Novartis Pharmaceuticals Corporation et al v. Breckenridge Pharmaceutical Inc.

Filing 182

TRIAL OPINION. Plaintiffs should submit an agreed upon form of final judgment within two weeks. Signed by Judge Richard G. Andrews on 3/28/2017. Associated Cases: 1:14-cv-01043-RGA, 1:14-cv-01196-RGA, 1:14-cv-01289-RGA(nms)

IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE

NOVARTIS PHARMACEUTICALS
CORPORATION and NOVARTIS AG,
Plaintiff;

v.

Civil Action No. 1: 14-cv-1043-RGA

BRECKENRIDGE PHARMACEUTICAL,
INC.,
Defendant.

NOVARTIS PHARMACEUTICALS
CORPORATION and NOVARTIS AG,
Plaintiff;

v.

Civil Action No. 1:14-cv-1196-RGA

WEST-WARD PHARMACEUTICALS
INTERNATIONAL LIMITED,
Defendant.
NOVARTIS PHARMACEUTICALS
CORPORATION and NOVARTIS AG,
Plaintiff;
Civil Action No. 1:14-cv-1289-RGA

v.
PAR PHARMACEUTICAL, INC.,
Defendant.

TRIAL OPINION

Daniel M. Silver, Esq., MCCARTER & ENGLISH, LLP, Wilmington, DE; Nicholas N. Kallas,
Esq., FITZPATRICK, CELLA, HARPER & SCINTO, New York, NY; Christopher E. Loh,
Esq., FITZPATRICK, CELLA, HARPER & SCINTO, New York, NY; Charlotte Jacobsen, Esq.,
FITZPATRICK, CELLA, HARPER & SCINTO, New York, NY; Christina L. Schwarz, Esq.,
FITZPATRICK, CELLA, HARPER & SCINTO, New York, NY.
Attorneys for Plaintiffs
Kelly E. Farnan, Esq., RICHARDS, LAYTON & FINGER, PA, Wilmington, DE; Selena
Molina, Esq., RICHARDS, LAYTON & FINGER, PA, Wilmington, DE; B. Jefferson Boggs,
Jr., Esq., MERCHANT & GOULD PC, Alexandria, VA; Matthew L. Fedowitz, Esq.,
MERCHANT & GOULD PC, Alexandria, VA; Christopher J. Sorenson, Esq., MERCHANT &
GOULD PC, Minneapolis, MN; Rachel C. Hughey, Esq., MERCHANT & GOULD PC,
Minneapolis, MN; Daniel R. Evans, Esq., MERCHANT & GOULD PC, Atlanta, GA.
Attorneys for Defendant Breckenridge Pharmaceutical, Inc.
David E. Moore, Esq., POTTER ANDERSON & CORROON LLP, Wilmington, DE; Bindu A.
Palapura, Esq., POTTER ANDERSON & CORROON LLP, Wilmington, DE; Stephanie E.
O'Byrne, Esq., POTTER ANDERSON & CORROON LLP, Wilmington, DE; Marta E. Gross,
Esq., GOODWIN PROCTER LLP, New York, NY; Keith A. Zullow Esq., GOODWIN
PROCTER LLP, New York, NY; Michael B. Cottler Esq., GOODWIN PROCTER LLP, New
York, NY; Steven J. Bernstein Esq., GOODWIN PROCTER LLP, New York, NY; Naomi
Birbach Esq., GOODWIN PROCTER LLP, New York, NY.
Attorneys for Defendant West-Ward Pharmaceuticals International Limited
Steven J. Fineman, Esq., RICHARDS, LAYTON & FINGER, PA, Wilmington, DE; Katharine
L. Mowery, Esq., RICHARDS, LAYTON & FINGER, PA, Wilmington, DE; Daniel G. Brown,
Esq., LATHAM & WATKINS LLP, New York, NY; Roger J. Chin, Esq., LATHAM &
WATKINS LLP, San Francisco, CA; Marc N. Zubick, Esq., LATHAM & WATKINS LLP,
Chicago, IL; Brenda L. Danek, Esq., LA THAM & WATKINS LLP, Chicago, IL; Parker M.
Tresemer, Esq., LATHAM & WATKINS LLP, Los Angeles, CA.
Attorneys for Defendant Par Pharmaceutical, Inc.

March

j£_ , 2017

I

Plaintiffs brought these patent infringement actions against Breckenridge Pharmaceutical,
Inc., Roxane Laboratories, Inc. 1, and Par Pharmaceutical, Inc. in 2014. (D.I. 1).2 Breckenridge,
Roxane, and Par each filed an Abbreviated New Drug Application ("ANDA"), seeking to engage
in the commercial manufacture, use, and sale of generic versions of Novartis's Zortress product.
(D.1. 141-1, ifif44, 52, 59). Plaintiffs allege that these ANDAs infringe U.S. Patent No. 5,665,772
("the '772 patent"). Plaintiffs further allege that by filing these ANDAs, Roxane and Breckenridge
induced infringement of U.S. Patent No. 6,239,124 ("the '124 patent") and Roxane and Par
induced infringement of U.S. Patent No. 6,455,518 ("the '518 patent").
At issue in these cases is the compound 40-0-(2-hydroxyethyl)-rapamycin, also referred
to as everolimus, which is the active ingredient in Novartis's Zortress product. Everolimus is a
derivative of the compound rapamycin and is claimed in the '772 patent. The only difference
between rapamycin and everolimus is that the hydroxyl group at the C-40 position in rapamycin
is replaced with a 2-hydroxyethyl group in everolimus. (Trial Transcript ("Tr.") 193:4-13).
Rapamycin has long been known to have beneficial medicinal properties, such as
antifungal activity (Tr. 96:11-12), anticancer activity (Tr. 96:13-97:3), and immunosuppressive
activity (Tr. 95:2-10). Rapamycin is recognized as having limited utility in pharmaceutical
applications as it has low bioavailability, high toxicity, and poor solubility. ('772 patent at 1: 3640). Rapamycin derivatives such as everolimus, however, have been shown to have better stability
and bioavailability, making them more desirable for pharmaceutical preparations. (Id. at 1:41-45).

1

On February 27, 2017, after post-trial briefing was completed, Defendant Roxane Laboratories, Inc. filed an
unopposed motion to substitute West-Ward Pharmaceuticals International Limited to replace Roxane Laboratories,
Inc, which the Court granted. (Civ. Act. No. 14-1196, D.I. 190, 191). Defendant West-Ward is now the owner of
the ANDAs at issue in this litigation and has not contested jurisdiction of this Court. (Civ. Act. No. 14-1196, D.I.
190 at iM!5-6). Any reference to Defendant Roxane in this opinion should, therefore, be construed as a reference to
Defendant West-Ward.
2 Unless otherwise indicated, all docket citations are to Civ. Act. No. 14-1043.

1

Also at issue are methods of treating or preventing transplant rejection using everolimus
and one of a class of compounds known as IL-2 transcription inhibitors. The '124 patent claims
the use of synergistically effective amounts of cyclosporin A and everolimus in weight ratios from
2:1to180:1. The proposed labels for both Roxane's and Breckenridge's generic products include
instructions for co-administration of cyclosporin A and everolimus for the prevention and
treatment of transplant rejection in kidney transplant patients. (D.1. 130-1, iMf 51, 58). The '518
patent claims the use of synergistically effective amounts of an IL-2 transcription inhibitor and
everolimus in weight ratios from 2:1 to 180:1. The proposed labels for both Roxane's and Par's
generic products include instruction for co-administration of the IL-2 transcription inhibitor
FK506, also known as tacrolimus, and everolimus for the prevention and treatment of transplant
rejection in liver transplant patients. (Id. at iii! 58, 66).
The Court held a bench trial on August 29-September 1, 2016. Defendants concede that
their proposed products meet all limitations of the '772 patent. (D.I. 152 at 3). Defendants argue
that Plaintiffs have not proven by a preponderance of evidence that Defendants induced
infringement of the '124 and '518 patents. Defendants further argue that the '772, '124, and '518
patents are invalid as obvious and for obviousness-type double patenting.
I.

