimed formula; it is not a method step and thus, does not require action to
infringe. The claim does not recite testing for the PG ester limitation; it just
describes a composition that would have less than 0.43% PG esters if one were to
test for them after storing the composition for three months at 25°C.
Defendants' proposal to construe the PG ester limitation as a method step
that requires actual storage under the specified conditions also fails because it
"renders [claim 9] nonsensical." See Becton, Dickinson & Co. v. Tyco Healthcare
Grp., LP, 616 F.3d 1249, 1255 (Fed. Cir. 2010) ("A claim construction that renders
asserted claims facially nonsensical cannot be correct." (internal quotation marks
and citations omitted)). Although claim 1 of the #797 patent requires the
composition to have "less than or equal to 0.11 % total PG esters at about 1 month
of storage at a temperature of about 5° C," claim 9 requires the same composition
to have "less than or equal to 0.43% total PG esters at about 3 months of storage at
a temperature of about 25° C." #797 patent at 12:61-63 (claim 1), 13:22-25
66
(claim 9). Under Defendants' proposed construction, to infringe, the user would
need to store the composition simultaneously at different temperatures, which is
impossible.
Defendants therefore directly infringe and induce infringement of claim 9 of
the #797 patent. With respect to direct infringement, Defendants agree that their
products have less than or equal to 0.43% total PG esters after storing them for
three months at a temperature of about 25°C and, other than with respect to a
stabilizing amount of an antioxidant, they stipulated to direct infringement of the
remaining limitations. D.I. 320 ,r 3. With respect to induced infringement,
Defendants will encourage others to administer their ANDA products through their
proposed labels. Although Defendants' proposed labeling does not mention the
claimed PG ester limitations, Defendants know "that [their ANDA products] meet
all of the claim limitations and, through [their] proposed label[s], encourage[]
patients to administer [their ANDA products] in a manner that infringes the
claimed method." Orexigen Therapeutics, Inc. v. Actavis Labs. FL, Inc., 282 F.
Supp. 3d 793, 816 (D. Del. 2017), rev'd in part on other grounds sub nom.
Nalpropion Pharm., Inc. v. Actavis Labs. FL, Inc., 934 F.3d 1334 (Fed. Cir. 2019).
"Whether the [user] who performs the method by administering the [products]
knows that the [products] meet the [PG ester limitations] is irrelevant for the
purposes of infringement." Id.
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VII. CONCLUSION
For the foregoing reasons, I find that all asserted claims of the asserted
patents are not invalid and that Defendants infringe and induce infringement of
each of the asserted claims.
The parties will be directed to submit a proposed order by which the Court
may enter final judgment consistent with this Opinion.
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