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Counsel For Plaintiffs: Kirkland Kirkland
Counsel For Plaintiffs: Kirkland Kirkland
Plaintiffs,
Civil Action No. 18-0823-CFC-JLH
V.
EAGLE PHARMACEUTICALS
INC.,
Defendant.
MEMORANDUM OPINION
Plaintiffs Par Pharmaceutical, Inc., Par Sterile Products, LLC, and Endo Par
Pharmaceuticals Inc. for infringement of two patents: U.S. Patent Nos. 9,744,209
(the #209 patent) and 9,750,785 (the #785 patent). Par alleges that Eagle' s
to§ 27l(e)(2)(A) of the Patent Act, 35 U.S.C. § 100, et seq. Eagle has alleged in
Civil Procedure 52(a)(l), I have set forth separately below my findings of fact and
preponderance of the evidence that Eagle's ANDA product will infringe the
The ANDA procedures out of which this case arise were established by FDA
regulations promulgated pursuant to the Federal Food, Drug, and Cosmetic Act
Laboratories, Ltd. v. Novo Nordisk A/S, 566 U.S. 399 (2012) this helpful summary
of the provisions of the Amendments and the FDA regulations that bear on this
case:
****
The generic manufacturer's second option is to file a so-
called paragraph N certification, which states that a listed
patent "is invalid or will not be infringed by the
manufacture, use, or sale of the generic drug." 21 U.S.C.
§ 355G)(2)(A)(vii)(N). A generic manufacturer will
typically take this path in either of two situations: if it
wants to market the drug for all uses, rather than carving
out those still allegedly under patent; or if it discovers, as
described above, that any carve-out label it is willing to
adopt cannot avoid the brand's use code. Filing a
paragraph IV certification means provoking litigation.
The patent statute treats such a filing as itself an act of
infringement, which gives the brand an immediate right to
sue [under] 35 U.S.C. § 271(e)(2)(A). Assuming the brand
does so, the FDA generally may not approve the ANDA
until 3 0 months pass or the court finds the patent invalid
or not infringed. Accordingly, the paragraph IV process is
likely to keep the generic drug off the market for a lengthy
period, but may eventually enable the generic company to
market its drug for all approved uses.
566 U.S. at 404-08 (irrelevant citations and internal quotation marks omitted).
4
II. FINDINGS OF FACT
adults with vasodilatory shock. D.I. 268-1 ,I 7. Vasostrict® works because its
February 2014, while that NDA was pending before the FDA, Par Pharmaceutical
Companies, Inc. acquired JHP, which subsequently changed its name to Par Sterile
Products, LLC. D.I. 268-1 ,I 8. Two months later, the FDA approved the
Vasostrict® NDA, and in November 2014 Par began selling Vasostrict®. D.I. 268-
3. Par listed the #209 and #785 patents in the Orange Book for
Vasostrict®. D.I. 268-1 ,I 34. The #785 patent is directed to specified vasopressin
pressure using such compositions. Both patents require that the vasopressin
5
mg/mL of vasopressin or a pharmaceutically-acceptable
salt thereof, wherein the unit dosage form further
comprises impurities that are present in an amount of0.9%
to 1. 7%, wherein the impurities have from about 85% to
about 100% sequence homology to SEQ ID NO.: 1, and
wherein the unit dosage form has a pH of 3. 7-3.9.
Claim 1 of the #785 patent (emphasis added). Claims 5 and 8 of the #785 patent
Claim 1 of the #209 patent (emphasis added). Claims 4, 5, and 7 of the #209
6
6. pH is a measurement of the acidity or basicity of an aqueous solution.
meaning it would have to a person of ordinary skill in the art at the time of the
invention." lnnova/Pure Water, Inc. v. Safari Water Filtration Sys., 381 F.3d
1111, 1116 (Fed. Cir. 2004). The parties offered at trial competing but similar
definitions of the artisan of ordinary skill to whom the asserted patents are
directed. Both parties stated that their positions "would not change if the Court
were to adopt the other side's definition" of a skilled artisan. D.I. 290 ,r 462; D.I.