LEGAL STANDARDS

A.

Obviousness-Type Double Patenting

"Obviousness-type double patenting is a judicially created doctrine that 'prohibit[s] a party
from obtaining an extension of the right to exclude through claims in a later patent that are not
patentably distinct from claims in a commonly owned earlier patent."' Pfizer, Inc. v. Teva Pharms.
USA, Inc., 518 F.3d 1353, 1363 (Fed. Cir. 2008) (internal citation omitted). There are two steps

to a double-patenting analysis. First, the court construes the claims of the commonly owned patents

2

and identifies the differences. See Pfizer, 518 F.3d at 1363 (citing Eli Lilly & Co. v. Barr Labs.,

Inc., 251 F.3d 955, 967 (Fed. Cir. 2001)). In the second step of the double patenting analysis, the
court determines whether the differences between the claims render them patentably distinct. See

Eli Lilly, 251 F.3d at 968. A later claim that is obvious over, or anticipated by, an earlier claim is
not patentably distinct from it. See id.

B.

Obviousness
A patent claim is invalid as obvious under 35 U.S.C. § 103 "ifthe 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 to which said subject matter pertains." 35 U.S.C. § 103; see also KSR Int 'l Co. v.

Teleflex Inc., 550 U.S. 398, 406-07 (2007). The determination of obviousness is a question of
law with underlying factual findings. See Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 688
F.3d 1342, 1359-60 (Fed. Cir. 2012). "The underlying factual inquiries include (1) the scope and
content of the prior art; (2) the differences between the prior art and the claims at issue; (3) the
level of ordinary skill in the art; and (4) any relevant secondary considerations .... " Western

Union Co. v. MoneyGram Payment Sys., Inc., 626 F.3d 1361, 1370 (Fed. Cir. 2010) (citing
Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966)).
A court is required to consider secondary considerations, or objective indicia of
nonobviousness, before reaching an obviousness determination, as a "check against hindsight
bias." See In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676
F.3d 1063, 1078-79 (Fed. Cir. 2012). Relevant secondary considerations include commercial
success, long felt but unsolved needs, failure of others, praise, unexpected results, and copying,
among others. Graham, 383 U.S. at 17-18; Ruiz v. A.B. Chance Co., 234 F.3d 654, 662-63 (Fed.

3

Cir. 2000); Tex. Instruments, Inc. v. US. Int'! Trade Comm 'n, 988 F.2d 1165, 1178 (Fed. Cir.
1993). Secondary considerations ofnonobviousness are important because they "serve as
insurance against the insidious attraction of the siren hindsight .... " W.L. Gore & Assocs., Inc. v.
Garlock, Inc., 721F.2d1540, 1553 (Fed. Cir. 1983).

A patentee is not required to present evidence of secondary considerations. See
Prometheus Labs., Inc. v. Roxane Labs., Inc., 805 F.3d 1092, 1101 (Fed. Cir. 2015). That said, if

the patent challenger establishes a prima facie case of obviousness, "the patentee would be well
advised to introduce evidence sufficient to rebut that of the challenger." Id. (quoting Pfizer, Inc.
v. Apotex, Inc., 480 F.3d 1348, 1360 (Fed. Cir. 2007)). There must be enough evidence,

however, for a finding that a given secondary consideration exists by a preponderance of the
evidence. See Apple, Inc. v. Samsung Elec. Co., Ltd., 839 F.3d 1034, 1053 (Fed. Cir. 2016) (en
bane). If there is, then the probative value of each secondary consideration will be considered in
light of the evidence produced. That does not mean, though, that the burden of persuasion on the
ultimate question of obviousness transfers to the proponent of the secondary consideration.
Pfizer, Inc., 480 F.3d at 1359. That burden stays always with the patent challenger. Id. at 1359-

60.
A party asserting that a patent is invalid as obvious must "show by clear and convincing
evidence that a skilled artisan would have been motivated to combine the teachings of the prior art
references to achieve the claimed invention, and that the skilled artisan would have had a
reasonable expectation of success in doing so." Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1361
(Fed. Cir. 2007). That "expectation of success need only be reasonable, not absolute." Id. at 1364.
"Whether an ordinarily skilled artisan would have reasonably expected success .... is measured
as of the date of the invention[] ...." Amgen Inc. v. F. Hoffman-La Roche Ltd, 580 F.3d 1340,

4

1362 (Fed. Cir. 2009).

C.

Infringement
A patent is infringed when a person "without authority makes, uses, offers to sell, or sells

any patented invention, within the United States ... during the term of the patent .... " 35
U.S.C. § 271(a). A two-step analysis is employed in making an infringement determination. See

Markman v. Westview Instruments, Inc., 52 F.3d 967, 976 (Fed. Cir. 1995) (en bane), ajj"d, 517
U.S. 370 (1996). First, the court must construe the asserted claims to ascertain their meaning and
scope. See id. The trier of fact must then compare the properly construed claims with the
accused infringing product. See id. This second step is a question of fact. Bai v. L & L Wings,

Inc., 160 F.3d 1350, 1353 (Fed. Cir. 1998). "Literal infringement ofa claim exists when every
limitation recited in the claim is found in the accused device." Kahn v. Gen. Motors Corp., 135
F.3d 1472, 1477 (Fed. Cir. 1998). "If any claim limitation is absent from the accused device,
there is no literal infringement as a matter oflaw." Bayer AG v. Elan Pharm. Research Corp.,
212 F.3d 1241, 1247 (Fed. Cir. 2000). The patent owner has the burden of proving infringement
by a preponderance of the evidence. See SmithKline Diagnostics, Inc. v. Helena Labs. Corp.,
859 F.2d 878, 889 (Fed. Cir. 1988).
35 U.S.C. § 271(b) provides that "[w]hoever actively induces infringement of a patent
shall be liable as an infringer." 35 U.S.C. § 271(b). "In order to prevail on an inducement claim,
the patentee must establish first that there has been direct infringement, and second that the
alleged infringer knowingly induced infringement and possessed specific intent to encourage
another's infringement." ACCO Brands, Inc. v. ABA Locks Mfrs. Co., 501 F.3d 1307, 1312 (Fed.
Cir. 2007) (internal quotation marks omitted). In other words, "inducement requires evidence of
culpable conduct, directed to encouraging another's infringement, not merely that the inducer

5

had knowledge of the direct infringer's activities." DSU Med. Corp. v. JMS Co., 471 F.3d 1293,
1306 (Fed. Cir. 2006) (en bane). "[S]pecific intent may be inferred from circumstantial evidence
where a defendant has both knowledge of the patent and specific intent to cause the acts
constituting infringement." Ricoh Co. v. Quanta Computer Inc., 550 F.3d 1325, 1342 (Fed. Cir.
2008). "[L]iability for induced infringement can only attach ifthe defendant knew of the patent
and knew as well that 'the induced acts constitute patent infringement."' Cammi! USA, LLC v.

Cisco Sys., Inc., 135 S. Ct. 1920, 1926 (2015) (quoting Global-Tech Appliances, Inc. v. SEB
S.A., 131 S. Ct. 2060, 2068 (2011)). The knowledge requirement maybe satisfied by showing

actual knowledge or willful blindness. See Global-Tech, 131 S. Ct. at 2068 (2011).
In Hatch-Waxman cases alleging that a proposed drug label will induce infringement by
physicians, "The pertinent question is whether the proposed label instructs users to perform the
patented method." AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042, 1060 (Fed. Cir. 2010). "The
label must encourage, recommend, or promote infringement." Takeda Pharm. USA, Inc. v. West-

Ward Pharm. Corp., 785 F.3d 625, 631 (Fed. Cir. 2015). "The mere existence of direct
infringement by physicians, while necessary to find liability for induced infringement, is not
sufficient for inducement." Id. Rather, "specific intent and action to induce infringement must
be proven." Id. (internal quotation marks omitted). Even where a proposed label does not
explicitly track the language of a claimed method, a package insert containing directives that will
"inevitably lead some consumers to practice the claimed method" provides sufficient evidence
for a finding of specific intent. See AstraZeneca, 633 F.3d at 1060; see also Abraxis Bioscience,

Inc. v. Navinta, LLC, 630 F. Supp. 2d 553, 570 (D.N.J. 2009) ("Statements in a package insert
that encourage infringing use of a drug product are alone sufficient to establish intent to
encourage direct infringement."), rev 'd and vacated on other grounds, 625 F.3d 1359 (Fed. Cir.

6

2010).

II.

VALIDITY OF THE '772 PATENT

A.

Findings of Fact
1. The '990 patent is a proper double-patenting reference for the '772 patent.
2. The '772 and '990 patents are both assigned to Novartis.
3. Each of claims 8, 9, 11-21, 25, and 27-35 of the '990 patent discloses all limitations of
claims 1-3 and 10 of the '772 patent.
4. Each of claims 25 and 27-35 of the '990 patent discloses all limitations of claim 7 of the
'772 patent.

B.

Conclusions of Law
Prior to trial, the parties stipulated that the '990 patent discloses all limitations of claims 1-

3, 7, and 10 of the '772 patent, and that the two patents are assigned to the same entity and share
named inventors. 3 (D.I. 152 at 5). The parties further stipulated "that ifthe Court finds the '990
patent is a proper double-patenting reference to the '772 patent, then the claims of the '990 patent
will render the Asserted Claims invalid for non-statutory double patenting." (Id. at 4). Therefore,
the only issue to be decided is whether the '990 patent is a proper double-patenting reference.
The unusual facts of this case are the result of the Uruguay Round Agreements Act
("URAA"), which changed how patent terms are determined, effective as of June 8, 1995. Any
patent issuing from an application filed prior to June 8, 1995, received a term of seventeen years
from the date of issuance or twenty years from the earliest effective filing date, whichever was
longer. 35 U.S.C. § 154(c)(l). Patents issuing from post-URAA applications receive a term of

3

Plaintiffs originally asserted claims 1-3, 7, and 10 of the '772 patent. (D.1. 130-1, ififl0-12). At trial, Plaintiff
withdrew claims 1-3. (Tr. 668:2-14). Defendants, however, still seek declaratory judgment of invalidity as to
claims 1-3. (D.I. 162 at 11 n.l).

7

twenty years from the earliest effective filing date. 35 U.S.C. § 154(a)(2).
The issue in this case is that, through the operation of the URAA, the '772 patent, which
issued from an earlier filed application, has a later expiration date than the later-filed '990 patent.
The application that issued as the '772 patent was filed on April 7, 1995 with an earliest
effective filing date of September 24, 1993. (D.I. 152 at 6). This pre-URAA patent received a
term of seventeen years from its issue date of September 9, 1997. (Id. at 6-7). Although the
original expiration date of this patent was, therefore, September 9, 2014, it received a patent term
adjustment of five years pursuant to 35 U.S.C. § 156 so that it now expires on September 9, 2019.
(Id. at 7).

The application that issued as the '990 patent began life as a divisional of the application
that issued as the '772 patent. (Id. at 8). This application was filed in 1997, making it a postURAA patent. It also has an earliest effective filing date of September 24, 1993. (Id.). This
patent, therefore, received a term of twenty years from the earliest effective filing date and expired
on September 24, 2013. (Id.).
While the Federal Circuit has not addressed the precise issue presented in this case, the
Court has addressed the issue of whether a later-filed but earlier expiring patent can serve as a
double-patenting reference for an earlier-filed but later-expiring patent. Gilead Sciences, Inc. v.
Natco Pharma Ltd., 753 F.3d 1208, 1212 (Fed. Cir. 2014). The patents at issue in Gilead were

both post-URAA patents that were not part of the same family and, therefore, had different priority
dates. Id. at 1210. The different priority dates led to a situation where the later-filed patent expired
before the earlier-filed patent. Id. The Gilead court emphasized that the "bedrock principle of our
patent system" that the prohibition on double patenting seeks to protect is the idea that when a
patent expires, the public is entitled to use the invention and any obvious modifications of the

8

invention claimed in the patent. Id. at 1214. According to the Federal Circuit, what matters in a
double patenting analysis, at least for post-URAA patents, is the expiration dates of the patents.
Id. at 1215. The Federal Circuit has since revisited this question and made explicit that "the

doctrine of obviousness-type double patenting continues to apply where two patents that claim the
same invention have different expiration dates." AbbVie, Inc. v. Mathilda & Terence Kennedy
Inst. ofRheumatology Trust, 764 F.3d 1366, 1374 (Fed. Cir. 2014).
Significant to the instant case is the fact that the Gilead decision cites to a Board of Patent
Appeals and Interferences ("BP AI" or "Board") decision with substantially similar facts to the
instant case. Id. at 1211 n.2. In that case, the Board found that a later-filed post-URAA patent
with an expiration date in 2015 could serve as a double-patenting reference for an earlier-filed preURAA patent with an expiration date in 2019. Ex Parte Pfizer, Inc., Patent Owner & Appellant,
2010 WL 532133, at *16 (Bd. Pat. App. & Interf. Feb. 12, 2010). The Board found that the laterexpiring pre-URAA patent would "extend Appellant's right to exclude the public from practicing"
the invention. Id. at *21. This, the Board concluded, was "precisely what obviousness-type double
patenting was intended to prevent." Id. This is the same reasoning applied by the Gilead court.
Gilead, 753 F.3d at 1214.
Other district courts have considered cases with facts substantially identical to the instant
case. In Janssen, the district court faced the same question and, in light of the Federal Circuit's
decision in Gilead, reached the conclusion that a later-filed post-URAA patent with an earlier
expiration date is a proper double-patenting reference for an earlier-filed pre-URAA patent with a
later expiration date. See Janssen Biotech, Inc. v. Celltrion Healthcare Co., Ltd., 2016 WL
5698362 (D. Mass. Sept. 28, 2016), appeal docketed, No. 17-1120 (Fed. Cir. Oct. 25, 2016). Other
district courts have also reached the same conclusion on identical facts. See MLC Intellectual

9

Property, LLC v. Micron Technology, Inc., 2016 WL 4192009, at *3 n.4 (N.D. Cal. Aug. 9, 2016)

("The fact that the patents in Gilead were governed by the URAA was not relevant to the Court's
reasoning."); DDB Technologies, LLCv. Fox Sports Interactive Media, LLC, 2014 WL 12167628,
at *3-4 (W.D. Tex. May 15, 2014) (applying reasoning from Gilead that "expiration date of the
patents should control").
Plaintiffs expend considerable effort attempting to distinguish this case from Gilead.
Plaintiffs argue first that Defendants have misread Gilead. (D.I. 170 at 8). According to Plaintiffs,
double-patenting is an equitable doctrine requiring Defendants to prove that the patentee has
obtained an unjustified extension of patent rights. (Id. at 11 ). Plaintiffs argue strenuously that
there has been no unjustified extension of patent rights in this case. (Id. at 15). I disagree. Gilead
reaffirms the long-standing principle that when a patent expires, the public is entitled to make use
of the claimed invention. Gilead, 753 F.3d at 1214. The "unjustified extension of patent rights"
here is the extension on the patent holder's term of exclusivity past the expiration date of a patent
that discloses the invention. The patentee in this case chose to seek two patents on the same
invention. If the term of one of those patents is allowed to extend past the expiration date of the
other, the patentee has obtained an unjustified extension of patent rights.
Plaintiffs next argue that Gilead and Abb Vie are inapplicable because the patentees in those
cases engaged in gamesmanship, acting strategically to obtain the benefit of a later expiration date.
(D .I. 170 at 8-11 ). According to Plaintiffs, Novartis' s actions here are unlike those of the patentees
in Gilead and Abbvie because Novartis did not violate any of the principles of double patenting.
(Id. at 14). Plaintiffs further argue that Novartis has not engaged in gamesmanship. (Id. at 21). I

disagree that there is no violation of double patenting principles and I find the argument about the
absence of gamesmanship irrelevant.