284 ,r 45. Accordingly, I will adopt Par's proposal that an artisan of ordinary skill
readings to the nearest tenth decimal and that, therefore, the pH limitation of the
7
asserted claims-i.e., the requirement that the pharmaceutical composition in the
#785 patent and the unit dosage form in the #209 patent have a pH between 3.7 and
3 .9-is met when the pH is greater than or equal to 3 .65 and less than or equal to
and sell a generic version ofVasostrict® before the asserted patents expire. D.I.
268-1 ,r 40.
10. Eagle's ANDA includes a paragraph IV certification that states
Eagle's belief that the asserted patents are invalid or will not be infringed by the
268-1141.
the product's manufacturing process and during its shelf life. Tr. 349:5-350:2;
DTX-327 at 1. Eagle's ANDA seeks approval for a product with a shelf life of 24
specification" and the "stability [pH] specification" of its ANDA product are 3 .4-
8
3.6. DTX-678 at 2 (stating that the "Release Specification" for pH is "3.4 - 3.6"
13. Like Eagle's ANDA, the parties throughout the trial used the terms
"release specification" and "stability specification." Par maintained at trial that the
definitions of these terms are matters of fact, Tr. 32:20-22, but Par's counsel also
told me during trial that both terms had a "regulatory definition," Tr. 32:20-33: 12.
14. Neither Par nor Eagle sought to introduce at trial expert testimony
15. The parties agree, and I find, that the FDA's definition of"release
specification" is set forth in 21 C.F .R. § 211.165. Section 211.165(a) provides that
"[f]or each batch of [a] drug product, there shall be appropriate laboratory
product, including the identity and strength of each active ingredient, prior to
release." The parties did not cite and I was unable to find an FDA regulation or
provision in the FDCA that defines "release." But§ 211.165 is titled "Testing and
release for dis-tribution." 21 C.F.R. § 211.165 (emphasis added). And the FDA's
holding" make clear that "release for distribution" means release in final packaged
9
symbols, or any combination of them, from which the complete history of the
drug product or other material can be determined") (emphasis added); 21 C.F .R. §
control of drug products"). Thus, I find that the release pH specification in Eagle's
ANDA means the pH specification for its ANDA product immediately prior to the
16. Par and Eagle agree, and I find, that Eagle's ANDA product cannot
lawfully be released for distribution unless, at the time of the release, the product
has a pH of between 3.4 and 3.6 (i.e., before rounding, between 3.35 and 3.64).
17. The parties agree, and I find, that "stability specification" means "the
acceptance criteria that a drug product should meet throughout its shelf-life." D.I.
284 1 84; D.I. 276 at 2. The FDA defines "acceptance criteria" as "the product
and unacceptable quality level, with an associated sampling plan, that are
necessary for making a decision to accept or reject a lot or batch (or any other
on these definitions and the stability pH specification set forth in Eagle's ANDA, I
10
find that Eagle's ANDA product cannot not lawfully be distributed for use and
would not be approved for distribution by the FDA unless, at all periods during the
product's shelf life, the product's pH is between 3.4 and 3.6 (i.e., before rounding,
between 3.35 and 3.64). Thus, to comply with its ANDA specifications, Eagle's
generic version ofVasostrict® must have a pH of3.4 to 3.6 at the time of its release
18. Eagle has manufactured to date 17 batches of its ANDA product. D.I.
268-1 ,r 44; Tr. 151:2-8. The batches are numbered SVAOOl through SVA017. It
is undisputed that two batches (SVAO 10 and SVAO 15) were rejected by Eagle for
reasons unrelated to any of the disputed issues in this case. The parties did not
time of their manufacture, the registration batches had release and stability pH
after the asserted patents were published in June 2017, Eagle narrowed the release
11
20. Batches SVA004 through SVA006 (referred to as "characterization
batches") were manufactured in March and April 2019. D.I. 268-1 ,r 46; Tr.