A patentee need not engage in gamesmanship or act

10

strategically in order to violate the principles of double patenting. Neither Gilead nor Abb Vie held
that gamesmanship is required. A patentee can obtain an unjustified extension of patent rights
without engaging in gamesmanship simply by seeking two patents on the same invention, as the
patentee did here. The only relevant issue is the earlier expiration date of the '990 patent, as it is
the extension of the period of exclusivity by virtue of the '772 patent's later expiration date that
violates the principles underlying the double patenting prohibition. The patentee's motives are not
relevant.
Plaintiffs next argue that expiration dates alone do not control the double patenting
analysis. (D.I. 170 at 17). According to Plaintiffs, the holdings and reasoning in Gilead and
Abb Vie are limited to the specific factual contexts of those cases. (Id. at 17-18). While it may be

true that Gilead did not establish a hard and fast rule that expiration dates control the double
patenting analysis, I am not persuaded that the facts of this case require a different analysis. I think
that the reasoning in Gilead is equally applicable to the facts of this case for the reasons I have
already stated.
Plaintiffs next argue that application of Gilead to the facts of this case would frustrate
legislative intent. (D.I. 170 at 19). Plaintiffs contend that allowing an earlier-expiring post-DRAA
patent to serve as a double patenting reference for a later expiring pre-DRAA patent would
effectively shorten the statutorily mandated terms of pre-DRAA patents. (Id. at 19-20). Plaintiffs'
argument misses the mark. 4 A patentee who chooses to seek a second patent for an obvious variant
of his invention, as the patentee did here, runs this risk and cannot claim in retrospect that only the

4

It seems to me that the only circumstance in which a pre-DRAA patent would be in danger of having its statutorily
mandated term shortened is if a patentee chose to seek a second patent on the same invention or an obvious
modification thereof. This is exactly what happened in this case. The patentee chose to seek two patents on the
same invention. The patentee must now live with the consequences of that choice, one of which is a period of
exclusivity governed by the expiration date of the earlier-expiring patent.

11

later-expiring patent counts.
Plaintiffs next argue that there is no harm to the public because "Novartis has not enjoyed
more than one patent term per invention." (Id. at 20). According to Plaintiffs, the '772 patent's
expiration date "is the same as it would have been had the '990 patent never issued." (Id.). This
argument also misses the mark. The patentee chose to file the application that matured into the
'990 patent. The patentee knew when the '990 patent issued on August 27, 2002 that it would
expire before the '772 patent, which had issued five years earlier. The harm to the public lies in
the inability to make use of an invention disclosed in an expired patent. That the '772 patent's
expiration date would be unchanged had the '990 patent never issued is irrelevant. The '990 patent
did issue and upon its expiration the public was entitled to make use of the invention it disclosed.
Plaintiffs next argue that the post-Gilead district court decisions cited by Defendants are
not binding precedent, and that they were incorrectly decided. (Id. at 22). Plaintiffs are correct
that these district court decisions are not binding precedent, but I find them persuasive and I agree
with the reasoning these courts used to reach their conclusions. Plaintiffs also argue that the BPAl
decision in Pfizer is not binding precedent. (Id. at 24). Plaintiffs cite again to two pre-Gilead
cases that rejected Pfizer's holding. (Id.). I am not persuaded. The pre-Gilead case law Plaintiffs
cite is inconsistent with Gilead's reasoning. Furthermore, the Gilead court cited Pfizer and directly
quoted the BP AI' s reasoning regarding the importance of patent term expiration date. Gilead, 753
F.3d at 1211 n.2. While Pfizer is not binding precedent, it was cited in a Court of Appeals decision
that is precedential, and I find the Board's reasoning persuasive.
After briefing was completed in this case, this Court issued a decision that Plaintiffs argue
is inconsistent with Janssen, MLC, and DDB. Merck Sharp & Dohme Corp. v. Teva Pharm. USA,
Inc., 2016 WL 6804914 (D. Del. Nov. 16, 2016), appeal docketed, No. 17-1366 (Fed. Cir. Dec.

12

16, 2016). The facts of Merck are distinguishable from the instant case, however. In Merck, both
patents at issue were pre-DRAA patents. Id. at *3. As the Gilead court acknowledged, pre-DRAA,
issue date was important in the double patenting analysis because "the expiration date was
inextricably intertwined with the issuance date." Gilead, 753 F.3d at 1215. Pre-DRAA, the laterissuing patent was the one subject to the double patenting bar. Id. at 1214. This is precisely what
Merck holds, rejecting the "oddity" of using a later issued pre-DRAA patent as a double patenting

reference for an earlier-issued pre-DRAA patent. Merck says nothing about whether an earlierexpiring post-DRAA patent can serve as a double patenting reference for a later-expiring preDRAA patent. Furthermore, the Merck opinion does not analyze, or even mention, the post-Gilead
cases that have considered this specific fact pattern. Therefore, I hold that Merck is not relevant
to this case and is not necessarily inconsistent with Gilead or the other post-Gilead district court
cases cited above.
Finally, Plaintiffs argue that a§ 156 patent term extension is not an unjustified extension
of patent rights. (D.I. 170 at 26). While this, in the abstract, is certainly true, it is not the§ 156
extension that is at issue here. What is at issue is the disclosure of the same invention in an earlierexpiring patent. Plaintiffs appear to be arguing, without citing a single case to support their
position, that a § 156 patent term extension somehow immunizes a patent from a double patenting
challenge. I disagree. The patent term extension provision of the Hatch-Waxman Act was
intended to restore to a patent the time lost in seeking FDA approval for the drug claimed in the
patent. I see no reason why such a patent term extension would protect a patent from a double
patenting challenge.
For the reasons discussed above, I find that the '990 patent is a proper double patenting
reference for the '772 patent. Therefore, claims 1-3, 7, and 10 of the '772 patent are invalid for

13

obviousness-type double patenting over the '990 patent. Because I find that the asserted claims of
the '772 patent are invalid for double patenting, there is no need to consider whether these claims
are obvious.

III.

VALIDITY OF THE '124 AND '518 PATENTS

Plaintiffs assert claim 7 of each of the '124 and '518 patents. The '518 patent is a
continuation of the application that issued as the '124 patent. The two patents share an identical
specification. The patents disclose that rapamycin had been discovered over twenty years prior to
the application date, but had not been marketed due in part to difficulties in formulation, poor
solubility, and poor bioavailability.

('124 patent at 1:47-51).

The rapamycin derivative

everolimus, on the other hand, has improved pharmacokinetic properties and is easier to formulate.
(Id. at 1:51-53).

Claim 7 of the' 124 patent teaches 1) methods for treating or preventing transplant rejection
comprising 2) co-administering 3) synergistically effective amounts 4) of cyclosporin A and
everolimus 5) in the weight ratio 2:1 to 180:1. Claim 7 of the '518 patent is identical with the
exception of element 4, which calls for an IL-2 transcription inhibitor in place of cyclosporin A.
The '518 patent identifies FK506, also known as tacrolimus, as an IL-2 transcription inhibitor.
('518 patent at 2:20-29).
Defendants argue that claim 7 of each of the '124 and '518 patents are invalid as obvious
over the prior art. Defendants also argue that these claims are invalid for obviousness type double
patenting over claim 11 of U.S. Patent No. 6,440,990 ("the '990 patent").
A.