352:2-9. The characterization batches were manufactured "in accordance with the
manufacturing process used for the registration batches." D.I. 268-1 ,r 47; DTX-
331 at 20. Eagle placed samples from Batches SVA00l through SAV006 into
evaluation, Eagle performed three distinct stability studies, storing the samples at:
(1) room temperature for 12 months; (2) refrigerated temperature for 24 months;
and (3) refrigerated temperature for a period of time ( 12 months for the registration
temperature for a period of time (12 months for the registration batches and 7.5
months for the characterization batches). DTX-331 at 4-7, 20-23; see also DTX-
727 at 4-7, 20-23; PTX-1427 at 4-7, 20-23; Tr. 353:18-354:10. Par has based its
product has a drift problem: when stored in refrigerated conditions, its pH tends to
rise."); D.I. 283 at 3 ("[T]he pH [of the ANDA product] tends to rise over time
when stored in refrigerated conditions."); D.I. 284 ,r,r 107-116 (analyzing only the
12
pH data from the refrigerated stability studies). Thus, unless otherwise noted, the
3.69 (which rounds to 3.7) at the 24-month mark-i.e., at the very end of
SVA00l 's a shelf life. DTX-331 at 9; DTX-727 at 9; see also DDX7-1; DTX-993
within the stability specification of3.4-3.6 for the duration of those batches' shelf
lives. Tr. 357:3-358:10; see also DDX7-1; DTX-993. After an investigation into
the lone out-of-specification result for SVA00l, "[t]he root cause ... was
determined to be [that] batch SVA00l was released at the upper limit of the pH
SVA00l, Eagle "optimized" its manufactwing process "to assure tighter control of
First, Eagle narrowed the specified pH range for its pH adjustment step-i.e., the
step where Eagle adds acid to its ANDA product to achieve its desired pH. The pH
range for this step for the pre-optimization batches had been 3.4-3.6 with a target
of 3 .5. For the post-optimization batches, Eagle changed the specified pH range to
13
3.42-3.49 with a target of3.45. Compare DTX-323 at 5 with DTX-323 at 10, 16;
see also DTX-324 at 25; Tr. 363:15-24, 371 :14-72:2. Second, Eagle added a new
366:22-67: 1. The pH stabilization step requires mixing the solution for no less
than 20 minutes, and then pulling samples from the mixing vessel to measure pH at
ten-minute intervals. DTX-323 at 10, 16; DTX-324 at 27; Tr. 365:7-13, 372:3-8.
Each pH measurement taken during the pH stabilization step must be within 0.03
pH units of the preceding measurement, DTX-323 at 10, 16; DTX-324 at 27; Tr.
365:23-366:2, and the pH measurement taken at the end of the stabilization step
must be between 3.42 and 3.50, DTX-323 at 10, 16; DTX-324 at 27; Tr. 365:21-
22, 372:9-13. Third, Eagle narrowed the in-process pH specifications for the pH
measurements taken immediately before and after a filtration step from 2.5-4.5
23. Eagle stated in its ANDA that these process and specification
future ... batches will remain within the proposed stability specifications through
the end of shelf life (24 months) for all labeled storage conditions." DTX-331 at
24; DTX-727 at 25; see also DTX-133 at 21 (Eagle stating to the FDA that the
14
within the established [pH] range during finished product manufacturing and
24. Eagle represented in its ANDA that it will use its optimized
(i.e., batches SVA007 through SVAO 17) has been manufactured using Eagle's
26. The pH measurements for the first six batches of Eagle's ANDA
product (i.e., the pre-optimization batches) and batches SVA007 through SVAO 17
27. Par argues that the post-optimization batches' data "show a tendency
for pH to rise between final in-process testing and release testing, by as much as
0.07 pH units, such that batches made at a pH within the latest in-process
specification (up to 3.54) can rise to at least pH 3.61 by the time of release." D.I.