Findings of Fact

1. The level of ordinary skill in the art is a medical doctor with experience and expertise in
using immunosuppressants and several years of experience treating conditions that require

14

immunosuppressants, including transplantation and autoimmune diseases, who, if necessary,
collaborates with an immunologist or pharmacologist.
2. The priority date for claim 7 of both the '124 and '518 patents is July 30, 1996.
3. WO'OlO, Tu, Kahan, Murgia, and Schreiber are prior art.
4. WO'OlO, Tu, Kahan, Murgia, and Schreiber do not teach a person of ordinary skill that coadministration of everolimus and cyclosporin A or tacrolimus would be safe and effective in
humans.
5. WO'OlO, Tu, Kahan, Murgia, and Schreiber do not teach a person of ordinary skill that coadministration of everolimus and cyclosporin A or tacrolimus would be synergistically effective.
6. WO'OlO, Tu, Kahan, Murgia, and Schreiber do not teach a person of ordinary skill the
weight ratio of everolimus to cyclosporin A or tacrolimus claimed in the '124 and '158 patents.
7. WO'OlO and Schreiber do not teach a person of ordinary skill that everolimus is an obvious
substitute for rapamycin.
8. Co-administration of synergistically effective amounts of everolimus and cyclosporin A at
weight ratios 12.5: 1 to 200: 1 would not have been obvious to one of ordinary skill in the art.
9. Co-administration of synergistically effective amounts of everolimus and tacrolimus at
weight ratios 12.5:1 to 200:1 would not have been obvious to one of ordinary skill in the art.
10. The '990 patent is a proper double patenting reference for both the '124 and '518 patents.
11. The asserted claims of the '124 and '518 patents are patentably distinct from claim 11 of
the '990 patent.
B.

Conclusions of Law

Defendants contend that co-administration of everolimus with cyclosporin A or tacrolimus
for prevention or treatment of transplant rejection would have been obvious to a person of ordinary

15

I
skill in the art. The essence of Defendants' obviousness argument is that the prior art teaches that
rapamycin could be safely co-administered with cyclosporin A or tacrolimus with synergistic
effectiveness and that everolimus would have been an obvious substitute for rapamycin.
Therefore, according to Defendants, the invention as a whole, including all limitations, would have
been obvious to a person of ordinary skill in the art. 5
The parties agree that a person of ordinary skill to whom the '124 and '158 patents are
directed is a medical doctor with experience and expertise in using immunosuppressants and
several years of experience treating conditions that require immunosuppressants, including
transplantation and autoimmune diseases, who, if necessary, collaborates with an immunologist or
pharmacologist. (Tr. 1214:8-22).
1.

Scope and Content of the Prior Art
i.

WO'OJO

The WO'OlO reference is the Patent Cooperation Treaty ("PCT") publication of
PCT/EP93/02604, the PCT counterpart of the '772 patent, filed on September 24, 1993. WO'OlO
discloses certain novel derivatives of rapamycin, including everolimus, that "have an improved
pharmacologic profile over rapamycin." (JTX-54 at p. 2; Tr. 1226:14-24). WO'OlO further
discloses everolimus as a preferred compound for immunosuppressive use, including treatment
and prevention of transplant rejection. (JTX-54 at pp. 3, 5; Tr. 1227:3-13, 1228:12-19). WO'OlO
teaches the use of everolimus in treating and preventing transplant rejection by administering a
"pharmaceutically effective dose."

(JTX-54 at pp. 4-5, 7).

5

WO'OlO further teaches that

The parties argued the obviousness of each limitation of the claims individually, so I will address these arguments
in turn, keeping in mind that the ultimate question is whether the claimed invention as a whole would have been
obvious as "obviousness requires a suggestion of all limitations in a claim." See CFMT, Inc. v. Yieldup Int'/ Corp.,
349 F.3d 1333, 1342 (Fed. Cir. 2003) (citing In re Gulack, 703 F.2d 1381, 1385 n. 9 (Fed.Cir.1983); In re Royka,
490 F.2d 981, 985 (CCPA 1974)).

16

I
!

f

I

everolimus "may be used in combination with Ciclosporin, FK-506, or their immunosuppressive
derivatives." (Id. at p. 8). It is undisputed that WO'OlO does not teach all elements of the asserted
claims of the '124 and '518 patents. (D.I. 162 at 43). Specifically, WO'OlO does not teach 1) coadministration of everolimus with cyclosporin A; 2) that co-administration would result in
synergistic effectiveness; or 3) the appropriate weight ratios. (Id.).
ii.

Tu

Tu describes the results of a study of co-administration of rapamycin and cyclosporin A in
mice. (Tr. 1253:14-23). Tu reports that co-administration with weight ratios of 12.5:1 to 200:1
results in a "modestly synergistic effect on survival." (Tr. 1325:12-23; JTX-48 at p. 181-82). It
is undisputed that Tu does not provide any information on co-administration of everolimus with
cyclosporin A. (Tr. 1253:19-21). It is further undisputed that Tu does not provide any direct
evidence regarding whether co-administration of rapamycin and cyclosporin A would result in
synergistic effectiveness in humans. (Tr. 1258:3-9).
iii.

Kahan

Kahan discusses the theoretical basis for synergistic effectiveness of combination treatment
with rapamycin and cyclosporin A. (Tr. 1245:12-23; JTX-24 at p. 21). It is undisputed that Kahan
does not provide information on combination treatment with everolimus and cyclosporin A. (Tr.
1328:24-1329:4). It is also undisputed that Kahan does not explicitly teach co-administration of
rapamycin and cyclosporin A. (Tr. 1249:9-13). Defendants argue, however, that Kahan's silence
on the relative timing of administration of the two drugs would be interpreted by a person of
ordinary skill to mean co-administration. (Tr. 1249:13-16).
iv.

Murgia

Murgia teaches that combination therapy with rapamycin and cyclosporin A in human

17

transplant patients does not result in increased toxic side effects compared to treatment with
rapamycin alone. (Tr. 1251:6-1252:11 ). It is undisputed that Murgia does not provide information
on combination treatment with everolimus and cyclosporin A.

(Tr. 1326:20-22). It is also

undisputed that Murgia does not explicitly teach co-administration of rapamycin and cyclosporin
A. (Tr. 1252:12-15). As with Kahan, however, Defendants argue that Murgia's silence on the
relative timing of administration of the two drugs would be interpreted by a person of ordinary
skill to mean co-administration. (Tr. 1252:17-21).

v.

Schreiber

Schreiber discloses a model that identifies binding domains and effector domains in
rapamycin and tacrolimus. (Tr. 1239:12-1240:6). According to Schreiber's model, rapamycin
and tacrolimus have identical binding domains but different mechanisms of immunosuppression.
(Tr. 1240:15-1241:4). Specifically, Schreiber posits that the C-40 position on rapamycin, the
position at which the molecule is altered by the addition of a hydroxyl group to create the
rapamycin derivative everolimus, lies outside both the binding and effector domains.

(Tr.

1241: 18-1242:3).

2.

Comparing Prior Art and Claimed Subject Matter
Defendants' expert, Dr. Tullius, opines that a person of ordinary skill in the art would have

been motivated to co-administer synergistic amounts of everolimus and an IL-2 inhibitor at the
ratios given in the asserted claims to treat or prevent transplant rejection.

(Tr. 1223:1-9).

Specifically, Dr. Tullius stated that the prior art references Tu, Kahan, and Murgia showed that
rapamycin and cyclosporin A had been shown to have synergistic effectiveness when coadministered.

(Tr. 1259:9-12). According to Dr. Tullius, this prior art, combined with the

teachings of WO'OlO and Schreiber about the similarities between everolimus and rapamycin,

18

would lead a person of ordinary skill to believe everolimus could be safely co-administered with
cyclosporin A or tacrolimus with synergistic effectiveness. (Tr. 1259:13-22). Dr. Tullius further
opined that a person of ordinary skill in the art would be able to combine the general knowledge
about the relative effectiveness of everolimus compared to rapamycin with the teachings of Tu and
WO'OlO to arrive at the claimed weight ratios.

(Tr. 1262:6-22).

Therefore, according to

Defendants, these references can be combined to suggest all limitations of claim 7 of each of the
'124 and '518 patents.
i.

Co-Administration

Defendants acknowledge that none of the references they rely on explicitly teaches coadministration of everolimus and cyclosporin A. (D.I. 162 at 43). Instead, Defendants argue that
the prior art discloses co-administration of rapamycin and cyclosporin A. As discussed below,
Defendants further argue that everolimus is an obvious substitute for rapamycin.
During claim construction, the parties did not identify "co-administration" as a term in
need of construction. The patents explicitly define co-administration to mean administering two
drugs "together or at substantially the same time." (' 124 patent at 6:20-26). Plaintiffs argue that,
at a minimum, the prior art did not teach co-administration. (D.I. 171 at 45). Plaintiffs further
urge that the prior art, in fact, taught away from co-administration. (Id. at 44-45). I do not think
it is necessary to decide whether the prior art taught away from co-administration as I think it is
evident that co-administration is not obvious under any combination of prior art cited by
Defendants.
Defendants rely on a combination of three references: Tu, which teaches co-administration
ofrapamycin and cyclosporin A in mice (JTX-048); Murgia, which teaches combination therapy
with rapamycin and cyclosporin A in humans, but is silent on timing (DTX-079); and Kahan,

19

which provides a theoretical basis for synergy when rapamycin and cyclosporin A are administered
as a combination therapy, but is also silent on timing (JTX-024). Defendants argue in post-trial
briefing that a person of ordinary skill "would have understood [silence on timing] to mean that
Cyclosporine and rapamycin were co-administered." (D.I. 162 at 39). This argument appears to
be based primarily on Dr. Tullius's testimony, first, that the prior art teaches co-administration,
and second, that co-administration of the two drugs would be important for ensuring patient
compliance. (Tr. 1259:23-1260:5; 1260:22-1261 :6).
As an initial matter, I am not persuaded that patient compliance would be sufficient
motivation for a physician to co-administer the two drugs, in the absence of evidence that it would
be safe for humans, in light of the known toxicity of each of these drugs. Dr. Tullius acknowledged
that both cyclosporin A and tacrolimus were known as of July 30, 1996 to have toxic side effects.
(Tr. 1309:14-1312:1). Everolimus and rapamycin were also known to have toxic side effects.
(' 124 patent at 1:53-55). Dr. Tullius admitted during his testimony that patient safety was more
important than convenience and that a physician would not co-administer two drugs without
evidence that doing so would be safe. (Tr. 1317:3-13).
Dr. Tullius also testified that both cyclosporin A and tacrolimus are metabolized by the
CYP3A enzyme and that any drug that inhibited CYP3A enzymes would increase blood levels of,
and, therefore, increase the toxicity of, cyclosporin A and tacrolimus. (Tr. 1311 :12-17; 1312:2-5).
One way to avoid increased toxicity is to not co-administer a CYP3A inhibitor with cyclosporin
A or tacrolimus. (Tr. 1312: 10-15). There was no evidence presented, however, about whether
everolimus was known in 1996 to be a CYP3A inhibitor. Plaintiffs did present evidence that it
was known in 1996 that over fifty percent of drugs used in humans "may be" CYP3A inhibitors.
(Tr. 1312: 18-23; PTX-952, p.140). While this does not represent definitive evidence that a person

20

of ordinary skill would have believed everolimus to be a CYP3A inhibitor, and, therefore,
dangerous to co-administer with cyclosporin A or tacrolimus, it does support the argument that a
physician would have exercised caution in considering co-administration of these drugs, especially
when considered in conjunction with the knowledge that all of these drugs were known to have
toxic side effects. Therefore, notwithstanding the desirability of co-administration from a patient
compliance stand-point, I reject Defendants' argument that co-administration would be obvious to
a person of ordinary skill simply because of the perceived importance of patient compliance.
I am also not persuaded that the prior art expressly teaches co-administration. Defendants

presented no direct evidence that co-administration of everolimus and cyclosporin A or tacrolimus
was known to be safe in humans in 1996. Defendants instead rely on Murgia, which they argue
discloses that co-administration ofrapamycin and cyclosporin A in humans was safe. (Tr. 1251 :41252:11).
The problem with Defendants' reliance on Murgia is that Murgia is silent on the timing of
administration ofrapamycin and cyclosporin A. (Tr. 1252:12-15). Dr. Tulius testified that "in the
absence of a clear characterization on the timing application, a POSA would have reasonably
expected that the timing was a coadministration of both agents." (Tr. 1252:17-21). I am not
convinced that silence on timing equates to co-administration, particularly in light of the known
toxicities of the two drugs. Furthermore, Murgia reports a small (N=43) Phase I study lasting only
fourteen days. (Tr. 1326:23-1327:22; DTX-079, p. 209). The authors report only a "preliminary
characterization of the side effects of' rapamycin. (DTX-079, p.215). I am dubious that a person
of ordinary skill would look at such a small Phase I trial and conclude that co-administration of
rapamycin and cyclosporin A in humans was safe.
There was also evidence in 1996 that co-administration of rapamycin and cyclosporin A

21

was not safe. Plaintiffs' expert Dr. Fung testified that there was evidence at least as early as 1991
that "co-administration of cyclosporine and rapamycin caused worsened kidney function" in rat
models. (Tr. 410:22-411:6). 6 Given the conflicting evidence in the prior art as of 1996, I find that
co-administration of rapamycin and cyclosporin A in humans would not have been obvious to a
person of ordinary skill in view of Murgia. Since the Kahan reference is also silent on timing, I
find this reference equally unhelpful to Defendants' argument.
The only prior art reference Defendants rely on that expressly discloses co-administration
is Tu, which reports on a study involving co-administration of cyclosporin A and rapamycin in
mice. (JTX-048). In light of my conclusions regarding Murgia and the general knowledge about
the toxicities of these drugs, I am not persuaded that a single reference disclosing co-administration
in an experimental study in mice would cause a person of ordinary skill to conclude that coadministration of these two drugs in humans would be safe.

Therefore, I find that co-

administration of rapamycin and cyclosporin A in humans would not have been obvious to a person
of ordinary skill in view of Tu in 1996.
Given the substantial evidence presented about the toxicities of the two drugs individually
and the lack of evidence about safety of co-administration in humans, I find that co-administration
of everolimus and cyclosporin A would not have been obvious to a person of ordinary skill in
1996.

ii.

Synergistically Effective Amounts

During claim construction, I construed the term "synergistically effective amounts" to
mean "amounts which are individually equal to or below their respective effective dosages for the
relevant indication and which together have a more than additive effect." (D.I. 69 at 3). One way

6 In fact, Dr. Fung also testified that this result was confirmed in human trials and that cyclosporin A and rapamycin
are not co-administered today; rather, the two drugs are administered four hours apart. (Tr. 411 :7-412:5).

22

of evaluating synergy is to calculate a value called the combination index from experimental data
related to the effective doses of each drug when used individually and in combination. (Tr.
1253:24-1254:12). A combination index of less than one indicates synergism, a value of one
indicates an additive effect, and a value above one indicates an antagonistic relationship. (Tr.
1256:22-1257:1).
Defendants do not contest that the prior art does not disclose synergistic effectiveness of
everolimus and cyclosporin A or tacrolimus. (Tr. 1322:21-1323:1). Instead, Defendants rely on
the rapamycin prior art and argue that everolimus would have been an obvious substitute for
rapamycin. {Tr. 1323:2-12). Defendants again rely on Tu (JTX-048) and Kahan {JTX-024).
Tu reports an experimental study in which rapamycin and cyclosporin A were coadministered in mice. (Tr. 1253:14-21). According to Dr. Tullius, Tu discloses synergy between
rapamycin and cyclosporin A. (Tr. 1253:21-23). Tu reports co-administration at a variety of
weight ratios, as well as calculations of the combination index for each of those ratios, with values
ranging from 0.01to1.5. (Tr. 1255:23-1256:22). Dr. Tullius opined that Tu would teach a person
of ordinary skill to expect synergy upon co-administration of rapamycin and cyclosporin A in
humans. (Tr. 1257:24-1258:9). According to Dr. Tullius, a person of ordinary skill would have
considered the combination index values above one, which show antagonism instead of synergy,
to be "outliers" and opined that if he were doing this research, he "would expect some variance."
(Tr. 1325:3-8). I am not convinced that a person of ordinary skill would have so easily dismissed
the variances in the data reported in Tu. The reference itself concludes that the combination index
values indicated "modest synergism, additivity or even antagonism." (Tr. 1325:12-17; JTX-048,
p. 179). Given that this is a single study, conducted in mice, I do not think that this reference
unequivocally shows synergism between rapamycin and cyclosporin A. At best, Tu establishes