283 at 5. Par also argues that pH stability data for the "optimized" batches shows
that pH continues to "drift" after release, by as much as 0.06 pH units. D.I. 283 at
5. But the data do not establish that Eagle's ANDA product has the "drift
problem" Par claims; instead, the pH data establish that it is more likely than not
that Eagle's ANDA product will not meet the 3.7-3.9 pH range claimed in the
15
asserted patents. The data show that Eagle has taken approximately 200 pH
ANDA stability specification and within the range of the pH limitation claimed in
every occasion that a pH measurement was taken since Eagle optimized its
asserted patents.
a tighter control over pH. As shown in the table below, the optimized process
DTX-993; Tr. 360:6-13, 361:2-16. The fact that none of the pH measurements for
the post-optimization batches approach the top end of Eagle's release specification
(3 .64) is telling, because the "root cause" of SVA00 1's out-of-specification (and
at 9; Tr. 362:2-10.
29. Par is correct that pH measurements for the tested batches varied over
the course of the batches' shelf lives. But this variability does not make it more
likely than not that Eagle's ANDA product will meet the claimed pH limitation. I
make this finding for two reasons. First, contrary to Par's suggestion, the stability
pH data for individual batches do not show a steady and inevitable creep (i.e., drift)
batch's shelf life. Moreover, these fluctuations do not reveal any discernible trend.
Second, the pH fluctuations observed over the shelf lives of the post-optimization
batches, as Par's expert admitted, are "in the neighborhood of ... [0] .05 and
product will be between 3.45 (that is, 3.50 minus 0.05) and 3.57 (that is, 3.52 plus
0.05) at the time of their release and over their shelf lives.
Eagle believes it is not bound by its representation to the FDA that it will use its
optimized manufacturing process to manufacture its ANDA product. Nor has Par
17
manufacturing process other than its optimized manufacturing process to
manufacture its ANDA product. Par argues that "Eagle has steadfastly refused to
lower its release pH specification below 3.6 (3.64 rounded)," D.I. 283 at 19, and
appears to suggest that I can infer from that "refusal" an intent to use a
manufacturing process other than Eagle's optimized process, see D.I. 283 at 19
("Eagle's refusal to [lower its release pH specification] speaks volumes about its
true intent-it clearly wishes to reserve the right to sell products that, at the time of
made at the upper end of its in-process pH specification can drift into that range by
the time of release testing."). But Par adduced no evidence at trial from which it
could be inferred that the FDA (or any other entity) asked Eagle to lower its release
pH specification, let alone that Eagle refused to comply with such a request. It also
makes sense that the FDA would not make such a request, since Eagle represented
to the FDA that it would use the optimized process and since the data for the
optimized process shared by Eagle with the FDA demonstrate that that process
results in products that comply with both the ANDA' s release pH specification and
31. I find therefore as a matter of fact that even if Eagle's ANDA product
were not required as a matter of law to maintain the stability pH specification set
forth in Eagle's ANDA, because Eagle will have to use the optimized
18
manufacturing process it committed to in its ANDA, the product Eagle will
manufacture and sell will not have a pH that would drift into the range of the pH
process will have a pH that does not meet the stability pH specification. The pH
measurement data adduced at trial demonstrates that if Eagle uses its optimized
process to manufacture its ANDA product, the product will have a pH that meets
inferred that Eagle believes it is not legally bound by the stability pH specification
in its ANDA.
Eagle will distribute a generic version of Vasostrict® that does not meet the
artisan of ordinary skill. Phillips v. AWH Corp., 415 F.3d 1303, 1313 (Fed. Cir.
2005) (en bane). The second step is to determine whether the accused products or
19
methods infringe the patent, by comparing those products or methods to the
Cir. 1995) (en bane), aff'd, 517 U.S. 370 (1996). The first step in the infringement
Novopharm, Ltd., 110 F.3d 1562, 1565 (Fed. Cir. 1997). A patentee bears the
Corp. v. Al George, Inc., 730 F.2d 753, 758 (Fed. Cir. 1984). 1
dispute concerning infringement and validity" of patents listed in the Orange Book.
district court's inquiry in a suit brought under§ 27l{e)(2) is the same as it is in any
other infringement suit, viz., whether the patent in question is 'invalid or will not be
infringed by the manufacture, use, or sale of the drug for which the (ANDA] is
1
Par alleges that Eagle's manufacture and sale of its ANDA product will directly
infringe and induce the infringement of the asserted patents. Because I find that
Eagle's ANDA product does not infringe the asserted patents, Par's theory of
induced infringement necessarily fails. See Epcon Gas Sys., Inc. v. Bauer
Compressors, Inc., 279 F.3d 1022, 1033 (Fed. Cir. 2002). ("[T]here can be no
inducement of infringement without direct infringement by some party.").
20
submitted."' Id. (italics in the original) (underline added) (quoting 21 U.S.C. §
traditional patent law principles and, if a product that an ANDA applicant is asking
the FDA to approve for sale falls within the scope of an issued patent, a judgment
USA, Inc., 731 F.3d 1271, 1278 (Fed. Cir. 2013). By the same token, if the product
that an ANDA applicant is asking the FDA to approve falls outside the scope of an
ANDA applicant] has asked the FDA to approve as a regulatory matter is the
subject matter that determines whether infringement will occur." Id. at 1278.
the ANDA' s specification directly addresses the elements of the asserted claims
that are at issue. "Because drug manufacturers are bound by strict statutory
provisions to sell only those products that comport with the ANDA' s description of
that directly addresses the issue of infringement will control the infringement
inquiry." Abbott Lab ys v. TorPharm, Inc., 300 F.3d 1367, 1373 (Fed. Cir. 2002).
requirements and the consequences that flow from failing to abide by them, courts
"cannot assume that [an ANDA filer] will not act in full compliance with its
asserted patent or necessarily does not infringe the patent, the specification dictates
the outcome of the infringement analysis. See Ferring B. V. v. Watson Lab ys, lnc-
Florida, 764 F.3d 1401, 1409 (Fed. Cir. 2014) ("In some cases, the ANDA
22
specification directly resolves the infringement question because it defines a
asserted patent claim or is outside the scope of such a claim."); Elan, 212 F.3d at
IV. DISCUSSION
patent and claims 1, 5, and 8 of the #785 patent. All the asserted claims require
construe this pH limitation and therefore it is understood to have its plain and
Eagle stipulated before trial that its ANDA product infringes every
limitation of the asserted claims except for the pH limitation. D.I. 268 ,r 58; D.I.
251 at 1. Thus, Par's infringement case turns on whether Eagle's ANDA product
I have already determined as a matter of fact that to comply with its ANDA
at the time of its release for distribution and for its entire shelf life. Accordingly,
the ANDA product Eagle is asking the FDA to approve cannot have at the time of
23
its release or at any time during its shelf life a pH between 3. 7 and 3. 9, and
Pharms., 731 F.3d at 1278. In other words, Eagle's ANDA's release and stability
addresses the issue of infringement raised by Par; and therefore the ANDA
D.I. 283 at 1.
These alleged facts, however, are neither undisputed nor correct. With
respect to the first alleged fact, as explained above, the pH measurements taken
from Eagle's batches negate Par's claims that Eagle's ANDA product has a "drift
24
problem." Par's second alleged fact makes too much of too little. It is true that
pH range of between 3 .4 and 3 .6; and it is true that a pH of 3 .64 would meet that
specification. But the release specification is not the only specification in Eagle's
ANDA; and it is not accurate to say that Eagle "seeks authority to release products
into the marketplace with pH values up to 3.64." Rather, Eagle seeks authority to
release products into the marketplace that satisfy both the release pH specification
and the stability pH specification, and thus it seeks authority to distribute products
that have a pH of between 3.4 and 3.6 from the time of their release for distribution
Par argues that the "release specification is the gatekeeper for what Eagle
will or will not be authoriz~d to sell and thereby defines the scope of its authority
under the ANDA." D.I. 283 at 1. But it is the entirety of Eagle's ANDA, not a
single specification in the ANDA, that "defines the scope of [Eagle's] authority
under the ANDA." Par wants me to assume that Eagle will comply with the
specification. It insists that "the stability specification is not a legal bar to finding
that [an ANDA filer] will not act infull compliance with its representations to the
25
FDA." 643 F.3d at 1378 (emphasis added). And as the court stated in Abbott
manner that directly addresses the issue of infringement will control the
asserted patent in In re Brimonidine had a pH limitation that did not overlap with
ANDA specified a release and stability pH between 6.5 and 6.7. 643 F.3d at 1376-
77. Relying on testing data from the defendant's ANDA, the district court found