23

that co-administration of rapamycin and cyclosporin A in mice may, under some circumstances,
result in modest synergism.
Dr. Tullius also opined that Kahan teaches that co-administration of rapamycin and
cyclosporin A would result in synergistic effectiveness. (Tr. 1245:12-18). Kahan provides a
theoretical basis for synergy and also reports the combination index values calculated in a variety
of experimental studies in animal models, including the study reported in Tu. (Tr. 1246:7-1247:6;
JTX-024, p. 21-22). Kahan also reports the results of Phase I clinical trials in humans showing
synergistic effectiveness. (Tr. 1248:9-23). The "essence" of what Kahan reports, according to Dr.
Tullius, is the "rational[e] for the application of rapamycin and cyclosporine and the expectation
of synergistic effects." (Tr. 1331 :9-22).
The problem with Dr. Tullius's characterization of Kahan is that it is a theoretical
argument, based primarily on the understanding, in 1996, of the mechanisms by which cyclosporin
A and rapamycin acted. (Tr. 1332:19-1333:2). The only experimental data reported showed, at
best, modest synergism and sometimes antagonism. Most of the experimental data available was
from animal models rather than humans. Based on Dr. Tullius's testimony, I understand Kahan to
be an argument for further study on the possible synergistic effectiveness of rapamycin and
cyclosporin A rather than a conclusive statement that one should expect synergism, particularly in
human subjects. I am not convinced that synergistic effectiveness in humans of everolimus and
rapamycin or tacrolimus would have been obvious in view of Tu and Kahan.

iii.

Substituting Everolimus for Rapamycin

Defendants argue that a person of ordinary skill would have been motivated to use
everolimus as a substitute for rapamycin in 1996. Specifically, Defendants argue that a person of
ordinary skill would have expected everolimus to have the same binding properties and the same

24

mechanism of immunosuppression as rapamycin. (1244:14-1245:4).
Defendants rely on WO'Ol 0 in view of Schreiber to argue that everolimus is an obvious
substitute for rapamycin. WO'Ol 0 discloses that everolimus is a rapamycin derivative with an
improved pharmacologic profile as compared to rapamycin. (Tr. 1226:10-21). WO'OIO also
discloses that the structure of everolimus is very similar to that ofrapamycin. (Tr. 1224:17-21).
The only chemical difference between the two compounds is the substitution at the C-40 position
of a 2-hydroxyethyl group in everolimus in place of the hydroxyl group in rapamycin. (Tr.
1227:21-1228:3; JTX-054).
Defendants rely on Schreiber for the proposition that a person of ordinary skill would
have understood that the two molecules would have the same mechanism of immunosuppression,
despite this small chemical difference. Schreiber discloses a model that identifies rapamycin's
binding domain, responsible for binding to the protein FKBP-12, and its effector domain,
responsible for its immunosuppressive activity. (Tr. 1239:12-1240:6). Rapamycin and
tacrolimus both bind to the protein FKBP-12. (Tr. 1239:16-18). Rapamycin and tacrolimus
have different immunosuppressive mechanisms, however. (Tr. 1239:22-1240:1). Schreiber
infers from these properties that the portions of the rapamycin and tacrolimus molecules that are
identical can be identified as the binding domain and the portions that are different can be
identified as the effector domain. (Tr. 1239:18-21; 1240:2-6). Defendants' expert Dr. Tullius
opined that because the C-40 position on rapamycin is outside of both the binding and effector
domains identified by Schreiber, a person of ordinary skill would have concluded that
everolimus would have the same binding and immunosuppressive properties as rapamycin. (Tr.
1241 :18-1242:3, 1244:14-1245:4).
In rebuttal, Plaintiffs offer the Van Duyne reference, which post-dates the Schreiber

25

reference and includes Schreiber as a co-author. (JTX-051). Van Duyne discloses a structural
study of the bound rapamycin-FKBP-12 complex. (Id.). Dr. Tullius admitted on crossexamination that Van Duyne reports that the C-40 hydroxyl group in rapamycin is involved in
binding with the FKBP-12 protein. (Tr. 1339:9-14). Dr. Tullius stated that Van Duyne was
specifically a structural study and, in his opinion, had no relevance to the integrated function and
structure model disclosed by Schreiber. (Tr. 1339:20-1340:5).
I am not convinced that a person of ordinary skill would have considered Van Duyne's
structural study irrelevant, particularly since Schreiber's model was based primarily on
inferences about the similarities and differences between rapamycin and tacrolimus. A person of
ordinary skill would have understood that if the C-40 hydroxyl group was involved in binding
with the FKBP-12 protein, then the binding properties of everolimus might be different than the
binding properties ofrapamycin. Furthermore, WO'OlO discloses that everolimus and
rapamycin have different properties, including differences in bioavailability and stability. (Tr.
1226:14-21; JTX-054). It seems to me that a person of ordinary skill in the art, knowing of these
differences and the equivocal evidence about the C-40 position's possible involvement in
binding, would not conclude that everolimus is an obvious substitute for rapamycin. Therefore, I
do not think that Defendants have proven by clear and convincing evidence that using
everolimus as a substitute for rapamycin would have been obvious in 1996 under WO'OlO in
view of Schreiber.
iv.

Weight Ratio

Defendants do not argue that any of the prior art references explicitly teaches the weight
ratios in claim 7 of each of the '124 and '518 patents. (D.1. 162 at 43). Defendants rely on Tu,
WO'OlO, and the Physicians' Desk Reference from 1995 to argue that a person of ordinary skill

26

t

I

I

could have arrived at weight ratios that fall within the claimed weight ratios. (Id. at 45-46).
Dr. Tullius opined that a person of ordinary skill would know, based on the teachings of
WO'OlO, that everolimus is less effective than rapamycin by a factor of three. (Tr. 1262:9-14)
This knowledge, combined with the teachings of Tu as to the appropriate weight ratios for coadministration of cyclosporin A and rapamycin in mice, would, according to Dr. Tulius, lead a
person of ordinary skill to choose a weight ratio in the range of 4:1 to 67:1, which is within the
range claimed in the' 124 and '518 patents. (Tr. 1262:6-8, 15-22). There are at least two problems
with Dr. Tullius's method, however. First, as Dr. Tullius admitted, WO'OlO provides only in vitro
data about the relative effectiveness of everolimus alone. (Tr. 1321 :9-1322:20). Second, as Dr.
Tullius also admitted, Tu provides weight ratios for co-administration of rapamycin and
cyclosporin A from an experimental in vivo study in mice, but no information on appropriate doses
in humans. (Tr. 1320:8-19). It seems to me that combining these two sources to arrive at a weight
ratio for synergistically effective use in humans is at best contrived. I am not persuaded that a
person of ordinary skill in the art would have been motivated to combine these references in this
way.
Dr. Tullius also stated that a person of ordinary skill would have consulted the Physicians'
Desk Reference (JTX-037) to determine an appropriate dose of cyclosporin A and would have
combined that information with the teachings of WO'Ol 0 about effective doses of everolimus to
obtain a weight ratio similar to that obtained from the teachings of Tu. (Tr. 1265:6-1266:19). This,
according to Dr. Tullius, would lead a person of ordinary skill to use these weight ratios in treating
human patients. (Tr. 1266:24-1267:4). Again, I am not persuaded. Dr. Tullius admitted that this
calculation required him to extrapolate from two unrelated sources which reported only the
individual effective doses of each drug. (Tr. 1319:6-1320:5). It seems to me, then, that his

27

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I
I
I

calculation does not account for synergistic effectiveness and, further, seems to require substantial
hindsight bias. Therefore, I find that the weight ratios in claim 7 of each of the '124 and '518
patents would not have been obvious to a person of ordinary skill in the art in 1996.
For the reasons given above, I find that Defendants have failed to prove that all limitations
of claim 7 of each of the '124 and '518 would have been obvious over the prior art.

3.