that the proposed drug product's pH would fall over its shelf life and that,
therefore, the defendant would need to manufacture the product with a pH of 7.0 or
above to achieve a pH of between 6.5 and 6.7 over the drug's shelf life. Id. Based
on that finding, the district court entered a judgment of infringement against the
defendant. The Federal Circuit reversed. In doing so, it cited the language quoted
above from Abbott that the ANDA "control[s ]" the infringement analysis and noted
26
use testing data to support a finding that Eagle would violate the binding
But even if I were to consider that data, it would not change the outcome of
this case. I have already found as a factual matter that Par failed to demonstrate by
a preponderance of the evidence that Eagle believes it is not bound by either its
ANDA stability pH specification or its representation to the FDA that it will use its
2
In support of its position that I can consider such data, Par cites passages from
Abbott Laboratories and Tyco Healthcare Group LP v. Mutual Pharmaceutical
Co., 762 F.3d 1338 (Fed. Cir. 2014). See Abbott, 300 F.3d at 1373 ("It is also
possible, at least in theory, that other evidence may directly contradict the clear
representations of the ANDA and create a dispute of material fact regarding the
identity of the compound that is likely to be sold following FDA approval."); Tyco
Healthcare, 762 F.3d at 1344 ("The question addressed in Elan and similar cases is
whether the product that the ANDA applicant will likely market if its application is
approved will infringe. That can occur in spite of the ANDA specification if, for
example, the ANDA is based on faulty testing or screening procedures.") (citations
omitted); id. ("[W]e agree with Tyco that it is not unreasonable for a patent owner
to allege infringement under section 271(e)(2)(A) if the patent owner has evidence
that the as-marketed commercial ANDA product will infringe, even though the
hypothetical product specified in the ANDA could not infringe."). I have spent
more hours than my caseload affords trying without success to reconcile these
passages with the unequivocal holdings from the Federal Circuit cases I have cited
above. I also wonder whether a district court has the necessary expertise or
constitutional authority to decide either while an ANDA is pending before the
FDA or after the FDA has approved the ANDA that the ANDA applicant
employed faulty testing or screening procedures.
27
manufacturing process other than its optimized process to manufacture its ANDA
optimized process will have a pH that does not meet its ANDA's stability pH
of the evidence that Eagle would distribute a generic version of Vasostrict® that
does not meet the 3.4-3.6 stability pH specification in its ANDA; and therefore,
ANDA product will infringe the 3.7-3.9 pH limitation in the asserted claims. At
most, Par proved at trial that ifEagle were not bound by its stability pH
specification and its representation to use its optimized manufacturing process then
Eagle could use a different manufacturing process that could result in a drug
product with a pH that meets the pH limitation in the asserted claims. Proof of that
See Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348, 1364 (Fed. Cir. 2003)
V. CONCLUSION
For the reasons discussed above, I find that Eagle does not infringe claims 1,
28
4, 5, and 7 of the #209 patent and claims 1, 5, and 8 of the #785 patent. 3
The Court will issue an Order directing the parties to submit a proposed
order by which the Court may enter final judgment consistent with this Opinion.
3 On page 3 0 of its posttrial brief, Par stated: "For similar reasons, Par is entitled to
a declaration of infringement under§ 271(a) and (b)." D.I. 283 at 30. It did not
elaborate. Having concluded that Par failed to prove by a preponderance of the
evidence that Eagle infringed the asserted patents, I will deny its application for a
declaratory judgment of infringement under§ 271(a) and (b).
29
APPENDIX TABLE 1
• Data for Appendix Table 1 were taken from DDX7-l and DTX-993.
• Samples were stored in both upright and inverted positions, denoted with a
"U" or "I", respectively, following the batch names. Storage orientation does not
affect the pH of Eagle's ANDA product. 'f.r. 316:1-9.
A-2