Obviousness-Type Double Patenting
Defendants also argue that claim 7 of each of the '124 and '518 patents are invalid for

obviousness type double patenting over claim 11 of the '990 patent in view of the same prior art
references cited in their obviousness argument. Plaintiffs do not contest that the '990 patent is a
proper double patenting reference.
Claim 11 of the '990 patent depends from claim 10 and claims a method of treating or
preventing transplant rejection by administering an effective amount of cyclosporin A and
everolimus. This claim does not disclose co-administration, synergistically effective amounts, or
the weight ratios claimed in the '124 and '518 patents. Defendants make the same arguments for
double patenting that they made for obviousness, using the same prior art references. I reject these
arguments for the same reasons I have already stated. Therefore, I find claim 7 of each of the '124
and '518 patents is not invalid for obviousness type double patenting.

IV.

INFRINGEMENT OF THE '124 AND '518 PATENTS
Plaintiffs assert claim 7 of each of the '124 and '518 patents. As discussed above, claim 7

of the '124 patent teaches 1) methods for treating or preventing transplant rejection comprising 2)
co-administering 3) synergistically effective amounts 4) of cyclosporin A and everolimus 5) in the
weight ratio 2:1to180:1. Claim 7 of the '518 patent is identical with the exception of element 4,
which calls for an IL-2 transcription inhibitor in place of cyclosporin A. The '518 patent identifies

28

FK506, also known as tacrolimus, as an IL-2 transcription inhibitor. ('518 patent at 2:20-29).

A.

Findings of Fact
1. A physician would look to the indications and usage section of Defendants' proposed labels
before prescribing everolimus to a transplant patient. The indications and usage section of
Defendants Roxane's and Breckenridge's proposed labels states, "Everolimus is indicated
for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk
receiving a kidney transplant." This section further states that everolimus is intended to be
administered "concurrently in combination with reduced doses of cyclosporine."
2. The indications and usage section of Defendants Roxane's and Par's proposed labels states,
"Everolimus is indicated for the prophylaxis of allograft rejection in adult patients
receiving a liver transplant." This section further states that everolimus is intended to be
administered "concurrently in combination with reduced doses of tacrolimus."

3. A physician would refer to the dosage and administration section of Defendants' proposed
labels to determine the appropriate doses of everolimus and cyclosporin A or tacrolimus.
In following the instructions found in the dosage and administration section of the proposed
labels, a physician would prescribe doses that fall within the weight ratios claimed in claim
7 of the '124 and '518 patents.
4. Quantitative analyses using data from humans generally, and use of the Berenbaum-Chou
equation on such data specifically, are not required to show synergistic effectiveness.
5. Co-administration of everolimus and cyclosporin A as directed in Defendants Roxane's
and Breckenridge's labels will result in synergistic effectiveness.
6. Co-administration of everolimus and tacrolimus as directed in Defendants Roxane's and
Par's labels will result in synergistic effectiveness.

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7. Defendants Roxane and Breckenridge had and have knowledge of the '124 patent.

8. Defendants Roxane's and Breckenridge's proposed labels teach all elements of claim 7 of
the '124 patent.
9. Defendants Roxane and Par had and have knowledge of the '518 patent.
10. Defendants Roxane's and Par's proposed labels teach all elements of claim 7 of the '518
patent.

B.

Conclusions of Law
Defendants concede that their proposed labels teach all elements of claim 7 with the

exception of the synergistic effectiveness element. 7 Specifically, Defendants argue that Plaintiffs
have not proven that co-administration of everolimus with cyclosporin A (for kidney transplant
indication) or tacrolimus (for liver transplant indication), as indicated on the label instructions,
would result in synergistic effectiveness.

Plaintiffs presented substantial evidence that co-

administration of these drugs results in synergistic effectiveness, including examples from the
patents themselves (Tr. 1092:15-1094:8), peer-reviewed journal articles (Tr. 1095:2-1098:21),
results of a clinical trial (Tr. 1099:8-1102: 13), and testimony of an expert with years of experience
treating transplant recipients using these and other drugs (Tr. 1102: 14-21 ).

Some of these

references evaluated synergistic effectiveness quantitatively using the Berenbaum-Chou equation.
(Tr. 1092:20-1094:8).
On cross-examination of Plaintiffs' expert, Dr. Henry, Defendants focused primarily on
the perceived importance of the Berenbaum-Chou equation for determining synergistic
effectiveness. (Tr. 1118:10-1122:13). According to Defendants, the evidence cited by Plaintiffs

7

At trial, Defendants also argued that Plaintiffs had not proven the weight-ratio element of the asserted claims. (Tr.
1040:12-18). In post-trial briefing, however, Defendants abandoned this argument, "[i]n view of the strength of
Defendants' argument that Novartis has not proven that the synergy element of the asserted claims." (D.I. 169 at 5,
n.4). Therefore, this argument is deemed waived.

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does not support a conclusion that co-administration results in synergistic effectiveness in humans
because none of the cited references evaluated synergistic effectiveness in humans using the
Berenbaum-Chou equation. (Tr. 1125:9-1129:7). I am not convinced that use of the BerenbaumChou equation is required for evaluating synergy as is contemplated in these patents. Defendants
have not argued, now or at claim construction, that "synergistically effective" meant
"synergistically effective as determined by the Berenbaum-Chou equation." Accordingly, the
term, as I have construed it, consistent with the specification, does not require a specific method
of evaluating synergistic effectiveness.
During claim construction, I found that the term "synergistically effective amounts" needed
to be construed only because the patent defined the term to have a narrower meaning than the plain
and ordinary meaning of the term. (D.1. 69 at 3). I construed the term, consistent with the
definition in the specification, to mean "amounts which are individually equal to or below their
respective effective dosages for the relevant indication and which together have a more than
additive effect." (Id.) Defendants' sole non-infringement argument is that Plaintiffs have not
shown that co-administration as instructed by their labels would "have a 'more than additive effect'
in human transplant patient." (D .I. 169 at 4 ). The essence of Defendants' argument is that this
"additive effect" must be proved through a quantitative analysis, which, Defendants contend,
Plaintiffs have not performed. (Id. at 5).
It seems to me that Defendants are asking me to interpret my construction of the term

"synergistically effective amounts" to implicitly require a quantitative analysis. This I will not do.
I am not persuaded that the word "additive" implies a quantitative analysis. There are a number
of ways of determining whether an effect is more than additive; performing a rigorous quantitative
analysis is only one of them. I think it is evident that an expert in the treatment of transplant

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patients could, as Dr. Henry did, examine clinical data, in light of a large body of pre-clinical data
that provides quantitative evidence, and opine on whether co-administration results in a greater
than additive effect. I find Dr. Henry's testimony on this matter credible.
Defendants' own expert, Dr. Rabb, admitted that the references cited by Plaintiffs confirm
that co-administration of these drugs results in synergistic effectiveness, evaluated using the
Berenbaum-Chou equation with animal models and in vitro data. (Tr. 1190:4-1191 :3). Dr. Rabb
further testified that there are no peer-reviewed publications that reach a different conclusion, even
for co-administration in humans. (Tr. 1194:24-1195:14). I am satisfied that experts in the field,
including Dr. Henry, have evaluated the clinical data from co-administration of everolimus and
cyclosporin A or tacrolimus in humans and have reached a consensus that co-administration results
in a more than additive effect, indicating synergistic effectiveness.
For these reasons, I find that Plaintiffs have met their burden of proving by a preponderance
of the evidence that Defendants' proposed labels induce infringement of claim 7 of the '124 and
'518 patents.

V.

CONCLUSION
Defendants proved that the asserted claims of the '772 patent are invalid for obviousness-

type double patenting. Defendants failed to prove by clear and convincing evidence that the
asserted claims of the '124 and '518 patents are invalid. Plaintiffs proved by a preponderance of
the evidence that Defendants Roxane and Breckenridge induced infringement of claim 7 of the
'124 patent and Defendants Roxane and Par induced infringement of claim 7 of the '518 patent.
Plaintiffs should submit an agreed upon form of final judgment within two weeks.

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